Quality in Radiation Oncology ͒ Todd Pawlickia and Arno J

Home , TheraSphere

Quality in radiation oncology ͒ Todd Pawlickia and Arno J. Mundt Department of Radiation Oncology, University of California, San Diego, La Jolla, California 92093 ͑Received 19 January 2007; revised 7 March 2007; accepted for publication 15 March 2007; published 17 April 2007͒ A modern approach to quality was developed in the United States at Bell Telephone Laboratories during the ﬁrst part of the 20th century. Over the years, those quality techniques have been adopted and extended by almost every industry. Medicine in general and radiation oncology in particular have been slow to adopt modern quality techniques. This work contains a brief description of the history of research on quality that led to the development of organization-wide quality programs such as Six Sigma. The aim is to discuss the current approach to quality in radiation oncology as well as where quality should be in the future. A strategy is suggested with the goal to provide a threshold improvement in quality over the next 10 years. © 2007 American Association of Physi- cists in Medicine. ͓DOI: 10.1118/1.2727748͔

Key words: quality, variation, process improvement, quality management

I. BACKGROUND AND INTRODUCTION In early 1942, Deming was invited to the Stanford University Statistics Department to lecture on potential ways they could The industrial revolution resulted in notable worldwide con- contribute to the war effort. Deming gave a series of lectures tributions including mass production. In the early part of the on using probability and statistics to provide a basis for ac- 20th century, the emphasis was to bring as much product to tion in creating high-quality manufactured products.4 Attend- market as possible in the shortest period of time, often with ees at these lectures and at others that followed included little attention to quality. The primary method to ensure qual- engineers from U.S. industries contributing to the war effort. ity was by inspection. Each component that created the final Most quality programs based on probability and statistics product was inspected to verify it was within the specifica- were terminated once the government contracts ended. Dem- tions set by product engineers. If a component was outside ing and others realized that quality can be no better than the specifications, then it was either scrapped or sent back for rework and subsequent reinspection. intent and commitment of senior management. During this period, American Telephone & Telegraph After the war, Deming went to Japan in 1950 to lecture on ͑AT&T͒ was hard at work building facilities to support a quality to the Union of Japanese Scientists and Engineers ͑ ͒ 5 universal telephone service. Western Electric Company ͑cre- JUSE . Juran was to follow in 1954 where he raised the ated by AT&T as a constant source of supply͒ was struggling issue of quality from the factory to the total organization. with problems of mass production, including the interchange Japanese industry readily adopted these new quality practices of parts, precision, and reliability.1 Scientists and engineers and Japanese researchers played an integral role in the de- at Bell Telephone Laboratories ͑Bell Labs͒, a subsidiary of velopment of quality. For example, Ishikawa of Tokyo Uni- AT&T, were engaged in product research as well as research versity emphasized seven quality tools now used in most 3 ͑ ͒ on problems of quality associated with mass production. A quality programs Table I . In 1976, the JUSE developed major emphasis was on the application of probability and and promoted a list of seven quality tools for management 3 statistics to quality. and planning ͑Table II͒. By the mid 1940s, significant progress was being made on By the late 1970s, several U.S. industrial sectors includ- new approaches to quality. Researchers at Bell Labs realized ing automobiles and electronics had been hit hard by Japan’s that product inspection was not adequate to ensure a high- high-quality competition. Japanese products were flowing quality product.1 It was much more important to control the into the U.S. that were less expensive and of much better variation in the process that created the product. A significant quality. This situation was highlighted to the U.S. public in invention was the control chart where data acquired by in- the 1980 NBC television documentary, “If Japan can…why 6 spection was plotted sequentially to characterize process can’t we?” In many ways, the start of the quality movement variation.2 Based in part on this work, W. Edwards Deming, in U.S. industry came as a direct response to the quality Joseph M. Juran, Kaoru Ishikawa, and others were creating revolution in Japan. Senior managers of U.S. companies new approaches to quality that extended beyond the manu- were now eagerly learning quality techniques introduced to factured product.3 Unfortunately for AT&T, much of this re- the Japanese, many first developed in the U.S. 40 years ear- search did not translate into their production efforts. lier. After entering World War II in December 1941, the U.S. During the past half-century, progress in health care has enacted legislation to gear the civilian economy to enhance been made by medical science and technology break- military production. The armed forces also helped suppliers throughs. While this has led to improvements in radiation by sponsoring training courses on ways to improve quality. oncology, a new focus on quality will continue to provide

TABLE I. Seven basic tools of quality. Optimal use of these tools is within a comprehensive quality program.

Tool Description

Cause-and-effect diagrama Identify many possible causes of a problem Check sheet Structured form to collect data on frequency of events Control chartb Quantify and predict variation in output of a process Histogram Document or communicate the distribution of data Pareto chart Data analysis to show which situations are more significant Scatter diagram Plotting method to determine if two variables are related Stratificationc Data separation so that patterns or conditions can be identified aAlso known as the fishbone diagram or Ishikawa diagram. bAlso known as the process behavior chart. cSometimes replaced with the flowchart or run chart. opportunities to improve patient care. In the next section, we The focus of research on quality in radiation oncology is present the current approach to quality in radiation oncology, on breakthrough innovation. The emphasis is largely on new which is followed by where we believe quality practices hardware or software products or on methods to utilize such should be over the next decade with suggested pathways to new equipment. Over the last several years, a limited number achieve these goals. of research papers have been devoted to adapting modern quality techniques to the radiation oncology 16–20 II. WHERE ARE WE NOW? environment. The consensus seems to be that automation, new machinery, and new computer systems will ensure Quality in healthcare has two dimensions: ͑1͒ high-quality optimal quality. It has been shown, however, that record and decision making and ͑2͒ high-quality performance.7 One as- verify systems do not remove all possible sources of error.13 pect of high-quality decision making is consistency of prac- In fact, entirely new failure modes are possible using such tice. Professional judgment and peer review are current 21 8 systems. Effective use of record and verify systems for methods to achieve consistency. Consistent decision making is also achieved by studying patterns of care.9 and by clinical improving quality requires a change in staff functions within trials.10 However, results of clinical trials can be confounded the new electronic environment. As a general rule, continued efforts on new equipment and software alone will not im- by inconsistent interpretation and implementation of the trial 22 criteria.11 A related problem with results published in the prove quality beyond its current level. literature is that the reported efficacy may not be generally The current approach to radiation oncology quality is to applicable if different levels of quality are used at different investigate incidents once they have occurred rather than in- institutions. With regard to high-quality performance, re- vestigating processes for potential problems. Within some ported error rates for significant events in radiation oncology departments or staff, the primary aim is making it through are low.12,13 The actual error rates are probably higher with the day, with no thought about the system or the future. This even more nonsignificant events that are never reported.14 approach to quality is summed up in the old adage, “If it There is theoretical evidence that even those nonsignificant ain’t broke, don’t fix it.” Such a philosophy can lead to latent events can play a role in the degree that radiotherapy is a errors in a process that can be manifested long into the benefit to patients.15 future.23 Hard work and best efforts in radiation oncology are

TABLE II. Seven quality tools for management and planning. These tools are used for abstract analysis as well as detailed planning.

Tool Description

Afﬁnity diagram Organizes a large number of ideas into natural relationships Relations diagram Understand cause and effect relationships Tree diagram Move the thought process from generalities to speciﬁcs Matrix diagram Understand how groups of items relate to one another Matrix data analysisa Compares options to criteria in order to choose the best option Arrow diagram Schedule and monitor tasks within a complex project Process decision Systematically identify what might go wrong in a plan program chart under development aSometimes replaced with the prioritization matrix.

Medical Physics, Vol. 34, No. 5, May 2007 1531 T. Pawlicki and A. J. Mundt: Quality in radiation oncology 1531 the main mode of operation to improve quality. An example consistent and up-to-date set of specifications for our proce- of this is the requirement to perform a measurement for ev- dures and equipment. Task Group reports that contain speci- ery IMRT case prior to treatment. Whether this actually im- fications ͑e.g., TG-40,32 TG-53,33 etc.͒ can be several years proves quality is still a point of debate.24 However, indepen- behind technology implementation and not easily updated. dent anthropomorphic-based IMRT plan verification can Furthermore, independent checks of subsystems are becom- bring user errors to light and thus lead to improvements in ing more difficult as newer technologies, such as Tomo- quality.25 When quality is in doubt, the response is to give therapy HiArt and Accuracy CyberKnife, are self-contained best efforts and check more parameters. This approach is planning and delivery systems. Specifications are needed for also applied to people and processes when a mistake occurs. these new systems as well. But, simply paying closer attention to people can create what Error reporting mechanisms ͑e.g., the ROSIS database, is known as the “Hawthorne effect”.2 That is, by just paying www.clin.radfys.lu.se͒ need continual development to allow closer attention, people do a better job. Nevertheless, it is optimal sharing of information, which will help to under- impossible to check everything. There are limited resources stand clinical processes, equipment, and their failure modes. and limited time to do all the work. Current appropriate staff- Quality and error reduction should go hand-in-hand. When a ing levels for physicists can be found in the Abt Report,26 but process is predictable, one can consider an error as being may need to be modified with new requirements and ap- built into the process, i.e., a given number of errors are guar- proaches to quality. anteed to occur. If high-quality processes with minimal variation are developed and implemented, then fewer errors should result. Variation, for example in a repeated set of III. WHERE SHOULD WE BE IN 10 YEARS? measurements, is an easy concept to appreciate. What may The International Organization for Standardization ͑ISO͒ not be so obvious is that clinical processes also contain created a set of international standards for quality known as variation. Without an appreciation of variation, it is difficult ISO 9000. Originally issued in 1987, a major revision was to predict the future of process operation or understand past presented in 2000.27 Elements of ISO 9000 include modern performance. It is also easy to blame others for errors over quality techniques such as the responsibility of senior man- which they have little control. agement and requirements of continuous improvement, There are, however, situations where even a single error which can be implemented using a comprehensive quality may result in catastrophic loss, for example a miscalibration program.28 The ISO standards have already been suggested of a new linear accelerator during acceptance or delivery for use in radiation oncology.16 The Joint Commission errors in a single-fraction radiosurgery treatment. A different ͑www.jointcommission.org͒ is partly responsible for encour- set of modern quality and error reduction tools are required aging radiation oncology departments into action. The qual- in these cases.34 Tools that can be useful are repeatability and ity mandate from the Joint Commission is specific to describ- reproducibility studies, checklists, mistake-proofing, and the ing a comprehensive quality program rather than a detailed usual independent verification checks. prescriptive emphasis focused on capability.29 A first step High-quality patient service is a necessity. A goal should should be to take action on those recommendations. Modern be to understand and also believe what patients want and use quality tools and organization-wide quality programs are al- that as a compass to define optimal quality. Quality and error ready used in other hospital environments.30,31 reduction programs should consist of process design, process Quality should depend more on the assessment of process implementation with statistical evaluation, and design im- data and less on the assessment of a patient’s health status provement based on the data the process provides. Vague post treatment ͑outcomes data͒. Patient outcome is a mis- statements on quality should no longer be acceptable such as leading quality metric because differences in patients’ char- “I think we are doing OK” or “things seem to be getting acteristics may lead to different results, even for the same better.” The new requirement should be the evaluation and delivery of care. A system view of department processes documentation of process behavior based on the data. should be adopted with a focus on reducing variation through the people who use them. Within a radiation oncology department, each job or group of workers is not simply addi- IV. HOW DO WE GET THERE? tive; their efforts are interdependent. One process of the sys- A modern approach to quality as found in most industries tem, in achieving some numeric goals, may inhibit the must be implemented in radiation oncology. Modern quality function of another process. Some process͑es͒ may operate at techniques developed in industry have already been sug- a loss to optimize the system as a whole. An example of this gested as important to healthcare.35,36 The concept of mea- is in treatment planning where a dosimetrist may have down surement and an appreciation of a system are essential to time waiting for the physician to draw contours on a com- achieve optimal quality. Measures of improvement should be puted tomography scan. Working to understand variation al- created together with a focus on specific projects that are lows one to first control a process and then to achieve real critical to a department’s success. Quality should be re- process improvement. High-quality means minimizing pro- stricted to problems of loss caused by variability of function cess variation and moving the average closer to the optimum and related harmful side effects, or it will slip out of the value. But what is the optimum value and what are accept- domain of medical physics into the psychological domain of able limits of variation? These questions are answered by a cultural or personal values.37 Facets of a modern approach to

Medical Physics, Vol. 34, No. 5, May 2007 1532 T. Pawlicki and A. J. Mundt: Quality in radiation oncology 1532 quality include senior management leadership, employee in- the physician care of patients.49 All of these aspects argue for volvement and empowerment, patient defined quality ͑pa- dedicated research sessions on quality and error reduction at tient satisfaction͒, a view of work as a system consisting of the AAPM and ASTRO annual meetings. different processes, and continuous improvement. Such models should help with gathering information and taking action B. Educate radiation oncology leadership efficiently and effectively. In-depth education on quality is Cultural change and strong management are necessary to needed along with skills transfer that will give a team and achieve optimal quality.50 Educating leadership does not re- individuals the power to lead sustainable change. Relevant fer to continuing education but rather an initial education on projects must be incorporated with broad training that is tied what optimal quality means and what methods and resources to an overall vision. Picking out a single quality tool or tech- are needed to achieve it. Success of new quality programs nique will lead to unimpressive results and ultimately not will hinge on the ability to obtain endorsement of and com- work. We believe the following six objectives are necessary mitment to the process from departmental senior managers to achieve the goal of optimal quality. and hospital leadership. A delineated vision and goals for the department and commitment of resources to support the pro- A. Encourage research on quality cess is necessary along with department-wide communication to spread the initiative and tools. Quality committees All technology research in radiation oncology is geared should report directly to departmental leadership. Early phy- toward improving the efficacy of radiation therapy. The vast sician and physicist buy-in to any program will be essential majority of that research, which is specific to quality, is fo- for success. Department chairs, physics directors, and admin- cused on new equipment and new procedures using the istrators need to be informed on modern quality and error equipment, i.e., breakthrough innovation. For example, in the reduction techniques. Successful continuation of new quality November 2006 issue of Medical Physics, there are seven programs will then depend on staff education. This should papers devoted to this type of research.38–44 There are no not be left to the annual meetings but rather be Web based papers in that issue devoted to modern industrial approaches and easily accessible to anyone. Medical and physics resi- to quality. Research sessions at the annual American Asso- dency programs should teach modern industrial quality tech- ciation of Physicists in Medicine ͑AAPM͒ and American So- niques and these should be tested for at the ABR board ex- ciety for Therapeutic Radiology and Oncology ͑ASTRO͒ ams. The most efficient way education can be achieved is meetings that are specific to techniques of quality and error through AAPM and ASTRO initiatives. reduction need to be instituted. This will provide an academic incentive for physicists and physicians to focus on C. New approach for AAPM QA task groups implementing and demonstrating the benefit of modern industrial quality techniques. Discussions at the annual meet- Specification of operating limits for equipment and proce- ings on quality and error reduction are inappropriately rel- dures is an essential part of developing a quality program. A egated to the professional ͑nonacademic͒ tracks at the annual consistent, up-to-date specification document for all aspects meetings. Research on modern approaches to quality may be of radiation oncology is required. At the rate of new technol- undervalued because it can be seen as not scientific or only ogy development and implementation, specifications will be incrementally innovative and lacking hard results. Incremen- changing rapidly. The first step is to collate existing specifi- tal innovation, however, can be just as important to our field cations ͑e.g., Table II of TG-40͒ into one place. These docu- as breakthrough innovation.45 This type of research on qual- ments should be condensed to the minimum necessary speci- ity needs to be done with the same academic requirements as fications rather than an exhaustive list of all possible things any scientific study.46 It will take a focused effort to sift to check. The specifications should be contained in a single through the many quality techniques for applicability to ra- document ͑or Web pages͒ for all aspects of radiation oncol- diation oncology. This includes metrics for process behavior ogy. This document should be “live” and readily available to charts, appropriate staffing levels, financial implications, and departments and vendors. A system of regular updates can be organization-wide approaches such as Total Quality Manage- accomplished by a joint organization with appointments ment, Quality Function Deployment, Six Sigma, Lean, etc. from the AAPM and ASTRO that has the authority to make Lean thinking, for example, is a system of methods that is necessary changes. The organization or committee will dis- geared toward identifying and eliminating all non-value- cuss specifications for new equipment and procedures or re- adding activities. How Lean a process can be made without visit antiquated specifications. For brand new equipment, the making it prone to errors is an area that requires research. committee can recommend temporary specifications based Research is also necessary to determine which metrics or on the experience and input from early adopters. A start in criteria are reliable to characterize a process and minimize this direction is the AAPM Therapy Committee’s assignment variation. Interesting quality techniques such as situational of a Quality Assurance and Outcome Improvement Subcom- awareness are themselves being investigated for optimal ap- mittee that is working to fast track recommendations for new plication to medicine and this type of work needs to be devices in the form of short Task Group reports. A subse- encouraged.47 Novel approaches such as Web-based audit quent initiative, after considerable research has been done, is systems may improve high-quality decision making in the for the AAPM Task Groups to make recommendations on future.48 Process control techniques may even play a role in organization- or department-wide quality programs and the

Medical Physics, Vol. 34, No. 5, May 2007 1533 T. Pawlicki and A. J. Mundt: Quality in radiation oncology 1533 use of modern quality tools. This step has begun with the F. Adopt a patient view of quality formation of TG-100, which has taken the approach to de- The highest bar one can set is to treat patients as custom- velop a framework for designing quality management activi- ers. It is easy for physicians and physicists to discount the ties. Specifically, TG-100 will investigate and present the patient’s expectations of health quality. The science of qual- technique of Failure Modes and Effects Analysis with spe- ity is making its way into healthcare and patients may be the cific examples to IMRT and HDR brachytherapy. Lastly, greatest resource to determine what needs to be improved.53 clear guidelines are needed for what constitutes quality, what Patient requirements should be related to quality characteris- constitutes an error, and how to report errors. Other fields 51 tics of the service being provided. A way to achieve this is to have also been plagued with confusing nomenclature. have patient advocates on departmental quality committees as well as on AAPM and ASTRO quality committees. Qual- D. Close collaboration with vendors ity characteristics identified with patient input should be tar- A closer and more formal collaboration with vendors geted for improvement and translated into necessary func- should be fostered to provide equipment and procedures to tions of staff and equipment. Patient survey data will be an customers. A first step is to facilitate data transfer between important tool to learn about the patient’s perception of care. competitive vendors’ systems, which has begun to be ad- But surveys must be used carefully as the potential for error dressed by the Integrating the Healthcare Enterprise ͑IHE͒ and bias can be significant.30 Quality improvement capacity Radiation Oncology ͑RO͒ Task Force. Vendor and user col- needs to be aligned with professional receptiveness, leader- laboration should also be more than mere financial support. ship, technical expertise, and survey data.54 It is important to The vendor’s expertise of their product should be combined remember that the patient is the greatest beneficiary of an with the user’s clinical knowledge to create optimal products optimal quality program. and processes. New equipment should be delivered with process behavior limits rather than specification limits. It is the V. CONCLUSION physicist’s responsibility to set specification limits and the Medical physicists and radiation oncologists have readily vendor’s responsibility to produce a product that meets those harnessed new technologies and have made many significant specifications. Long-term relationships should be developed contributions to radiation oncology over the years. Much like with vendors to reduce variation in product output and create medicine, quality is also an art and there is a need for inves- a steady stream of incremental innovations. Vendors should tigation. Scientific training leads physicists and oncologists be encouraged to work closely with clinicians and reward to wait for convincing evidence for the effectiveness of new their employees for participating in peer-reviewed publica- techniques before incorporating any change of procedures to tions. Collaborative research, even vendor initiated research, treat patients. However, our field should not quickly dismiss should be encouraged and receive the same level of aca- approaches to quality that have roots in probability and sta- demic scrutiny and standards as any other type of research 52 tistics with many years of practical experience and demon- work. This type of collaborative research should not be strated benefit in other fields. seen as inferior to pure academic pursuits. After all, discoveries or innovations that never make it to market are of little benefit to patients. ACKNOWLEDGMENTS The authors would like to thank the Associate Editor and E. Utilize resources outside radiation oncology referees for many constructive comments that made their Collaboration with other professional societies that have way into the final version of this manuscript. expertise in quality and error reduction is needed. For ex- a͒ Electronic mail: [email protected] ample, the American Society for Quality ͑www.asq.org͒, the 1J. M. Juran, “Early SQC: A historical supplement,” Qual. Prog. 30, National Quality Forum ͑www.qualityforum.org͒, the Insti- 73–81 ͑1997͒. 2 tute for Healthcare Improvement ͑www.ihi.org͒, and the Na- M. Best and D. Neuhauser, “Walter A Shewhart, 1924, and the Hawthorne ͑ ͒ factory,” Qual. Saf. Health. Care 15, 142–143 ͑2006͒. tional Patient Safety Foundation www.npsf.org provide 3N. R. Tague, The Quality Toolbox, 2nd ed. ͑ASQ Quality, Milwaukee, WI, valuable information and contacts on how to improve qual- 2005͒. ity. These societies may provide the opportunity to identify 4N. R. Mann, Keys to Excellence: The Deming Philosophy ͑Prestwick researchers interested in improving quality in healthcare. House, Clayton, 1989͒. 5C. S. Kilian, The World of W. Edwards Deming ͑SPC, Knoxville, 1992͒. Similarly, contact with colleagues in schools of management 6“If Japan can… why can’t we?” ManagementWisdom.com, http:// or departments of industrial and systems engineering may www.managementwisdom.com/ifjapcanwhyc.html, 8 January 2007. provide needed expertise from fields outside medical physics 7D. Blumenthal, “Quality of care—What it is?,” N. Engl. J. Med. 335, ͑ ͒ and medicine. Collaborating with these researchers will pro- 891–894 2006 . 8R. H. Brook, E. A. McGlynn, and P. D. Cleary, “Measuring quality of vide new opportunities to learn about current quality oppor- care,” N. Engl. J. Med. 335, 966–970 ͑2006͒. tunities that may be applicable to radiation oncology. There 9J. F. Wilson and J. Owen, “Quality research in radiation oncology: A is also much to learn from other journals such as Quality self-improvement initiative 30 years ahead of its time?,” J. Am. Coll. ͑ ͒ Management Journal, Quality Engineering, Quality and Radiol. 2, 1001–1007 2005 . 10T. Kron, C. Hamilton, M. Roff, and J. Denham, “Dosimetric intercom- Safety in Healthcare, and Quality Progress just to name a parison for two Australasian clinical trials using an anthropomorphic few. phantom,” Int. J. Radiat. Oncol., Biol., Phys. 52, 566–579 ͑2002͒.

Medical Physics, Vol. 34, No. 5, May 2007 1534 T. Pawlicki and A. J. Mundt: Quality in radiation oncology 1534

11C. A. Perez, P. Gardner, and G. P. Glasgow, “Radiotherapy quality assur- therapy treatment planning,” Med. Phys. 25, 1773–1829 ͑1998͒. ance in clinical trials,” Int. J. Radiat. Oncol., Biol., Phys. 10͑Suppl 1͒, 34D. Hutchison, “Chaos theory, complexity theory, and health care quality 119–125 ͑1984͒. management,” Qual. Prog. November, 69–72 ͑1994͒. 12R. M. Macklis, T. Meier, and M. S. Weinhous, “Error rates in clinical 35P. P. Harteloh and F. W. Verheggen, “Quality assurance in health care. radiotherapy,” J. Clin. Oncol. 16, 551–556 ͑1998͒. From a traditional towards a modern approach,” Health Policy 27,261– 13 G. Huang, G. Medlam, J. Lee, S. Billingsley, J. P. Bissonnette, J. Ringash, 270 ͑1994͒. G. Kane, and D. C. Hodgson, “Error in the delivery of radiation therapy: 36G. Laffel and D. Blumenthal, “The case for using industrial quality man- Results of a quality assurance review,” Int. J. Radiat. Oncol., Biol., Phys. agement science in health care organizations,” JAMA, J. Am. Med. As- 61, 1590–1595 ͑2005͒. soc. 262, 2869–2873 ͑1989͒. 14 C. Szerlag, “Best practices,” ADVANCE 16, 80–85 ͑2006͒. 37G. Taguchi, Introduction to Quality Engineering ͑American Supplier In- 15 A. L. Boyer and T. Schultheiss, “Effects of dosimetric and clinical uncer- stitute, Dearborn, MI, 1986͒. tainty on complication-free local tumor control,” Radiother. Oncol. 11, 38O. Hupe and J. Brunzendorf, “A novel method of radiochromic film do- ͑ ͒ 65–71 1988 . simetry using a color scanner,” Med. Phys. 33, 4085–4094 ͑2006͒. 16 J. W. H. Leer, R. Corver, J. J. A. M Kraus, J. Ch. Togt, and O. J. S. 39A. L. McNiven, M. Mulligan, T. Kron, and J. J. Battista, “The response of Buruma, “A quality assurance system based on ISO standards: experience prototype plane-parallel ionization chambers in small megavoltage x-ray in a radiotherapy department,” Radiother. Oncol. 35,75–81͑1995͒. ͑ ͒ 17 fields,” Med. Phys. 33, 3997–4004 2006 . K. Holli, P. Laippala, A. Ojala, and M. Pitkanen, “Quality control in 40A. S. Meigooni, S. B. Awan, and K. Dou, “Feasibility of calibrating health care: an experiment in radiotherapy planning for breast cancer elongated brachytherapy sources using a well-type ionization chamber,” patients after mastectomy,” Int. J. Radiat. Oncol., Biol., Phys. 44, 827– Med. Phys. 33, 4184–4189 ͑2006͒. 833 ͑1999͒. 41 18 A. Piermattei, A. Fidanzio, G. Stimato, L. Azario, L. Grimaldi, G. M. A. Pitkanen, K. A. Holli, A. T. Ojala, and P. Laippala, “Quality assur- D’Onofrio, S. Cilla, M. Balducci, M. A. Gambacorta, N. Di Napoli, and ance in radiotherapy of breast cancer–variability in planning target vol- N. Cellini, “In vivo dosimetry by an aSi-based EPID,” Med. Phys. 33, ume delineation,” Acta Oncol. 40, 50–55 ͑2001͒. 4414–4422 ͑2006͒. 19B. Tomadsen, S. W. Lin, P. Laemmrich, T. Waller, A. Cheng, B. Caldwell, 42C. Talamonti, M. Casati, and M. Bucciolini, “Pretreatment verification of R. Rankin, and J. Stitt, “Analysis of treatment delivery errors in brachy- IMRT absolute dose distributions using a commercial a-Si EPID,” Med. therapy using formal risk analysis techniques,” Int. J. Radiat. Oncol., Phys. 33, 4367–4378 ͑2006͒. Biol., Phys. 57, 1492–1508 ͑2003͒. 43S. Yoo, G. Y. Kim, R. Hammoud, E. Elder, T. Pawlicki, H. Guan, T. Fox, 20T. Pawlicki, M. Whitaker, and A. L. Boyer, “Statistical process control G. Luxton, F. F. Yin, and P. Munro, “A quality assurance program for the for radiotherapy quality assurance,” Med. Phys. 32, 2777–2786 ͑2005͒. 21 on-board imager,” Med. Phys. 33, 4431–4447 ͑2006͒. G. A. Patton, D. K. Gaffney, and J. H. Moeller, “Facilitation of radio- 44 therapeutic error by computerized record and verify systems,” Int. J. Ra- O. A. Zeidan, S. A. L. Stephenson, S. L. Meeks, T. H. Wagner, T. R. diat. Oncol., Biol., Phys. 56, 50–57 ͑2003͒. Willoughby, P. A. Kupelian, and K. M. Langen, “Characterization and use 22W. E. Deming, The New Economics for Industry Government, Education, of EBT radiochromic film for IMRT dose verification,” Med. Phys. 33, ͑ ͒ 4064–4072 ͑2006͒. 2nd ed. MIT, Cambridge, MA, 1993 . 45 23P. Scalliet, “Risk, society and system failure,” Radiother. Oncol. 80,275– D. Thwaites, “Quality assurance into the next century,” Radiother. Oncol. ͑ ͒ 54, vii–ix ͑2000͒. 281 2006 . 46 24A. Niemierko, “Quality assurance and validation of individual IMRT J. E. Ibrahim, “Translating quality into research: Do we need more re- treatment plans before delivery,” Med. Phys. 31, 421–422 ͑2004͒. search into quality or should quality activities be conducted using the 25G. S. Ibbott, A. Molineu, and D. S. Followill, “Independent evaluations of principles and methodological rigour of scientific research?,” J. Qual. IMRT through the use of an anthropomorphic phantom,” Technol. Cancer Clin. Pract. 20, 63–64 ͑2000͒. 47 Res. Treat. 5, 481–487 ͑2006͒. H. Singh, L. A. Petersen, and E. J. Thomas, “Understanding diagnostic 26Abt Associates Inc., Washington DC, 2003, pp. 1–74. errors in medicine: a lesson from aviation,” Qual. Saf. Health. Care 15, 27ISO 9000 and Other Standards, American Society for Quality, http:// 159–164 ͑2006͒. 48 www.asq.org/learn-about-quality/iso-9000/overview/overview.html, 8 P. Dixon and B. O’Sullivan, “Radiotherapy quality assurance: time for January 2007. everyone to take it seriously,” Eur. J. Cancer 39, 423–429 ͑2003͒. 49 28R. Lupan, I. C. Bacivarof, A. Kobi, and C. Robledo, “A relationship P. B. Boggs, “Peak expiratory flow rate control chart: a breakthrough in between Six Sigma and ISO 9000:2000,” Qual. Eng. 17, 719–725 ͑2005͒. asthma care,” Ann. Allergy Asthma Immunol. 77, 429–432 ͑1996͒. 50 29M. R. O’Leary, Lexikon, Joint Commission on Accreditation of Health- T. Kehoe and L.-J. Rugg, “From technical quality assurance of radio- care Organization ͑JACHO, Oakbrook Terrace, 1994͒. therapy to a comprehensive quality of service management system,” Ra- 30R. G. Carey and R. C. Lloyd, Measuring Quality Improvement in Health- diother. Oncol. 51, 281–290 ͑1999͒. care: A Guide to Statistical Process Control Applications ͑ASQ Quality, 51K. H. Yu, R. L. Nation, and M. J. Dooley, “Multiplicity of medication Milwaukee, WI, 2001͒. safety terms, definitions and functional meanings: when is enough 31W. H. Ettinger, “Six Sigma: adapting GE’s lessons to health care,” enough?,” Qual. Saf. Health. Care 14, 358–363 ͑2005͒. Trustee 54, 10–15 ͑2001͒. 52P. Pronovost and R. Wachter, “Proposed standard for quality improve- 32G. J. Kutcher, L. Coia, M. Gillin, W. F. Hanson, S. Leibel, R. J. Morton, ment research and publication: one step forward and two steps back,” J. R. Palta, J. A. Purdy, L. E. Reinstein, and G. K. Svensson, “Compre- Qual. Saf. Health. Care 15, 152–153 ͑2006͒. hensive QA for radiation oncology: report of AAPM Radiation Therapy 53B. L. Sadler, “To the class of 2005: Will you be ready for the quality Committee Task Group 40,” Med. Phys. 21, 581–618 ͑1994͒. revolution?,” J. Qual. Pat. Saf. 32, 54–55 ͑2006͒. 33B. Fraass, K. Doppke, M. Hunt, G. Kutcher, G. Starkschall, R. Stern, and 54E. Davies and P. D. Cleary, “Hearing the patient’s voice? Factors affect- J. Van Dyke, “American Association of Physicists in Medicine Radiation ing the use of patient survey data in quality improvement,” Qual. Saf. Therapy Committee Task Group 53: Quality assurance for clinical radio- Health. Care 14, 428–432 ͑2005͒.

Medical Physics, Vol. 34, No. 5, May 2007 The future of PACS Paul G. Nagy Department of Diagnostic Radiology, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, Maryland 21201 ͑Received 26 February 2007; revised 2 May 2007; accepted for publication 2 May 2007; published 11 June 2007͒ How will the future of picture archiving and communication systems ͑PACS͒ look, and how will this future affect the practice of radiology? We are currently experiencing disruptive innovations that will force an architectural redesign, making the majority of today’s commercial PACS obsolete as the field matures and expands to include imaging throughout the medical enterprise. The common architecture used for PACS cannot handle the massive amounts of data being generated by even current versions of computed tomography and magnetic resonance scanners. If a PACS cannot handle today’s technology, what will happen as the field expands to encompass pathology imaging, cone-beam reconstruction, and multispectral imaging? The ability of these new technologies to enhance research and clinical care will be impaired if PACS architectures are not prepared to support them. In attempting a structured approach to predictions about the future of PACS, we offer projections about the technologies underlying PACS as well as the evolution of standards development and the changing needs of a broad range of medical imaging. Simplified models of the history of the PACS industry are mined for the assumptions they provide about future innovations and trends. The physicist frequently participates in or directs technical assessments for medical equipment, and many physicists have extended these activities to include imaging informatics. It is hoped that by applying these speculative but experienced-based predictions, the interested medical physicist will be better able to take the lead in setting information technology strategies that will help facilities not only prepare for the future but continue to enjoy the benefits of technological innovations without disruptive, expensive, and unexpected changes in architecture. A good PACS strategy can help accelerate the time required for innovations to go from the drawing board to clinical implementation. © 2007 American Association of Physicists in Medicine. ͓DOI: 10.1118/1.2743097͔

Key words: PACS, information systems, Moore’s law, technology assessment

I. INTRODUCTION this market is still being driven by medical device manufacturers. Those factors are important in the PACS industry’s Why make predictions about the future of picture archiving somewhat “later adopter” path ͑in the classic pattern of tech- ͑ ͒ and communication systems PACS ? Our ability to deliver nologic innovations͒ when compared with other computer quality care is increasingly dependent upon information tech- industry sectors. By looking at other domains in the com- ͑ ͒ nologies IT that drive all aspects of image acquisition, puter industry, therefore, we can make modest predictions communication, interpretation, and storage. A radiology de- about the future of PACS with some confidence. Noted fu- partment can no longer operate with film and expect to ef- turist William Gibson is often quoted as saying, “The future ͑ ͒ 1 fectively process and read a computed tomography CT is here. It’s just not widely distributed yet.” These predic- study from a modern scanner. Architectural decisions about tions, too, may not occur at precisely the forecast intervals today’s PACS technology can lead to limitations where new but, barring extraordinary intervening circumstances, will al- imaging modalities and techniques are not supported or im- most certainly prove valid. age data cannot be economically stored and retrieved adequately for medical management decisions. The ability to Prediction 1. Moore’s law will hold true for at least grow and innovate relies on having an, open, flexible, and another 10 years scalable architecture. This paper presents six predictions that, if taken together, present a scenario for the next generation of The fundamental predictor often cited in the computer PACS. industry when planning for future growth is Moore’s law.2 We are taught as scientists that all extrapolations ͑includ- Gordon Moore, cofounder of Intel®, predicted in 1965 that ing, perhaps especially, predictions͒ are fraught with uncer- the number of transistors on a microprocessor would con- tainty, so that it is important to clearly state the assumptions tinue to double every 24 months with the cost remaining the on which such extrapolations are based. One of the key as- same.3 Moore was conservative in his original forecast, pre- sumptions in looking to the future of PACS is that the indus- dicting that this trend would continue for a decade. Instead, try has a relatively small market size compared with other IT Moore’s law has held true for more than 40 years, from a industries. Despite its mission-critical clinical application, time when a microprocessor had 1-2000 transistors to to-

2676 Med. Phys. 34 „7…, July 2007 0094-2405/2007/34„7…/2676/7/$23.00 © 2007 Am. Assoc. Phys. Med. 2676 2677 Paul G. Nagy: The future of PACS 2677 day’s standard model dual-core 64-bit processors with more than 200ϫ106 transistors.4 Moore’s law has also proven accurate for other technologies in the computer industry, such as storage. September 2006 marked the 50th anniversary of the magnetic hard drive.5 The first hard drive, invented by IBM, was made up of 50 24-in. aluminum platters holding 5 MB worth of data and weighing more than a ton.6 Today’s hard drive capacity is 1 TB ͑1000 gigabytes͒,7 within a 3.5-in. enclosure weighing less than 1 kg ͑1.5 lb͒. Debate has long focused on when and how Moore’s Law will either meet its quantum limits,8 user needs will be far outpaced by capacity,9 or the computer fabrication industry will no longer be able to support rapid continuous growth.10 Most experts ͑including Moore himself͒ believe that Moore’s law will continue to be valid for at least another 10 years.11 Another popular notion is that Moore’s law has become a self-fulfilling prophecy driving consumer expectations and marketing.12 In 2004, the International Technology Roadmap for Semiconductors, a large consortium of semiconductor vendors including Intel®, performed technical analyses on the limitations of technology and issued a detailed consensus report suggesting that Moore’s law will be pertinent for the next 15–20 years13 as more nanotechnology is incorporated into the fabrication process. One important but not always appreciated aspect of Moore’s law is that it does not represent a constant linear growth rate of one technology but, FIG. 1. Growth in number of images per study and number of CT studies instead, a succession of overlapping sigmoids of different performed between 1998 and 2006. technologies.14 As one technology matures and flattens out, a new technology takes its place to drive the industry. With hard drives this effect can be seen in differing technologies heat and consume less power so that more can be aggregated such as antiferromagnetically coupled media, perpendicular in a single enclosure. Applications such as e-mail and data- disk heads, and paramagnetic materials. In semiconductors, base servers with more than 100 input/output requests per this can be seen in a continuous stream of smaller fabrication second require higher speed storage systems, because they methodologies that require ramp-up time before achieving are driven by the seek time needed for the cylinder to rotate economies of scale. under the drive head. For applications such as PACS, the key If Moore’s law continues to hold true, in 2012 the average metric is in throughput and does not depend on seek times personal computer will be equipped with more than 109 tran- but, instead, on throughput rates in tens to hundreds of mega- sistors ͑the rough equivalent of a 40-GHz system͒ and will bytes per second. Putting more than ten hard drives into a have a 3-TB hard drive. In 2017, by the same predictive redundant array of inexpensive disks configuration will com- metrics, the average $1000 desktop computer will have more bine nearly linearily the throughput speeds of the individual than 6ϫ109 transistors ͑the rough equivalent of a 320-GHz disks and exceed a gigabit network performance system͒, with a 24-TB hard drive. ͑Ͼ100 MB/s͒ needed for fast image delivery in a PACS system. The other primary benefit of using 7200-rpm SATA drives is that they are less expensive, currently available at Prediction 2. PACS storage and archives will be all less than $2000 per terabyte of enterprise class storage, with spinning serial advanced technology attachment 8 times the market volume of small computer system inter- „SATA… archives with high-density storage faces ͑SCSIs͒ and Fibre Channel high-speed drives. farms driven by the performance requirements This is encouraging news but not sufficiently encouraging of clinical applications for just-in-time delivery to warrant reducing next year’s operating budget for storage. The high-density online market hosts a growing industry A study performed at the Mayo Clinic in 2002 indicated that focusing on backup storage systems and systems with large medical imaging data growth was outstripping the computer files, such as PACS. Today’s enterprise-class storage systems expansion capabilities predicted by Moore’s law.16 Experi- can house up to 42 1000-GB, 3.5-in., 7200-rpm SATA drives ence at the University of Maryland over the past 8 years has in a 6-in. rack enclosure ͑4U͒ and can maintain 42 TB of seen rapid growth in storage needs, at a pace only slightly storage with subsecond access times.15 The key to this mar- slower than Moore’s law. As shown in Fig. 1, the number of ket is using slower drives of 7200 rpm rather than Fibre CT studies increased from 10 165 in 1998 to 57 713 in 2005 Channel 15 000-rpm drives. The slower drives generate less ͑14.7% and 24.6% of total study volumes in those respective

Medical Physics, Vol. 34, No. 7, July 2007 2678 Paul G. Nagy: The future of PACS 2678

Prediction 3. The commoditization of the server hardware market will allow the utilization of high-density processing farms, such as blade architectures, which can provide a new level of fault tolerance, processing horsepower, and scalability A blade farm is a server processing farm in which the equivalent of 16-20 servers can be placed in the same 8 in. of rack space that once could house only one or two servers. Procuring the power and network cabling for staging a normal server can be time consuming and expensive. In a blade configuration, a chassis provides a common housing for the blades as well as power and networking. These servers are typically dual-processor, dual-core systems that can provide FIG. 2. Storage usage per year has seen growth predominantly from an the equivalent of 64 processors in a single-chassis unit. escalation in the number of CT studies and CT study volume. Blade server sales accounted for 6% of all server sales in 2006, but, with an increase of more than 30% over 2005, represented the fastest growing market segment.21 Another advantage of blade systems is that they contain their own years͒. The number of images per study in the department is network backbones, which can run at terabit transfer rates within and between blade enclosures, accelerating server-to- also increasing, from an average of 69 in 1998 to 234 images 22 per study in 2006. Figure 2 shows the 8-year growth in stor- server communications. age demand resulting from these two trends. This escalating An inexpensive server processor farm provides useful growth is equal to a doubling in storage every 2.5 years, only functions. The first and most important for the PACS indus- slightly slower than Moore’s predicted doubling of computer try is that using multiple servers for the same function within capabilities every 2 years. a PACS provides fault tolerance by removing single points of failure. In an August 2006 survey of data centers, hardware Two trends will continue to increase imaging data storage failure was the leading cause ͑49%͒ of unplanned outages.23 use. One is the archiving requirements associated with sub- Moving parts, such as spinning hard drives, fans in power millimeter ͑thin͒-slice CT data. The University of Maryland supplies, CPUs, and robotic arms are generally the first to does not routinely archive thin-slice data but is planning to fail in a server. The potential costs in labor and disruption begin doing so in the third quarter of 2007.17 This change in with unplanned outages can provide a reasonable investment practice will double our study volume and synchronize our justification for additional servers, each of which should cost growth with that predicted by Moore’s law. The other factor less than $5000. Most institutions running PACS as mission- ϫ is the potential move of CT manufacturers to 1024 1024 critical applications will have uptime guarantees equal to or matrix sizes, an innovation that could quadruple dataset in excess of 99.9%, equating to less than 9 h of downtime sizes. ͑scheduled or unscheduled͒ within a year. Such an uptime High-density spinning-disk storage devices simplify the rate is not realistically achievable with single-hardware de- older hierarchical storage model used in PACS, in which pendencies. In 5 years, the use of fault-tolerant distributed ͑ images are available on line for a period of time typically 6 systems, such as blade farms, should be predominant, and, in ͒ months or so and then go to a DVD or tape library. 10 years, few or no single-server systems will be running in Spinning-disk storage systems are displacing tape systems as critical environments. backups in other markets because of their competitive pric- Another advantage of a multiple or distributed server en- ing and superior performance. Retrieving data from backup vironment is scalability. An enterprise running with a single on tape for either migration or recovery from a failure takes server is not only vulnerable to single points of failure but to significant time. One study on migration suggested that mi- performance bottlenecks. As PACS systems grow to meet gration of PACS data from a tape archive takes roughly a enterprise demands in other departments, it is important to 18 third of the time that original acquisition required. Six incorporate the capability to quickly scale server require- years of data backed up on tape might realistically take up to ments. 19 2 years to transfer to a new system. The final advantage of large, inexpensive computing Spinning disks themselves are on a limited lifetime as a server environments is their ability to facilitate the introduc- technology. Solid state disks ͑SSDs͒ are a type of nonvolatile tion into clinical use of a new class of applications that re- memory that retains information unpowered popular in por- quire massive number crunching, such as computer-aided di- table media players. SSDs have no moving parts, consume agnosis ͑CAD͒, volumetric organ segmentation, content- less power, and are faster than spinning disks in seek time based image retrieval, and real-time registration and and latency. SSDs are currently six times as expensive per subtraction of deformable volumetric datasets. gigabyte as spinning hard drives. They are predicted to re- Distributed systems require a redesign in architecture to place the spinning disk by 2012.20 take full advantage of the fault tolerance, scalability, and

Medical Physics, Vol. 34, No. 7, July 2007 2679 Paul G. Nagy: The future of PACS 2679 processing power these systems can provide. Consider, as an radiology. The second innovation was the use of dynamic example, the performance and scale of the Google Internet compression to spare the network bandwidth in delivering search engine, which provides subsecond querying of a cata- images to the client. log of more than 25ϫ109 Web pages. This single application The fifth generation of PACS will be distinguished by is distributed among 450 000 servers around the globe.24 server-side rendering. There are two factors that will drive the industry towards server-side computing. One is the growth in volumetric data generated in a single study; the Prediction 4. The next generation of PACS will rely larger the study, the longer the time required to deliver those heavily upon server-side video rendering for large images to the client. The second is the limitations in growth datasets. The first three generations of of network speeds resulting from high labor costs associated architecture simply cannot handle the large with re-laying cabling throughout a medical institution. Al- volumetric datasets being generated by today’s CT though storage growth may keep up with imaging volume and magnetic resonance imaging scanners growth, network transfer performance will not. The result is To better understand this prediction, it is important to look that images can be stored, but it may take longer and longer at the history of PACS and the evolving shift between the to send specific sets of images to the requesting physician. client and server. The housing and processing of images has The solution will require leaving the images on the server been consistently moving from the workstation client to the and rendering them from there. server over the past 20 years. It should be noted that this is a A server-side rendering farm is a group of servers dedi- very simple model, and that significant differences character- cated to displaying volumetric data and providing a remote ize different vendors even within the same generation of session to the end users. This allows all the large volumetric technology. Nevertheless, the general trend is away from the datasets to stay in the data center and spares the network client and toward the server for image storage, processing, connection to the enterprise by sending only a presentation and visualization. of the data and not the data itself. Physicians throughout the The first generation of PACS, from the mid-1980s to the enterprise have considerable use for and are coming to de- early 1990s, were essentially screen-capturing systems that pend on three-dimensional visualization of volumetric data. fed images off the modalities into workstations using propri- The current model of deploying specialized workstations etary networking and file format protocols. These systems throughout a hospital is unsupportable and far too expensive. cost more than $20 million, and fewer than 25 such systems Server-side rendering systems can deploy lighter clients were deployed. Systems based on this architecture are no throughout a hospital with lower support costs and greater longer in production. accessibility to the tools through site licensing instead of The development of the second generation, from the early fixed seat licensing, which forces the physician to go to the to mid-1990s, was driven by the military’s Digital Imaging workstation to use the tools. Within 5 years, the majority of Network-PACS proposals that required implementation of PACS vendors will either develop or support server-side ren- the Digital Imaging and Communications in Medicine dering systems for volumetric data. ͑DICOM͒ standard for image file formats and communica- One trend that the PACS industry should explore lies in tion. Images were routed to workstations from the modalities recent innovations made in the computer game industry. As a via DICOM. Studies were routed to several workstations in result of the massive processing power required to create an effort to anticipate the reading location of the radiologist. realistic, real-time, immersive graphical environments for Systems were limited to radiologists, with no enterprise dis- computer gamers, the processing power on a video card fre- tribution. quently exceeds the number of transistors on the computer’s The third generation of PACS introduced the use of on- CPU.25 Silicon Graphics developed and released a common demand central architectures, in which images were central- low-level library called OpenGL to display and render geo- ized into a primary storage pool and could be pulled quickly metric shapes.26 Several vendors specialize in server-side vi- from any diagnostic workstation. Only requested studies sualization of volumetric data through OpenGL libraries, were sent to workstations. Because images were stored cen- software CPU algorithms, or proprietary hardware tech- trally, lightweight Web-based image viewers were deployed niques. These systems will continue to evolve, and new to begin to address the imaging needs of referring physicians PACS systems will likely be designed around this visualiza- within the enterprise. tion methodology. The fourth generation began in the late 1990s and was defined by two significant contributions. The first is a single client for users outside of radiology as well as inside. This Prediction 5. The next-generation desktop client innovation was enabled by extending Web browsers or by software applications will combine functionality, performance, and deployability using portable byte code engines such as the Java virtual machine or the C sharp common language infrastructure in- The client application of newer generations of PACS will stead of thick clients. This approach minimized the support be thinner. Traditional PACS applications had to be written costs incurred by installing the thick applications on hun- with direct access to the Windows application program inter- dreds of computers throughout an enterprise. This also deliv- face to provide file access and Windows response time in ered a full-featured application to assist physicians outside of scrolling and manipulating images. These applications,

Medical Physics, Vol. 34, No. 7, July 2007 2680 Paul G. Nagy: The future of PACS 2680 known as thick clients, have traditionally been written in creasingly untenable for radiologists to sacrifice productivity C++. The downside to direct access to low levels within the while tethered to specific locations needed to gain access to Windows® operating system is the potential for shared li- sets of specialized tools. brary conflicts in versioning, known colloquially as “DLL The solution will be an increasing trend toward opening hell.” These clients can be deployed within the limited con- up the business logic of a PACS. One popular view of soft- fines of dedicated workstations in the radiology department ware development sees three encapsulated layers: the appli- but require hands-on access for support. Support for deploy- cation layer, business logic layer, and data layer. The data ment beyond radiology is usually extremely challenging. layer, also known as the model, is at the bottom, where im- Thinner clients, such as Web clients, are easy to deploy ages and persistent data reside in the database. The business throughout thousands of workstations, because they provide logic layer, also known as the controller, is the brains of the a standard browser application framework that limits access system and includes all the rules for the application, such as to low-level libraries. This unfortunately also limits function- autorouting, hanging protocols, worklists, and study status. ality and performance on the client. The common middle The application layer, also known as the view, is the direct ground that most PACS systems use for writing their clients human user interface, where the focus is on usability. These is through byte code engine-based programming languages layers are encapsulated to allow for rapid and flexible soft- such as Java and C#. These clients provide better deployabil- ware development. Opening the business layer will allow ity than thick clients and better functionality than thin third-party vendors to query unread worklists, route images clients.27 on demand, and set dictation status remotely from indepen- One exciting technology that appears to provide the best dent workstations. of both worlds is Asynchronous Javascript and XML This business logic can be exposed to third-party work- ͑AJAX͒. Used in applications such as Google Maps, AJAX stations in several ways. The most likely will be through methodologies bring a thick-client look and feel through a DICOM general purpose worklist and service-oriented archi- Web browser. Combining AJAX browser clients with server- tectures. DICOM has a standard for the general purpose side rendering systems has the potential to move perfor- worklist, which is intended for postprocessing steps and ra- mance requirements off the network and the client onto the diology interpretation workflow, much as DICOM modality server while providing full functionality to the client. A com- workflow is used for acquisition workflow. A service- plete rewrite of applications is required to take advantage of oriented architecture ͑SOA͒ exposes a discoverable machine AJAX, so the industry will not move to this new technology interface ͑known as Web Services͒, to the business logic of for several years. Another clear advantage of AJAX and the application. A Web Service is a set of XML documents some byte code engines is their ability to be operating sys- transmitted over Hypertext Transfer Protocol. This process is tem independent and perform on Windows® as well as other behind the much-advertised Web 2.0 applications. SOAs are platforms such as Macintosh OS X and Linux. Although useful in that they provide better adaptability to changing Microsoft® Windows® will still be around in 5 years, there business needs as well as flexibility to accommodate future will be an increasing heterogeneity in operating systems, es- technologies. pecially in the mobile platform market. Regardless of how such change is accomplished, the trend is clearly toward an escalating need for integration and trans- Prediction 6. Third-party diagnostic workstations and parency of workflow in radiology. Today, DICOM modality specialized systems will be seamlessly integrated performed procedure steps can transmit the status of a pa- into clinical workflow. This will result from PACS tient, including arrival, initiation of scanning, completion of becoming more flexible through better standards- scanning, etc. DICOM storage commitment ensures the safe based interoperability and service-oriented delivery of the images to the PACS system. This transpar- architectures ency allows other systems throughout the hospital to better Volumetric imaging has brought both progress and advan- utilize radiology services by tracking patients. The challenge tages to visualization and parameterization of organ systems is to reduce the cost and speed of implementing these inter- and pathologies in the past 10 years, thanks in no small part faces so that they become “plug and play” utilities. The In- to the medical physics community. At the same time, the tegrating the Healthcare Enterprise initiative is working to range of visualization techniques has expanded rapidly along take existing standards and accelerate their adoption into the with new modalities, hybrid imaging technologies, and inno- clinical environment by creating common use cases and vative procedures. No single PACS vendor can innovate in demonstrating them in real time at “Connectathons,” forums all the subspeciality areas of image visualization and analy- in which vendors showcase their integration capabilities. sis, including but not limited to mammography, ultrasound, Open standards have the longest shelf life in technology nuclear medicine, cardiology, chest imaging, perfusion imag- lasting decades. The entire reason we develop and adhere to ing, functional imaging, registration and fusion imaging, CT standards is to take advantage of their consistency in an en- colonoscopy, not to mention all the new tomosynthesis and vironment where all the other technology is changing rap- CAD applications coming to market. idly. Today the market is already becoming saturated with One disturbing byproduct of these advances has been the the majority of radiology operations using PACS. As sites increasing proliferation of specialty workstations with lim- have learned their lessons with their first PACS system and ited integration into clinical workflow. It is becoming in- begin to migrate to newer systems over the next 5 years, the

Medical Physics, Vol. 34, No. 7, July 2007 2681 Paul G. Nagy: The future of PACS 2681 emphasis will become increasingly important on open stan- 15 December 2006. 3 dard integration. Although the DICOM transfer syntax might G. Moore, “Cramming more components onto integrated circuits,” Elec- tronics 38, 114–117 ͑1965͒; ftp://download.intel.com/museum/ evolve, the main DICOM object model will be relatively Moores_Law/Articles-Press_Releases/Gordon_Moore_1965_Article.pdf, unchanged in 10 years and will be one of the few things 8 January 2007. recognizable to systems used today. 4V. Freeman, “Athlon 64 X2 4800+ processor review,” Sharkey Extreme, June 22, 2005. http://www.sharkyextreme.com/hardware/cpu/article.php/ 3514901, 9 January 2007. II. CONCLUSION 5S. Levy, “The hard disk that changed the world,” Newsweek, August 7, Institutions should develop strategies for “future proof- 2006, http://www.msnbc.msn.com/id/14096484/site/newsweek/, 8 Janu- ary 2007. ing” their technology buying decisions. The most important 6“A brief history of the hard disk drive,” DUX Computer Digest, May 19, factor is to ensure that the purchasing model allows the in- 2005. http://www.duxcw.com/digest/guides/hd/hd2.htm, 8 January 2007. stitution to enjoy the market benefits of Moore’s law. The 7S. Olsen, “Hitachi Global Storage announces 1TB Hard Drive,” Daily most direct way to accomplish this is to move to a software- Tech., January 5, 2007. http://www.dailytech.com/article.aspx?newsid ϭ5590, 8 January 2007. only model in which hardware purchases are made indepen- 8 M. Kanellos, “Intel scientists find wall for Moore’s Law,” ZDNet News, dently of the PACS vendor, with only minimum hardware December 1, 2003. http://news.zdnet.com/2100-9584_22_5112061.html, requirements for servers, storage, and workstations. This al- 9 January 2007. lows a site to regularly replace hardware at market value and 9D. Mohney, “Moore’s Law meets market saturation,” The Inquirer, De- ϭ enjoy benefits in better performance, reliability, and cost. cember 5, 2002. http://www.theinquirer.net/default.aspx?article 6559, 9 January 2007. Another recommended task is to hold discussions with the 10“Rock’s law of the doubling of fabrication costs,” Wikipedia, the Free PACS vendor on ways to incorporate third-party worksta- Encyclopedia, http://en.wikipedia.org/wiki/Rock%27s_law, 15 December tions into the clinical workflow. The lowest cost, long-term 2006. 11 solution for customers is integration through openly pub- M. Kanellos, “Moore’s Law to roll on for another decade,” CNET News, February 10, 2003, http://news.com.com/2100-1001-984051.html, 9 Janu- lished standards and not piecemeal vendor partnerships with ary 2007. proprietary interfaces. Vendors should also provide a road- 12B. Schaller, “The origin, nature, and implications of Moore’s Law,” Mi- map detailing the ways in which they plan to incorporate crosoft Research, September 26, 1996; http://research.microsoft.com/ volumetric datasets for visualization and archiving without ~gray/Moore_Law.html, 9 January 2007. 13P. Gargini, “Sailing with the ITRS into nanotechnology,” PowerPoint compromising the productivity of the radiologists. presentation, ftp://download.intel.com/technology/silicon/ Physicists have a real opportunity to provide the technical Paolo_Semicon_West_071904.pdf, 15 December 2006. leadership that will help to shape strategies as radiology de- 14C. M. Christenson, The Innovator’s Dilema: The Revolutionary Book that partments meet the challenges of the future. Physicists are Will Change the Way You Do Business ͑Collins Business Essentials, New York, 2003͒. ideally suited to provide informatics leadership because of 15K. Schwartz, “Nexan gives ATA more muscle with SATABeast,” eWeek- our proficiency with technology, intimate domain knowledge .com, October 18, 2005, http://www.eweek.com/article2/ of imaging, and close partnership with clinical staff and phy- 0,1895,1872607,00.asp, 9 January 2007. 16 sicians. Informatics is a natural extension for many physi- B. J. Erickson, K. R. Persons, N. J. Hangiandreou, E. M. James, C. J. cists and an avenue for both career growth and contributions Hanna, and D. G. Gehring, “Requirements for an enterprise digital image archive,” J. Digit Imaging 14, 72–82 ͑2001͒. to operations and productivity. Important discussions in the 17C. Meenan, B. Daly, C. Toland, and P. Nagy, “Use of a thin-section medical physics community have focused on the role of the archive and enterprise 3D software for long-term storage of thin-slice CT datasets.” J. Digit Imaging 19͑suppl 1͒,84–88͑2006͒. physicist in implementing and supporting information sys- 18 tems in a hospital.28,29 Both sides agree that IT is certainly an F. M. Behlen, “A DICOM document-oriented approach to PACS infrastructure,” J. Digit Imaging 11͑3 suppl. 1͒, 35–38 ͑1998͒. opportunity; the debate is over whether changes should be 19F. M. Behlen, R. E. Sayre, J. B. Weldy, and J. S. Michael, “Permanent’ made to the requirements of an already large curriculum of records: Experience with data migration in radiology information system physicist training. It is clear that more discussion is neces- and picture archiving and communication system replacement,” J. Digit ͑ ͒ ͑ ͒ sary on the new and challenging opportunities in the practice Imaging 13 2 suppl. 1 , 171–174 2000 . 20P. Thibodeau, “Flash memory not ready to explode as PC storage tech- of medical physics. What is undisputed is that unique to the nology,” Computer World, April 3, 2007, http:// medical discipline, the radiologist and the physicist have had www.computerworld.com/action/article.do?command 30 ϭviewArticleBasic&articleIdϭ9015478, 15 April 2007. a mutually supportive relationship for more than a century. 21 The radiologist needs IT guidance and support in information M. Fontecchio, “Blade server growth drives revenue Q3 ’06,” Search- DataCenter.com, November 22, 2006. http// systems now more than ever before. searchdatacenter.techtarget.com/originalContent/ 0,289142,sid80_gci1231203,00.html, 9 January, 2007. 22 ACKNOWLEDGMENTS Hewlett-Packard, Inc, “HP BladeSystem c-class servers blades— interconnects, News Release,” http://h18004.www1.hp.com/products/ I would like to thank Dr. Nancy Knight from the Univer- blades/components/c-class-interconnects.html, 9 January 2007. sity of Maryland School of Medicine and Dr. William 23DM Review Editorial Staff, “The 24ϫ7 challenge: IOUG 2006 survey on Hendee from the Medical College of Wisconsin for their ex- high availability trends,” DM Review, August 29, 2006, http:// www.dmreview.com/editorial/newsletter_article.cfm?articleIdϭ1061768, pert assistance in preparing this manuscript. 9 January 2007. 24“Google,” Wikipedia, the Free Encyclopedia, http://en.wikipedia.org/ 1“William Gibson,” www.wikipedia.com, http://wn.wikiquote.org/wiki/ wiki/Google#Technology, 31 January 2007. William_Gibson, 29 May 2007. 25T. Wilson and J. Tyson, “How graphics cards work,” HowStuffWorks, 2Moore’s Law Diagram, Wikipedia, the Free Encyclopedia, http:// http://computer.howstuffworks.com/graphics-card.htm, 9 January 2007. en.wikipedia.org/wiki/Image:Moore_Law_diagram_%282004%29.png, 26N. D. Terry, “Introduction to OpenGL,” Tulane University Class CPEN

Medical Physics, Vol. 34, No. 7, July 2007 2682 Paul G. Nagy: The future of PACS 2682

461/661, Spring 1997, http://www.eecs.tulane.edu/Terry/OpenGL/ 29G. C. Nikiforidis, G. C. Kagadis, and C. G. Orton, “It is important that Introduction.html, 9 January 2007. medical physicists be involved in the development and implementation of 27C. Toland, C. Meenan, M. Toland, N. Safdar, P. Vandermeer, and P. Nagy, integrated hospital information systems,” Med. Phys. 33, 4455–4458 “A suggested classiﬁcation guide for PACS client applications: The ﬁve ͑2006͒. degrees of thickness,” J. Digit Imaging 19͑suppl 1͒, 78–83 ͑2006͒. 30P. R. Almond, “Foreword,” Radiation Physics, in A History of the Radio- 28J. R. Halama and W. Huda, “Medical physicists should assume PACS logical Sciences, Vol. III, edited by P. R. Almond ͑Radiology Centennial, responsibilities,” Med. Phys. 29, 1913–1915 ͑2002͒. Reston, 1996͒, pp. v–ix.

Medical Physics, Vol. 34, No. 7, July 2007 BGRT: Biologically guided radiation therapy—The future is fast approaching! Robert D. Stewart School of Health Sciences, Purdue University, 550 Stadium Mall Drive, West Lafayette, Indiana 47907-2051 ͒ X. Allen Lia Department of Radiation Oncology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226 ͑Received 3 January 2007; revised 9 August 2007; accepted for publication 10 August 2007; published 11 September 2007͒ Rapid advances in functional and biological imaging, predictive assays, and our understanding of the molecular and cellular responses underpinning treatment outcomes herald the coming of the long-sought goal of implementing patient-speciﬁc biologically guided radiation therapy ͑BGRT͒ in the clinic. Biological imaging and predictive assays have the potential to provide patient-speciﬁc, three-dimensional information to characterize the radiation response characteristics of tumor and normal structures. Within the next decade, it will be possible to combine such information with advanced delivery technologies to design and deliver biologically conformed, individualized therapies in the clinic. The full implementation of BGRT in the clinic will require new technologies and additional research. However, even the partial implementation of BGRT treatment planning may have the potential to substantially impact clinical outcomes. © 2007 American Association of Physicists in Medicine. ͓DOI: 10.1118/1.2779861͔

Key words: biologically guided radiation therapy, biological imaging, outcome modeling, LQ model

I. INTRODUCTION strategy to integrate biological information into treatment The efficacy of radiotherapy ͑RT͒ is ultimately determined plans for the next generation of RT, i.e., biologically guided ͑ ͒ by our ability to deliver doses of radiation sufficient to eradi- radiation therapy BGRT . Although the full implementation cate a tumor, while adequately sparing nearby normal struc- of BGRT will undoubtedly require new technologies and ad- tures. Until now, the practice of RT has been based on the ditional research to advance our understanding of biological premise that effective treatments require the delivery of uni- mechanisms, we believe that even a partial implementation form radiation doses to all target volumes. The uniform-dose of BGRT treatment planning has the potential to substantially theorem1 provides some justification for this treatment strat- impact clinical outcomes within the next ten years. egy. However, the uniform-dose approach only yields the best possible tumor control for the implausible situation in II. MODELS FOR THE PREDICTION OF TREATMENT which all regions of the tumor have exactly the same bio- OUTCOMES logical characteristics and sensitivities to radiation. Biologi- Implementation of BGRT requires the identification of cal factors that modulate treatment outcomes include such suitable biological objectives to facilitate the intercompari- factors and processes as a cell’s capacity for repair, acute and son and ranking of treatment plans. The two main biological chronic hypoxia, cell proliferation, the spatial distribution objectives are to maximize local tumor control probabilities and density of tumor clonogens, and the differential sensitiv- ͑TCPs͒ while simultaneously minimizing normal tissue com- ity of cells to radiation during the cell cycle. Genetic and plication probabilities ͑NTCPs͒. As an alternative to specify- other patient-specific factors that impact on radiation re- ing biological objectives in terms of TCP and NTCP values, sponses are seldom considered in radiation treatment plan- concepts such as the biologically effective dose ͑BED͒15 and ning for specific patients. equivalent uniform dose ͑EUD͒16 are sometimes used for Theoretical studies and the accumulated clinical data2–14 treatment plan ranking and intercomparison. Regardless, ef- strongly suggest that the treatment plans designed to exploit fective tumor control presumably requires the reproductive patient- and tumor-specific biological features will substan- inactivation of all aberrant target cells. The direct killing of tially improve treatment outcomes. However, the complexity cells by radiation also contributes to normal tissue complica- of biological systems and our incomplete knowledge of the tions, although intercellular communication, cell-matrix in- mechanisms underpinning tumor and normal-tissue re- teractions, and other factors influence the collective response sponses, pose many challenges for the clinical implementa- of normal tissues to radiation.17–19 tion of biological criteria into the treatment planning process. A representative NTCP model is briefly reviewed to high- To advance patient-specific treatment planning without un- light some of the challenges and research needs associated duly jeopardizing patient care, we propose a three-phase with the important dose-limiting issue of normal tissue tox-

3739 Med. Phys. 34 „10…, October 2007 0094-2405/2007/34„10…/3739/13/$23.00 © 2007 Am. Assoc. Phys. Med. 3739 3740 R. D. Stewart and X. A. Li: Biologically guided radiation therapy 3740 icity. A method to identify isoeffective prescription doses is regimens.35 However, with the exception of a few introduced. The putative relationship between cell death studies33,36,37 that use parameters derived from more recent ͑ ͒ mechanisms and the linear-quadratic LQ survival complication data, the original TD50 estimates of Burman model20–23 is also examined to highlight the need for better et al.25 are still nearly always used for treatment planning outcome models and as a cautionary note about the potential applications. The tolerance doses reported by Burman et al.25 strengths and weaknesses of using the LQ model to guide the need to be updated based on the new clinical data, e.g., more identification of equivalent prescription doses and patient- accurate patient-specific volumetric dosimetric data for specific dose distributions. Examples illustrating the impact newer treatment planning and delivery technologies. In addi- of uncertainties in biological parameters, including the ef- tion, differences exist in delivered dose patterns between fects of interpatient heterogeneity in tumor radiosensitivity older and newer modalities, such as high dose gradients with parameters, are presented and discussed within the context of intensity modulated RT ͑IMRT͒, large doses to smaller vol- patient-specific treatment planning and the future of outcome umes versus small doses to large volume when comparing modeling. fixed-beam with rotational delivery. The accuracy of the effective volume method for DVH reduction is an open ques- II.A. Lyman–Kutcher–Burman NTCP model tion that raises many questions about the accuracy of NTCP Much of our knowledge of normal-tissue tolerances estimates derived from the LKB model. To improve confi- comes from the seminal publication of Emami et al.24 The dence in the prediction of normal tissue complications for authors used data from the literature and personal experience partial-volume irradiation, the 3D dose distribution delivered to compile tolerance-dose values for uniform irradiation of to each patient needs to be recorded. twenty-eight critical structures. In the accompanying article by Burman et al.25 the tolerance data were used to determine II.B. Poisson TCP model parameters for the phenomenological NTCP model proposed by Lyman.26 Because the Lyman model is defined for uni- The most commonly used TCP model is based on the form irradiation, and normal tissues are rarely irradiated uni- Poisson distribution.38,39 With the Poisson model, the prob- formly, several algorithms to convert a heterogeneous dose ability that all tumor cells are inactivated is given by distribution into a uniform dose distribution resulting in the N N ␥ ͑ ͒ same NTCP have been proposed. The effective volume ͟ ͫ ͚ ␳ ͑ ͒ i T−Tlag ͬ ͑ ͒ TCP = TCPi = exp − vi iS Di e . 4 method for dose-volume histogram ͑DVH͒ reduction pro- i=1 i=1 posed by Kutcher and Burman27 is the most commonly used Here, ␳ denotes the expected number of tumor clonogens approach. The combination of the DVH reduction algorithm i per cm3 in the ith tissue region, v is the volume of the ith and Lyman’s NTCP model, which is often referred to as the i tissue region ͑cm3͒, S͑D ͒ is the fraction of the tumor cells in Lyman–Kutcher–Burman ͑LKB͒ model, provides a phenom- i the ith tissue region that survive total treatment dose D , and enological method to estimate NTCP values for uniform or i T is the overall time to complete the treatment. The effects of nonuniform irradiation of many critical tissue structures. 28,29 subclinical disease on tumor control can be incorporated into The LKB model can be described by three equations: Eq. ͑4͒ by decreasing the clonogen density ͑␳ parameter͒ in t 1 2 −x ր 2 ͑ ͒ regions outside the gross tumor volume. For the special case NTCP = ͱ ͵ e dx 1 ␳ ͑ 2␲ ϱ when i =0 i.e., the tissue region does not contain any tumor − ͒ cells , TCPi equals unity regardless of dose. After time interval Tlag, accelerated tumor repopulation becomes effective Deff − TD50 t = ͑2͒ and is characterized by rate constant, ␥. The tumor repopu- mTD50 ␥ ͑ ͒ lation rate is conveniently expressed as =ln 2 /Td, whereTd is the effective tumor doubling time. Regional differences in 1/n n ͑ ͒ Deff = ͚ͩ viDi ͪ , 3 cell proliferation within the tumor can be accommodated by i adjusting the ␥ parameter. Other effects associated with dif- where Deff is the dose that, if given uniformly to the entire ferences in tumor radiation sensitivity parameters among pa- volume, will lead to the same NTCP as a nonuniform dose tients ͑interpatient heterogeneity͒ and within the tumor ͑in- ͑ ͒ ͑ ͒ distribution Deff is sometimes referred to as equivalent uni- tratumor heterogeneity are implicit in Eq. 4 , i.e., within ͒ ͑ ͒ form dose, EUD , TD50 is the uniform dose given to the the S Di term. entire organ volume that results in a 50% risk of complica- The estimation of radiobiologic parameters from a patient tions, m is a measure of the slope of the sigmoid curve rep- population with heterogeneous radiation response parameters resented by the integral of the normal distribution, n is a is notoriously challenging.40 Also, the Poisson TCP model parameter that describes the magnitude of the volume effect, does not provide a fully adequate representation of the sta- and Di and vi are the dose and fractional volume, respec- tistical aspects of tumor growth kinetics during a course of tively, of each bin used to tabulate the differential DVH. radiation therapy.41,42 The Logistic or Gompertz growth ki- The LKB model has been widely used as an auxiliary tool netic models43–45 may be more appropriate than the simple to evaluate and compare treatment plans,30–32 guide dose- exponential growth kinetics used in many tumor control escalation studies,33,34 and select tumor doses for new models, including Eq. ͑4͒.

Medical Physics, Vol. 34, No. 10, October 2007 3741 R. D. Stewart and X. A. Li: Biologically guided radiation therapy 3741

Despite the limitations and approximations, the Poisson misrepair,53,54 gives rises to intra- and interchromosomal and TCP model provides some potentially useful constraints to chromatid aberrations, some of which render cells unable to guide the selection of dose distributions needed to achieve produce viable progeny.55 tumor control. For example, in treatment planning, we are The two major evolutionarily conserved pathways avail- seeking the distribution of Di values such that the overall able to rejoin DSB in eukaryotes are homologous recombi- TCPХ1. Because the overall TCP is the product of the TCP nation ͑HR͒ and nonhomologous end joining ͑NHEJ͒.56,57 In values for all N tissue regions, the Poisson TCP model pre- the HR pathway, a damaged chromosome is aligned with an dicts that treatment failure will occur if the TCP for any undamaged chromosome that has sequence homology. The tissue region is zero. These so-called biological cold spots genetic information stored in the undamaged chromosome is may arise because some regions of tissue are underdosed or then used as a template for the repair of the damaged chro- because some tumor cells are particularly resistant to radia- mosome. Because the HR pathway has an undamaged tem- tion or are rapidly dividing. Equation ͑4͒ implies that the plate to guide the repair process, DSB may be rejoined with- 1/N ͑ ͒ equality constraint TCPi =TCP may be imposed without out any loss of genetic information i.e., correct repair .In decreasing the overall chance of achieving local tumor con- contrast, the NHEJ pathway does not require a template with ͑ ͒ ␳ ␳ ␥ ␥ trol. For the special case when 1 i = , vi =v, and i = for sequence homology. Instead, a series of proteins bind to the i=1 to N and ͑2͒ all tumor cells are equally sensitive to break-ends of the DSB, some of which have exo- and endo- radiation, the Poisson TCP model predicts that the optimal nuclease activity that is responsible for the removal of dam- ͑ ͒ dose distribution is a uniform dose distribution, i.e., Di =D aged nucleotides, and directly rejoin ligate the break. In for i=1 to N ͑see also Webb et al.1͒. The observation that the CHO-K1 cells, the rejoining of DSBs formed by the I-SceI overall TCP is a product of TCP values for a series of sub- endonuclease produces deletions of 1 to 20 base pair ͑bp͒.58 volumes also provides some justification for the use of the Rare deletions up to 299 bp as well as the aberrant insertion EUD concept16 as a surrogate dosimetric quantity for the of 45 to 205 bp also occur.58 Ionizing radiation can create assessment and intercomparison of treatment plans.46 That is, DSBs composed of more than 10 or even 20 lesions,59 and uniform and nonuniform dose distributions are biologically the NHEJ pathway is unlikely to correctly repair complex equivalent, as long as they produce the same overall TCP. DSBs such as those formed by ionizing radiation.57 That is, correct rejoining of the DSB formed by ionizing radiation is unlikely to be synonymous with correct repair ͑restoration of II.C. Cell death and the double strand break the original base pair sequence͒. Instead, correct DSB rejoin- Models for local tumor control and, to a lesser extent, ing most likely produces small-scale mutations ͑deletions, normal-tissue complications, are intimately linked to the re- insertions, or other sequence alterations͒. A subset of these productive death or outright killing of cells by radiation. Re- small-scale mutations may be lethal. Also, unrepairable or productive death may be defined as some form of molecular incompletely repaired DSB may contribute directly or indi- or cellular damage that suffices to permanently inhibit cell rectly to cell killing. division, whereas cell death encompasses apoptosis, necro- Although DSB are widely viewed as the most critical sis, mitotic catastrophe, and other more immediate modes of form of DNA damage produced by radiation, other types of cell dissolution. Reproductive death suffices to achieve local clustered damage are still potentially significant. For ex- tumor control, although apoptosis and other cell dissolution ample, several experiments have shown that complex single modes are certainly an effective way to permanently inhibit strand breaks ͑SSBs͒ or other forms of nonDSB clustered cell division. Decades of research on the mechanisms of for- damage can sometimes be converted into a DSB as a result mation and consequences of chromosome aberrations21,47,48 of unsuccessful excision repair.60,61 The formation of addi- provide a conceptually appealing framework to link double tional DSB through the unsuccessful excision repair of non- strand break ͑DSB͒ induction and processing to reproductive DSB clustered damage may result in additional binary mis- cell death. A DSB is formed when the passage of radiation repair and, ultimately, increase the yield of lethal exchanges, through a cell creates a cluster of DNA lesions that effec- or at the very least, increase the yield of small-scale muta- tively cuts the DNA double helix into two smaller pieces. tions and unrepairable or incompletely repaired DSB. Obser- Experiments have shown that the yield of many types of vations such as these suggest that complex clustered damage, clustered DNA lesions, including DSB, are proportional to and repair mechanisms other than NHEJ and HR ͑e.g., exci- absorbed doses up to several hundred Gy for low and high sion repair͒, impact on a cell’s ability to tolerate radiation LET radiation.49–52 Experiments such as these imply that damage ͑see also the review by Wallace62͒. single-hit mechanisms are responsible for the induction of Despite the potential appeal of attributing cell death ex- DSB and other types of clustered damage by radiation. clusively to the induction and processing of DNA damage, Once formed, the break-ends associated with one DSB other biological processes are known to modulate the appar- may be rejoined to their correct partner ͑correct rejoining͒ or ent survival response of cells exposed to ionizing radiation. to a break-end associated with a different DSB ͑incorrect For example, low dose,63 microbeam,64–66 and medium rejoining͒. A third alternative is that one or both break-ends transfer experiments67 provide compelling evidence that cells may never be rejoined to another break-end ͑incomplete re- damaged by radiation communicate with undamaged ͑by joining or an unrepairable DSB͒. The breakage and incorrect stander͒ cells through factors transmitted through the extra- reunion process, which has also been referred to as binary cellular matrix68 and through gap junctions.69,70 Intercellular

Medical Physics, Vol. 34, No. 10, October 2007 3742 R. D. Stewart and X. A. Li: Biologically guided radiation therapy 3742 signals communicated to bystander cells initiate many of the deliver a fraction in IMRT has the potential to have a signifi- same effects as direct cellular irradiation,71,72 including cant impact on tumor control for tumors with a low ␣/␤ ratio signal-mediated death. It is likely that radiation-damaged and a short repair half-time.73 cells also respond to intercellular signals, although their re- Although the mechanistic basis of the LQ has been chal- sponse to these signals may or may not be the same as the lenged and remains open to vigorous debate,74–77 the inter- ones exhibited by bystander cells. pretation of the LQ survival model in terms of DSB induction and processing provides an explanation for the linear- quadratic dependence on dose of the surviving fraction and, II.D. Linear-quadratic survival model equally important, provides a conceptual framework to un- In the LQ survival model, the fraction of cells that survive derstand the interplay between damage repair processes and absorbed dose D ͑Gy͒ may be conveniently written as dose protraction ͑dose rate͒ effects. Studies showing that defects in DSB repair mechanisms reduce cell survival directly GD S͑D͒ = expͫ− ␣Dͩ1+ ͪͬ. ͑5͒ implicate DSB processing in survival responses.78,79 In addi- ␣ ␤ / tion, positive correlations among chromosomal damage and When interpreted in terms of the induction and processing of clonogenic survival provide strong circumstantial evidence DSB, the ␣D term represents the expected number of lethal that DSB induction and processing is an important cell kill- 80 damages arising from DSB formed by the same track ͑hit͒, ing mechanism. In one study, Cornforth and Bedford dem- including possibly unrepairable DSB, small-scale mutations onstrated that, in plateau-phase cultures of AG1522 normal ͑correct but error-prone DSB rejoining͒ and complete or in- human fibroblasts, asymmetric exchanges exhibited a near complete intratrack binary misrepair. This latter process may one-to-one correlation with the logarithm of the surviving occur when multiple DSB are formed by the same track. The fraction, as would be predicted by Eq. ͑5͒ when ␣D ␤GD2 term represents the formation of lethal exchanges +␤GD2 is interpreted as the expected number of lethal aber- through the pairwise interaction of break-ends associated rations per cell. Studies such as this one suggest that the with DSB created by different tracks, i.e., intertrack binary conversion of DSB into lethal exchanges through intra- and misrepair. Because DSB rejoining by HR requires an intact intertrack binary misrepair are an especially important cell- chromosome with sequence homology to act as a template killing mechanism and provides some justification for confor repair, the intra- and intertrack binary misrepair reactions sidering the LQ as more than a purely phenomenological responsible for the formation of most exchanges are likely model. accomplished by NHEJ rather than HR. The mathematical simplicity of the LQ survival model is The Lea-Catcheside dose-protraction factor G is given both its strength and weakness. Low-dose hyper- 81–83 by23 radiosensitivity and adaptive responses notwithstanding, ϱ the strength of the LQ is that trends in clonogenic survival 2 t ͵ ˙ ͑ ͒͵ Ј ˙ ͑ Ј͒ −␭͑t−tЈ͒ ͑ ͒ can often be adequately predicted in vitro and in vivo using a G = 2 dtD t dt D t e , 6 D −ϱ −ϱ minimum number of adjustable parameters ͑␣, ␣/␤, and ␭ or ␶͒. However, when contrasted to the underlying biology, the ˙ −1 where D͑t͒ is the instantaneous absorbed dose rate ͑Gy h ͒ LQ model can only be viewed as a highly idealized repre- at time t͑h͒. This dose rate function captures the temporal sentation of a very complex, time-dependent sequence of pattern of radiation delivery in its entirety, including split- biophysical events and processes. That is, the aggregate ef- dose and multifraction irradiation schemes. The biophysical fects of many time- and cell-cycle dependent processes are interpretation of Eq. ͑6͒ is that break-ends associated with a represented by a single set of time- and cell-cycle indepen- DSB created at time tЈ may, if it is not first rejoined to its dent radiosensitivity parameters, ␣, ␣/␤, and ␭ ͑or ␶͒. This correct partner, interact with break-ends associated with a oversimplification of the underlying biology implies that the second DSB produced at time t. The rate of DSB rejoining is collective radiation response of a population of cells, even if characterized by ␭ or, alternatively, the effective half-time this cell population has uniform and stable genetic traits, is for DSB repair, ␶ϵln 2/␭. In the LQ model, cellular radia- determined by a distribution of values for ␣, ␣/␤, and ␭ tion sensitivity is characterized by three biological param- rather than one ͑true͒ set of values. This inherent variability −1 −1 eters: ␣͑Gy ͒, ␣/␤͑Gy͒, and ␭͑h ͒ or ␶͑h͒. For the special in cellular radiosensitivity is further amplified by a host of case when ͑1͒ time to deliver each fraction is short compared other patient- or tumor-specific factors.84–86 to the repair half-time and ͑2͒ the time interval between frac- Our ability to accurately estimate a TCP using the LQ tions is large compared to the protraction for n daily frac- model is ultimately limited by our lack of knowledge of the 22 tions is G=1/n. For situations in which the fraction deliver most appropriate parameter distributions for ␣, ␣/␤, and ␭ time is not short compared to the repair half-time ͑e.g., see and by our incomplete knowledge of how well the LQ model 73 Wang et al. ͒, the formula relates dose to clonogenic survival ͑reproductive death͒.To reduce the possibility that treatment plans are inappropriately G1 2 G = = ͑e−x + x −1͒, ͑7͒ overoptimized for a specific combination of radiosensitivity n nx2 parameters, distributions of values for ␣, ␣/␤, and ␭ should ϵ ͑ ͒ ␶ is more appropriate. Here, x ln 2 T1 / and T1 is the frac- be used to predict treatment indicators ͑e.g., EUD or BED͒ tion delivery time ͑time to deliver one fraction͒. The time to and outcomes rather than point estimates.87–90 The use of

Medical Physics, Vol. 34, No. 10, October 2007 3743 R. D. Stewart and X. A. Li: Biologically guided radiation therapy 3743

͑ ͒ ͑ ͒ FIG. 1. Prescription doses for the treatment of prostate cancer equivalent to 37 daily fractions of 2 Gy filled circle . A fraction delivery time T1 parameter ͓ ͑ ͔͒ ͑ ͒ of 10 min is used to compute G1 for all treatments refer to Eq. 7 . Solid lines denote prescription doses estimated using the Fowler et al. Ref. 91 radiosensitivity parameters. Dashed lines indicate prescription doses estimated using the Wang et al. ͑Ref. 92͒ radiosensitivity parameters. parameter distributions in treatment planning applications Although uncertainties in radiosensitivity parameters ap- can help quantify uncertainties in treatment outcomes arising pear an overwhelming obstacle for the direct application of from the inherent variability in radiosensitivity parameters, biological models in treatment planning, many issues associ- as well as from the use of an oversimplified or incomplete ated with the inadequacy of biological models and radiosen- model, such as the LQ, to predict cell killing. sitivity parameters can be circumvented through the use of isoeffect calculations. Consider as an example the task of identifying biologically equivalent prescription doses for the II.E. Biologically guided prescription dose and individualized treatments treatment of prostate cancer. To identify isoeffective total treatment doses, correct Eq. ͑5͒ for repopulation effects and For many reasons, estimates of radiobiological parameters then take the logarithm and apply the quadratic formula to derived from clinical data often have substantial levels of obtain uncertainty. To illustrate, an analysis of clinical data for pros- 91 tate cancer by Fowler et al. suggests the following radi- ␣/␤ ͱ 4G͑ln S − ␥T͒ −1 −1 ͭ ͮ ␣ ͑ D = −1+ 1− osensitivity parameters: =0.039 Gy 0.0196 Gy , 2G ␣͑␣/␤͒ 0.0587 Gy−1͒, ␣/␤=1.49 Gy ͑1.25 Gy,1.76 Gy͒, ␶=1.49 h ͑1.42 h,2.86 h͒, and T is effectively infinite. The values in ␣/␤ 4G ␥T d = ͭ−1+ͱ1+ ͩBED + ͪͮ. ͑8͒ parentheses are the estimated 95% confidence interval for the 2G ␣/␤ ␣ parameters. Because the effective tumor doubling time is effectively infinite, the value of Tlag has no impact on tumor To identify isoeffective prescription doses, S or equivalently control calculations. A similar analysis of clinical data for BEDϵ−ln S/␣ are held constant ͑e.g., S=1.36ϫ10−3 for the prostate cancer by Wang et al.92 suggests the alternate Fowler et al. parameters and S=1.53ϫ10−7 for the Wang et radiosensitivity parameters: ␣=0.15±0.04 Gy−1, ␣/␤ al. parameters͒ in Eq. ͑8͒ while GХ1/n ͑protraction factor͒ ␶ ͑ ͒ =3.1±0.5 Gy, =0.267 h but less than 1.5 h , Td =42 days, and T ͑total treatment time͒ are adjusted to reflect other frac- and Tlag=0 days. The observation that two different groups tionation schedules of interest. Figure 1 shows the biologi- can analyze similar datasets and arrive at very different sets cally equivalent ͑isosurvival͒ prescription doses derived us- of radiosensitivity parameters undermines confidence in the ing Eq. ͑8͒. Despite the seemingly large differences in direct application of biological models for the prediction of Fowler et al. and Wang et al. parameters and predicted clini- treatment outcomes. For a representative treatment consist- cal outcome ͑S=10−3 or 10−7͒, both sets of radiosensitivity ͑ ͒ ing of 37 daily fractions of 2 Gy with T1 =10 min , the sur- parameters predict quite similar prescription doses for n=1 viving fraction obtained with the Fowler et al. parameters is to 50. For n=23 to 50, the isoeffective fraction sizes pre- 1.36ϫ10−3 and the surviving fraction obtained with the dicted with both sets of radiosensitivity parameters differ Wang et al. parameters is 1.53ϫ10−7. Calculations such as from each other by less than 3%. this one further undermine confidence in our ability to reli- The results shown in Fig. 1 demonstrate that the seem- ably predict treatment outcomes. ingly large differences in the population-averaged radiosen-

Medical Physics, Vol. 34, No. 10, October 2007 3744 R. D. Stewart and X. A. Li: Biologically guided radiation therapy 3744

FIG. 2. Potential impact of interpatient heterogeneity on the determination of isoeffective prescription doses. All prescription doses are equivalenttoa ͑ ͒ ͑ ͒ reference treatment composed of 37 fractions of 2 Gy filled circles . A fraction delivery time T1 parameter of 10 min is used to compute G1 for all treatments ͓refer to Eq. ͑7͔͒. The solid and dotted lines are the mean and 95% confidence interval, respectively, derived from estimated prescription doses for 104 patients. Patient radiosensitivity parameters sampled from a uniform probability density function using Monte Carlo methods: ␣ ͑0.1 Gy−1 to 0.3 Gy−1͒, ␣ ␤ ͑ ͒ ␶ ͑ ͒ ͑ ͒ / 1Gyto10Gy, 0.1 h to 6 h , and Td 30 d to 365 d . sitivity parameters reported by Fowler et al.91 and Wang the form of a clinically accepted treatment, is explicitly con- et al.92 have a modest impact on estimates of isoeffective sidered ͑e.g., the filled circles in Figs. 1 and 2͒. In addition, prescription doses. However, patients treated in the clinic Eq. ͑8͒ suggests an easy way to manage the inherent risks exhibit different responses to the same prescription dose. To associated with altering an accepted treatment, i.e., manage illustrate the potential impact of this interpatient heterogene- risk by making small rather than large changes in the number ity on estimates of isoeffective prescription doses, consider a of daily fractions. The results shown in Figs. 1 and 2 suggest scenario in which radiosensitivity parameters for a hypotheti- that a change from 37 fractions of 2 Gy to n=30orton cal patient population are randomly distributed in the follow- =50 may be accomplished with a nominal risk for altered ing range: ␣ ͑0.1 Gy−1 to 0.3 Gy−1͒, ␣/␤ ͑1Gyto10Gy͒, ␶ tumor control. Large changes in an accepted treatment ͑e.g., ͑ ͒ ͑ ͒ 0.1 h to 6 h , and Td 30 d to 365 d . This range of param- n=37 to n=5 or 10͒ are potentially risky because of interpa- eters encompasses a large portion of the radiosensitivity patient heterogeneity. Large changes in an accepted treatment rameters typical of mammalian cells. To identify an isoeffec- are also risky because altering the fractionation schedule may tive prescription dose, a patient’s radiosensitivity parameters substantially alter normal tissue toxicity. Small changes in an are sampled using Monte Carlo methods and used to com- accepted treatment plan are also advisable to minimize the pute S for a reference treatment ͑i.e., 37 fractions of 2 Gy͒. potential for unanticipated consequences associated with the Equation ͑8͒ is then used to compute isoeffective prescrip- approximations and simplifications inherent in the LQ model tion doses for that patient by changing n͑GХ1/n͒ and T.A and other biological factors, e.g., bystander effects and low- distribution of isoeffective doses can be constructed by re- dose hyper-radiosensitivity. peating this algorithm for the entire patient population. Fig- In addition to interpatient heterogeneity, radiosensitivity ure 2 shows the mean ͑solid line͒ and 95% confidence inter- parameters vary within a tumor, because, for example, of val ͑dashed lines͒ on isoeffective prescription doses for 104 genomic instability and developmental or functional distur- patients. For small changes in the number of fractionation bances in tumor vasculature. Developmental and functional ͑e.g., n=30to40͒, isoeffective prescription doses are nearly disturbances in the tumor vasculature produce varying levels the same for all patients despite substantial levels of interpa- of acute and chronic hypoxia93 and are often associated with tient variability in radiosensitivity parameters. For more radi- more advanced stages of disease.94,95 Cells irradiated under cal changes in the number of fractionation ͑e.g., n=5 or 10͒, hypoxic conditions are much less sensitive to radiation, and differences in radiosensitivity parameters among the hypo- substantially higher doses may be necessary to inactivate tu- thetical patient population give rise to substantial differences mor cells in regions of a tumor with intermediate or extreme in the predicted isoeffective prescription doses. levels of hypoxia. Intratumor variations in radiosensitivity An appealing aspect of using isoeffect methods for treat- parameters enhance the risks associated with making large ment planning is that clinical judgment and experience, in changes in clinically accepted treatment plans. However, in-

Medical Physics, Vol. 34, No. 10, October 2007 3745 R. D. Stewart and X. A. Li: Biologically guided radiation therapy 3745 tratumor heterogeneity is also a potential opportunity to im- and Wang et al.92 for prostate cancer, estimates of biological prove treatment outcomes through techniques such as “dose parameters derived from clinical data are averaged over a painting by numbers.”96–98 The objective of dose painting by patient population and often have a high degree of uncer- numbers is to use biological information to identify a dose tainty. However, as Figs. 1 and 2 illustrate, uncertainties in distribution that achieves biological rather than physical biological parameters can be substantially mitigated through ͑dose͒ conformity. the use of isoeffect calculations. Regardless, the path to im- The attempt to identify a biologically conformal dose dis- proved modeling of treatment outcomes will most likely re- tribution can be cast in terms of isoeffect calculations. To quire a multifaceted, iterative research program that includes illustrate, imagine that a technique is developed to noninva- better documentation of dosimetric and biological informa- ͑ ͒ sively estimate oxygen pO2 levels within a tumor. The tion for individual patients as well as additional effort to measured pO2 level can then be converted to an oxygen en- improve the accuracy of dose delivery for a variety of treat- ͑ ͒ 99 ͑ hancement ratio OER using the formula OERi = mK ment modalities. As suitable clinical datasets accumulate, it ͓ ͔ ͒ ͑ ͓ ͔ ͒ ͓ ͔ + O2 i / K+ O2 i , where m=2.7, K=0.25, and O2 i de- may become possible to extract patient-specific radiosensi- notes the oxygen concentration in the ith region of the tumor. tivity parameters for use in outcome modeling. Even incom- ͑ ͒ This OER may be interpreted as the ratio of the dose to the plete biological information e.g., information on pO2 levels hypoxic cells to the dose to the aerobic cells required to has the potential to substantially enhance the treatment plan- produce the same number of DSB per cell,99 and it ranges ning process by guiding the selection of appropriate, patient- from one for fully aerobic cells to about three for extreme specific dose distributions. levels of hypoxia. The analyses of Carlson et al.99 suggest that OER values are nearly independent of cellular radiation III. CLINICAL IMPLEMENTATION OF BGRT sensitivity ͑i.e., ␣ and ␣/␤͒. Although isoeffect calculations provide useful techniques For cells irradiated in vitro, Carlson et al.99 have shown to guide the RT planning process even without patient- that radiosensitivity parameters for hypoxic ͑H͒ and aerobic specific information, the full benefits of BGRT can only be ͑A͒ cells are well approximated by ␣ =␣ /OER and H A realized in the clinic when new methods and technologies ͑␣/␤͒ =OER͑␣/␤͒ . The relationships among radiosensi- H A become available to assess and predict patient-specific radia- tivity parameters for aerobic and hypoxic cells imply that the tion responses. The effort to implement biologically optimal dose to regions of the tumor with reduced oxygen levels treatment plans within the clinic will also require research to needs to be increased by a factor equal to the OER to achieve address practical issues associated with the accurate delivery the same surviving fraction as well oxygenated regions of the of spatially and temporally complex dose distributions. In tumor.99,100 Hence, a biologically conformal dose distribution this section, we briefly discuss using biological images to might be achieved by designing a treatment to deliver dose acquire patient-specific biological information for BGRT. A D =OER ·D to the ith region of the tumor. Here, D is a i i three-phase strategy for the clinical implementation of BGRT clinically accepted prescription dose. is proposed. Other new technologies not discussed here, such The suggested approach to individualize a treatment to as DNA microarrays,103,104 also have substantial potential to correct for the effects of hypoxia will necessitate a validated aid in the clinical implementation of BGRT. technique to determine pO2 levels within the tumor. In addition, the application of the suggested strategy is not without III.A. Extracting radiosensitivity parameters from risk because of uncertainties associated with the formula to biological imaging determine the OER. However, the observation that isoeffect calculations are relatively insensitive to uncertainties in bio- Recent advances in biological and functional imaging logical parameters ͑e.g., Figs. 1 and 2͒ suggests that the ap- have significantly increased the likelihood that BGRT will be proach may still provide useful guidance for treatment indi- implemented in the clinic in the next decade. In particular, vidualization. The example also illustrates how future positron emission tomography ͑PET͒ and functional mag- technological developments and knowledge of the molecular netic resonance imaging ͑fMRI͒ have become widely used in and cellular mechanisms underlying radiation sensitivity the clinic in recent years. In addition to 18F-labeled fluoro- might be translated into the clinic and used to guide the deoxyglucose ͑FDG͒ PET imaging, which is the most com- treatment planning process. monly used tracer and is likely associated with local radiosensitivity including tumor burden and hence of clonogen density ͑␳ parameter in Eqs. ͑4͒ and ͑7͒͒, tracers of hypoxia II.F. Research needs for outcome modeling i ͑misonidazole͒, angiogenesis ͑AV␤3 integrin͒, glucose me- Outcome modeling is challenging in part because biologi- tabolism ͑labeled FDG͒, amino acid metabolism ͑labeled ty- cal parameters used in these models are patient, tumor, and rosine, methionine͒, and tumor cell proliferation ͑labeled organ specific101,102 and in part because TCP and NTCP mod- thymidine͒ are being developed.105–107 Several fMRI tech- els are highly nonlinear. That is, seemingly small, patient- niques under development are expected to provide tumor specific differences in physical or biological factors can re- physiological and micro-environmental information, such as sult in very different clinical outcomes for treatment plans blood flow ͑perfusion or diffusion͒, angiogenesis, hypoxia, that are otherwise identical. As illustrated by the very differ- and pH, and to identify radiation sensitive regions in normal ent radiosensitivity parameters reported by Fowler et al.91 tissues,105,108–110 for several tumor sites including brain,

Medical Physics, Vol. 34, No. 10, October 2007 3746 R. D. Stewart and X. A. Li: Biologically guided radiation therapy 3746

sion 20/20 paper will be devoted to the important role that biologic and functional imaging will undoubtedly play in BGRT.

III.B. Three-phase strategy for the clinical implementation of BGRT Technologies for RT delivery, such as IMRT, image- guided IMRT ͑IG-IMRT͒, novel brachytherapy, targeted RT, and proton and heavy ion therapy, have rapidly advanced over the last ten years, and this trend will most likely continue for the next decade. Advances in RT delivery, particularly in IG-IMRT, will enable the direct integration of not only anatomic, but also biological images into treatment units to guide the delivery process. The 4D ͑space+time͒ FIG. 3. Simplified relationships between relative cerebral blood volume anatomic and biological imaging using CT, MRI, PET and ͑rCBV͒ and ␣ ͑solid line͒ or ␣/␤ ͑dashed line͒ for malignant glioma ͑Ref. other modalities will enable the treatment of moving targets ͒ 114 . and substantially reduce ͑or eliminate͒ the inadvertent irradiation of normal tissues. Techniques for charged particle ͑e.g., protons, helium, and carbon ions͒ therapy will advance prostate, and cervix. Regions of tumor burden can also be and provide new capabilities in the clinic for delivery of ͑ ͒ 111,112 identified through the use of MR spectroscopy MRS . biologically conformed RT. A growing trend in biological imaging is the incorporation of 113 Although the physical and biological methods and tech- multiple imaging modalities into the same system. nologies needed to implement BGRT are advancing quickly To design biologically conformal, patient-specific treat- and hold great promise for the future of RT, the potential ments, methods are needed to relate information from costs of implementing some technologies may be found pro- patient-specific functional and biological images to radiosen- hibitive for routine use in the clinic. The integration of the ͑ ␣ sitivity parameters used in NTCP and TCP models e.g., , multiple technologies required for BGRT will require exten- ␣ ␤ ␶ ␳͒ / , , and . Biological imaging typically provides nu- sive clinical validation. In particular, the use of incomplete or merical information that reflects some regional biological inaccurate biological information to preferentially target se- characteristic of the tumor or a critical structure relative to a lected regions of a tumor at the expense of other tumor re- well-defined standard. One way to use this information to gions may jeopardize treatment outcomes. For reasons such guide the treatment planning process is to separate patients as these, we believe an incremental approach is advisable for into several groups of patients with similar tumor and/or nor- the clinical implementation of BGRT, as illustrated in Fig. 4 ͑ mal tissue response characteristics. An empirical trial and and briefly explained below. error͒ approach could then be used to identify a biologically optimal treatment regimen for each patient group. An alternative, potentially faster and more conceptually appealing III.B.1. Phase I population based treatments method is to develop rules to transform regional ͑voxel- based͒ signal information into patient-specific estimates of the parameters used in outcome modeling ͑e.g., ␣, ␣/␤, ␶, • Use anatomic and biological images to define targets and ␳͒. Then, isoeffect methods such as the ones outlined in and important organs. Sec. II E can be used to guide the selection of patient- • Use historical and empirical knowledge of tumor and specific dose distributions. normal tissue responses to select population-based pre- Although the effort to correlate information from func- scriptions corrected for tumor type, stage, location, and tional and biological imaging with the radiosensitivity pa- prior and/or concurrent treatment modalities. The pre- rameters is nontrival, substantial progress in this area is scription may use dose as surrogate and may require likely in the next ten years. For example, as reported uniform dose within the target. recently,114 relative cerebral blood volume ͑rCBV͒ maps can • Identify single or combined RT modality ͑e.g., IMRT, be obtained with dynamic susceptibility contrast-enhanced 3DCRT, brachytherapy͒ based on their dose volume MRI techniques and combined with tumor grade and radi- merits and generate plans according to the prescription. osensitivity information112,115 to delineate spatial distribu- • Evaluate the plan using dose volume parameters as the tions of the ␣ and ␣/␤ radiosensitivity parameters. Figure 3 primary criteria and outcome prediction ͑e.g., EUD, shows a simplified relationship between rCBV and radiosen- TCP, and NTCP or the method outlined in Sec. II E͒ as sitivity parameters for malignant glioma.114 Additional re- secondary criteria. search is needed to develop and, especially, validate rules for • Deliver the planned treatment with IGRT. Document 3D the conversion of information from functional and biological dose maps delivered to the tumor targets and all impor- imaging into patient-radiosensitivity parameters. A future Vi- tant organs for outcome analysis.

Medical Physics, Vol. 34, No. 10, October 2007 3747 R. D. Stewart and X. A. Li: Biologically guided radiation therapy 3747

FIG. 4. Flowchart illustrating a proposed three-phase strategy to implement BGRT in the clinic.

• Periodically follow up the patient after the treatment to • Follow up the patient and analyze the data to refine the document outcome ͑e.g., local tumor control and nor- outcome prediction models and/or model parameters. mal tissue toxicities͒ and to acquire anatomic and biological images, and/or tissue assays. Correlate the out- As the clinical implementation of Phases I and II of come with information from imaging and/or assays with BGRT practice proceeds, other more aggressive treatment the dose delivered. Use these data to refine models approaches may be considered as advances in imaging, pre- and/or model parameters for radiation response dictive assays, delivery technologies, and confidence in radi- prediction. osensitivity parameters and outcome-prediction models increase. Examples of more aggressive strategies include treatment strategies to boost local tumor control, such as boosting the dose to the selected tumor regions with moder- III.B.2. Phase II boost dose to selected tumor ate decreases in the dose to other tumor regions. Or alterna- regions tively, the dose to the entire tumor region might be increased if patient-specific modeling predicts only a nominal chance normal tissue complications will increase. Potential strate- • Generate the plan according to the population-based gies to enable boosting the entire tumor dose include increas- prescription ͑Phase I͒. ing the dose to selected regions of a treatment-limiting organ • Identify target regions of the tumor that are potentially or allowing a smaller increase in the dose to large sections of radioresistant based on biological images and/or tissue one or more organs. Biological imaging or assays may be assays. used to identify these regions of the organ that are function- • Use outcome modeling and related methods to estimate ally less important. the size of the dose boost needed to enhance local tumor control in radioresistant regions of the tumor. • Develop a treatment plan using proper RT modalities III.B.3. Phase III individualized adaptive BGRT ͑e.g., IMRT, brachytherapy͒ capable of delivering the boost close to the required doses without decreasing the dose to any other region of the tumor and with no ͑or • Use the validated outcome prediction models developed minimal͒ change in the dose to all the important organs. in Phases I and II to specify nonuniform dose plans Evaluate the plan with outcome prediction models ͑e.g., using patient-specific information from imaging, predic- EUD, BED, TCP, and NTCP͒ to estimate any gain in tive assays, and outcome prediction models, taking into local tumor control. account molecular genetics and other prior and con- • Deliver the plan with IGRT and document the 3D dose comitant therapy. delivered to each patient. • After one or more treatment fractions, perform addi- • Acquire biological images and/or assays periodically tional imaging or other biomarker studies to assess the during and after the treatment. change in radiation response of the tumor and normal

Medical Physics, Vol. 34, No. 10, October 2007 3748 R. D. Stewart and X. A. Li: Biologically guided radiation therapy 3748

tissue. If changes ͑e.g., regression in tumor volume, duction of patient-specific BGRT into the clinic can be ac- change in the levels of hypoxia, accelerated repopula- celerated through a multifaceted research program to tion in certain regions, and/or deteriorated normal tissue improve biological and functional imaging, predictive as- injury͒ are observed, the treatment plan should be re- says, and biophysical modeling of treatment outcomes. New optimized to account for these changes. The new plan treatment planning tools that incorporate biological objec- should be delivered subsequently. This re-imaging and tives into the treatment planning process are also needed. replanning process should be repeated as needed con- The accumulation and analysis of clinical data for modern sidering both benefit and practicality. treatment modalities, and the preclinical and clinical evalua- • Document 3D dose delivered to each patient. tion of new tools and techniques for patient-specific treat- • Acquire additional information about treatment out- ment planning is highly desirable. comes for each patient using biologic imaging and/or Although the technologies and techniques needed for the tissue assays. full implementation of patient-specific treatment planning • Relate prior-, during-, and post-treatment data to bio- may require more than a decade to develop and validate, logical mechanisms. even the partial implementation of BGRT treatment planning has the potential to enhance local tumor control without an With such an iterative three-phase process, we believe undue increase in damage to normal tissues. The validation that BGRT may be safely introduced into the clinic. The and implementation of robust tools and technologies for the success of BGRT will ultimately hinge on three major mile- prediction of patient-specific outcomes also has the potential ͑ ͒ stones: 1 the further development and validation of out- to improve the efficiency and costs of delivering RT. Why come models for tumor response and normal tissue compli- deliver a treatment consisting of six to eight weeks of daily ͑ ͒ cations, 2 the accuracy of patient-specific radiosensitivity fractions if an alternate plan with the same treatment out- parameters derived from biological imaging and functional come can be achieved with a plan, such as stereotactic RT or ͑ ͒ assays, and 3 advances in RT planning and delivery meth- accelerated hypofractionated RT, that only requires one or odology and technology. two weeks to deliver? The coming decade will surely be an exciting time for the practice of BGRT. IV. SUMMARY ACKNOWLEDGMENT The ongoing and rapid development of RT technology, This work is supported in part by a research grant from such as IMRT, IG-IMRT, novel brachytherapy, targeted RT, Siemens Oncology Care Systems. proton and heavy ion therapies, technologies for the charac- ͒ terization of the human genome, and the dazzling advances a Author to whom correspondence should be addressed. Electronic mail: in biological and functional imaging modalities have signifi- [email protected] 1 cantly increased the potential usefulness of implementing S. Webb, P. M. Evans, W. Swindell, and J. O. Deasy, “A proof that uniform dose gives the greatest TCP for fixed integral dose in the plan- BGRT treatment planning in the clinic. Biological image mo- ning target volume,” Phys. Med. Biol. 39, 2091–2098 ͑1994͒. dalities, which are currently being introduced into the clinic, 2R. I. Mackay and J. H. Hendry, “The modelled benefits of individualizing are expected to improve the definition of tumor targets and radiotherapy patients’ dose using cellular radiosensitivity assays with in- ͑ ͒ normal structures and provide patient-specific information herent variability,” Radiother. Oncol. 50, 67–75 1999 . 3S. Levegrun, A. Jackson, M. J. Zelefsky, E. S. Venkatraman, M. W. that can be used to guide the treatment planning. New imag- Skwarchuk, W. Schlegel, Z. Fuks, S. A. Leibel, and C. C. Ling, “Risk ing modalities will also provide new opportunities to quan- group dependence of dose response for biopsy outcome after three- tify tumor and normal-tissue responses during or after a dimensional conformal radiation therapy of prostate cancer,” Radiother. Oncol. 63, 11–26 ͑2002͒. course of radiation therapy. The ability to rapidly assess 4 K. S. C. Chao, W. R. Bosch, S. Mutic, J. S. Lewis, F. Dehdashti, M. A. treatment outcomes with surrogates for long-term disease- Mintun, J. F. Dempsey, C. A. Perez, J. A. Purdy, and M. J. Welch, “A free survival will in turn speed our ability to extract useful novel approach to overcome hypoxic tumor resistance: Cu-ATSM-guided information about the biological effectiveness of alternate intensity-modulated radiation therapy,” Int. J. Radiat. Oncol., Biol., Phys. 49, 1171–1182 ͑2001͒. and refined radiation treatments. 5I. Turesson, J. Carlsson, A. Brahme, B. Glimelius, B. Zackrisson, and B. The integration of biological imaging, radiation response Stenerlow, “Biological response to radiation therapy,” Acta Oncol. 42, relationships, and knowledge of the molecular basis of can- 92–106 ͑2003͒. 6 cer has the potential to dramatically improve RT outcomes A. Brahme, J. Nilsson, and D. Belkic, “Biologically optimized radiation therapy,” Acta Oncol. 40, 725–734 ͑2001͒. by tailoring the treatment process to the biological character- 7A. Brahme, “Biologically optimized 3-dimensional in vivo predictive istics of specific patients. Combining advanced delivery assay-based radiation therapy using positron emission tomography- techniques, such as IG-IMRT, with the selection of patient- computerized tomography imaging,” Acta Oncol. 42, 123–136 ͑2003͒. 8 specific, biologically conformal prescription doses is the next S. M. Bentzen, “Radiation therapy: Intensity modulated, image guided, biologically optimized and evidence based,” Radiother. Oncol. 77,227– frontier in RT and substantial progress is likely within the 230 ͑2005͒. coming decade. We believe the three-phase strategy to imple- 9B. Vanderstraeten, W. Duthoy, W. De Gersem, W. De Neve, and H. Thie- ment BGRT in the clinic outlined in this paper has the po- rens, “͓18F͔fluoro-deoxy-glucose positron emission tomography ͓͑ ͔ ͒ tential to substantially advance patient-specific treatment 18F FDG-PET voxel intensity-based intensity-modulated radiation therapy ͑IMRT͒ for head and neck cancer,” Radiother. Oncol. 79,249– planning while minimizing the risks associated with the in- 258 ͑2006͒. troduction of new technologies for patient care. The intro- 10J. O. Deasy, “Partial tumor boosts: Even more attractive than theory

Medical Physics, Vol. 34, No. 10, October 2007 3749 R. D. Stewart and X. A. Li: Biologically guided radiation therapy 3749

predicts?” Int. J. Radiat. Oncol., Biol., Phys. 51, 279–280 ͑2001͒. and R. K. Schmidt-Ullrich, “Stereotactic body radiation therapy of lung 11W. A. Tome and J. F. Fowler, “On the inclusion of proliferation in tumour tumors: Preliminary experience using normal tissue complication control probability calculations for inhomogeneously irradiated tumours,” probability-based dose limits,” Am. J. Clin. Oncol. 28, 591–596 ͑2005͒. Phys. Med. Biol. 48, N261–N268 ͑2003͒. 36L. A. Dawson, M. Biersack, G. Lockwood, A. Eisbruch, T. S. Lawrence, 12Y. Cao, C. I. Tsien, V. Y. Nagesh, L. Junck, R. Ten Haken, B. D. Ross, T. and R. K. Ten Haken, “Use of principal component analysis to evaluate L. Chenevert, and T. S. Lawrence, “Clinical investigation survival predic- the partial organ tolerance of normal tissues to radiation,” Int. J. Radiat. tion in high grade gliomas by mri perfusion before and during early stage Oncol., Biol., Phys. 62, 829–837 ͑2005͒. of RT,” Int. J. Radiat. Oncol., Biol., Phys. 64, 876–885 ͑2006͒. 37A. J. Hope, P. E. Lindsay, I. El Naqa, J. R. Alaly, M. Vicic, J. D. Bradley, 13M. Alber, F. Paulsen, S. M. Eschmann, and H. J. Machulla, “On biologi- and J. O. Deasy, “Modeling radiation pneumonitis risk with clinical, do- cally conformal boost dose optimization,” Phys. Med. Biol. 48, N31–N35 simetric, and spatial parameters,” Int. J. Radiat. Oncol., Biol., Phys. 65, ͑2003͒. 112–124 ͑2006͒. 14C. C. Ling and X. A. Li, “Over the next decade the success of radiation 38S. Webb and A. E. Nahum, “A model for calculating tumour control treatment planning will be judged by the immediate biological response probability in radiotherapy including the effects of inhomogeneous distri- of tumor cells rather than by surrogate measures such as dose maximiza- butions of dose and clonogenic cell density,” Phys. Med. Biol. 38,653– tion and uniformity,” Med. Phys. 32, 2189–2192 ͑2005͒. 666 ͑1993͒. 15H. R. Withers, H. D. Thames, and L. J. Peters, “A new isoeffect curve for 39W. A. Tomé and J. F. Fowler, “On the inclusion of proliferation in tumour change in dose per fraction,” Radiother. Oncol. 1, 187–191 ͑1983͒. control probability calculations for inhomogeneously irradiated tumours,” 16A. Niemierko, “Reporting and analyzing dose distributions: A concept of Phys. Med. Biol. 48, N261–N268 ͑2003͒. equivalent uniform dose,” Med. Phys. 24, 103–110 ͑1997͒. 40S. Levegrun, A. Jackson, M. J. Zelefsky, M. W. Skwarchuk, E. S. Ven- 17E. L. Travis, “Organizational response of normal tissues to irradiation,” katraman, W. Schlegel, Z. Fuks, S. A. Leibel, and C. C. Ling, “Fitting Semin. Radiat. Oncol. 11, 184–196 ͑2001͒. tumor control probability models to biopsy outcome after three- 18S. M. Bentzen, “Preventing or reducing late side effects of radiation dimensional conformal radiation therapy of prostate cancer: Pitfalls in therapy: Radiobiology meets molecular pathology,” Nat. Rev. Cancer 6, deducing radiobiologic parameters for tumors from clinical data,” Int. J. 702–713 ͑2006͒. Radiat. Oncol., Biol., Phys. 51, 1064–1080 ͑2001͒. 19J. M. Allan and L. B. Travis, “Mechanisms of therapy-related carcinogen- 41S. L. Tucker, H. D. Thames, and J. M. Taylor, “How well is the prob- esis,” Nat. Rev. Cancer 5, 943–955 ͑2005͒. ability of tumor cure after fractionated irradiation described by Poisson 20G. W. Barendsen, “Dose-survival curves of human cells in tissue culture statistics?” Radiat. Res. 124, 273–282 ͑1990͒. irradiated with alpha-, beta-, 20-kV.x- and 200-kV.x-radiation,” Nature 42S. L. Tucker and J. M. Taylor, “Improved models of tumour cure,” Int. J. 193, 1153–1155 ͑1962͒. Radiat. Biol. 70, 539–553 ͑1996͒. 21K. H. Chadwick and H. P. Leenhouts, “A molecular theory of cell sur- 43Z. Bajzer, “Gompertzian growth as a self-similar and allometric process,” vival,” Phys. Med. Biol. 18, 78–87 ͑1973͒. Growth, Dev. Aging 63, 3–11 ͑1999͒. 22H. D. Thames, “An ‘incomplete-repair’ model for survival after fraction- 44C. P. Calderon and T. A. Kwembe, “Modeling tumor growth,” Math. ated and continuous irradiations,” Int. J. Radiat. Biol. 47, 319–339 Biosci. 103, 97–114 ͑1991͒. ͑1985͒. 45H. McAneney and S. F. O’Rourke, “Investigation of various growth 23R. K. Sachs, P. Hahnfeld, and D. J. Brenner, “The link between low-LET mechanisms of solid tumour growth within the linear-quadratic model for dose-response and the underlying kinetic of damage production/repair radiotherapy,” Phys. Med. Biol. 52, 1039–1054 ͑2007͒. misrepair,” Int. J. Radiat. Biol. 72, 351–374 ͑1997͒. 46M. A. Ebert, “Viability of the EUD and TCP concepts as reliable dose 24B. Emami et al., “Tolerance of normal tissue to therapeutic irradiation,” indicators,” Phys. Med. Biol. 45, 441–457 ͑2000͒. Int. J. Radiat. Oncol., Biol., Phys. 21, 109–122 ͑1991͒. 47J. R. Savage, “A brief survey of aberration origin theories,” Mutat Res. 25C. Burman, G. J. Kutcher, B. Emami, and M. Goitein, “Fitting of normal 404, 139–147 ͑1998͒. tissue tolerance data to an analytic function,” Int. J. Radiat. Oncol., Biol., 48L. Hlatky, R. K. Sachs, M. Vazquez, and M. N. Cornforth, “Radiation- Phys. 21, 123–135 ͑1991͒. induced chromosome aberrations: Insights gained from biophysical mod- 26J. T. Lyman, “Complication probability as assessed from dose-volume eling,” BioEssays 24, 714–723 ͑2002͒. histograms,” Radiat. Res. 104, S13–S19 ͑1985͒. 49M. Frankenberg-Schwager, “Induction, repair and biological relevance of 27G. J. Kutcher and C. Burman, “Calculation of complication probability radiation-induced DNA lesions in eukaryotic cells,” Radiol. Technol. 29, factors for non-uniform normal tissue irradiation: The effective volume 273–292 ͑1990͒. method,” Int. J. Radiat. Oncol., Biol., Phys. 16, 1623–1630 ͑1989͒. 50K. Rothkamm and M. Löbrich, “Evidence for a lack of DNA double- 28R. Mohan, G. S. Mageras, B. Baldwin, L. J. Brewster, G. J. Kutcher, S. strand break repair in human cells exposed to very low x-ray doses,” Leibel, C. M. Burman, C. C. Ling, and Z. Fuks, “Clinically relevant Proc. Natl. Acad. Sci. U.S.A. 100, 5057–5062 ͑2003͒. optimization of 3-D conformal treatments,” Med. Phys. 19, 933–944 51D. Frankenberg, H. J. Brede, U. J. Schrewe, C. Steinmetz, M. ͑1992͒. Frankenberg-Schwager, G. Kasten, and E. Pralle, “Induction of DNA 29X. A. Li, J. Z. Wang, R. D. Stewart, and S. D. DiBiase, “Dose escalation double-strand breaks by 1H and 4He ions in primary human skin fibro- in permanent brachytherapy for prostate cancer: Dosimetric and biologi- blasts in the LET range of 8 to 124 keV/␮m,” Radiat. Res. 151, 540–549 cal considerations,” Phys. Med. Biol. 48, 2753–2765 ͑2003͒. ͑1999͒. 30B. Sanchez-Nieto and A. E. Nahum, “BIOPLAN: Software for the bio- 52B. M. Sutherland, P. V. Bennett, H. Schenk, O. Sidorkina, J. Laval, J. logical evaluation of radiotherapy treatment plans,” Med. Dosim. 25, Trunk, D. Monteleone, and J. Sutherland, “Clustered DNA damages in- 71–76 ͑2000͒. duced by high and low LET radiation, including heavy ions,” Phys. 31M. M. Miften, S. K. Das, M. Su, and L. B. Marks, “A dose-volume-based Medica 17͑Suppl 1͒, 202–204 ͑2001͒. tool for evaluating and ranking IMRT treatment plans,” J. Appl. Clin. 53S. B. Curtis, “Lethal and potentially lethal lesions induced by Med. Phys. 5, 1–14 ͑2004͒. radiation—A unified repair model,” Radiat. Res. 106, 252–270 ͑1986͒. 32B. Warkentin, P. Stavrev, N. Stavreva, C. Field, and B. G. Fallone, “A 54C. A. Tobias, “The repair-misrepair model in radiobiology: Comparison TCP-NTCP estimation module using DVHs and known radiobiological to other models,” Radiat. Res. Suppl. 8, S77–S95 ͑1985͒. models and parameter sets,” J. Appl. Clin. Med. Phys. 5, 50–63 ͑2004͒. 55J. S. Bedford, “Sublethal damage, potentially lethal damage, and chromo- 33C. J. McGinn, R. K. Ten Haken, W. D. Ensminger, S. Walker, S. Wang, somal aberrations in mammalian cells exposed to ionizing radiations,” and T. S. Lawrence, “Treatment of intrahepatic cancers with radiation Int. J. Radiat. Oncol., Biol., Phys. 21, 1457–1469 ͑1991͒. doses based on a normal tissue complication probability model,” J. Clin. 56S. P. Jackson, “Sensing and repairing DNA double-strand breaks,” Car- Oncol. 16, 2246–2252 ͑1998͒. cinogenesis 23, 687–696 ͑2002͒. 34K. E. Rosenzweig, J. L. Fox, E. Yorke, H. Amols, A. Jackson, V. Rusch, 57P. A. Jeggo, “The fidelity of repair of radiation damage,” Radiat. Prot. M. G. Kris, C. C. Ling, and S. A. Leibel, “Results of a phase I dose- Dosim. 99, 117–122 ͑2002͒. escalation study using three-dimensional conformal radiotherapy in the 58F. Liang, M. Han, P. J. Romanienko, and M. Jasin, “Homology-directed treatment of inoperable nonsmall cell lung carcinoma,” Cancer 103, repair is a major double-strand break repair pathway in mammalian 2118–2127 ͑2005͒. cells,” Proc. Natl. Acad. Sci. U.S.A. 95, 5172–5177 ͑1998͒. 35D. Y. Song, S. H. Benedict, R. M. Cardinale, T. D. Chung, M. G. Chang, 59V. A. Semenenko and R. D. Stewart, “A fast Monte Carlo algorithm to

Medical Physics, Vol. 34, No. 10, October 2007 3750 R. D. Stewart and X. A. Li: Biologically guided radiation therapy 3750

simulate the spectrum of DNA damages formed by ionizing radiation,” 83M. C. Joiner, P. Lambin, and B. Marples, “Adaptive response and induced Radiat. Res. 161, 451–457 ͑2004͒. resistance,” C. R. Acad. Sci. III 322, 167–175 ͑1999͒. 60V. A. Semenenko, R. D. Stewart, and E. J. Ackerman, “Monte Carlo 84S. M. Bentzen, H. D. Thames, and J. Overgaard, “Does variation in the in simulation of base and nucleotide excision repair of clustered DNA dam- vitro cellular radiosensitivity explain the shallow clinical dose-control age sites. I. Model properties and predicted trends,” Radiat. Res. 164, curve for malignant melanoma?” Int. J. Radiat. Biol. 57, 117–126 ͑1990͒. 180–193 ͑2005͒. 85S. M. Bentzen, “Steepness of the clinical dose-control curve and variation 61V. A. Semenenko and R. D. Stewart, “Monte Carlo simulation of base and in the in vitro radiosensitivity of head and neck squamous cell carci- nucleotide excision repair of clustered DNA damage sites. II. Compari- noma,” Int. J. Radiat. Biol. 61, 417–423 ͑1992͒. sons of model predictions to measured data,” Radiat. Res. 164, 194–201 86H. Suit, S. Skates, A. Taghian, P. Okunieff, and J. T. Efird, “Clinical ͑2005͒. implications of heterogeneity of tumor response to radiation therapy,” 62S. S. Wallace, “Enzymatic processing of radiation-induced free radical Radiother. Oncol. 25, 251–260 ͑1992͒. damage in DNA,” Radiat. Res. 150͑5 Suppl͒, S60–S79 ͑1998͒. 87A. Dasu, I. Toma-Dasu, and J. F. Fowler, “Should single or distributed 63H. Nagasawa and J. B. Little, “Induction of sister chromatid exchanges by parameters be used to explain the steepness of tumour control probability extremely low doses of ␣-particles,” Cancer Res. 52, 6394–6396 ͑1992͒. curves?” Phys. Med. Biol. 48, 387–397 ͑2003͒. 64T. K. Hei, L. J. Wu, S. X. Liu, D. Vannais, C. A. Waldren, and G. 88B. Warkentin, P. Stavrev, N. A. Stavreva, and B. G. Fallone, “Limitations Randers-Pehrson, “Mutagenic effects of a single and an exact number of of a TCP model incorporating population heterogeneity,” Phys. Med. a particles in mammalian cells,” Proc. Natl. Acad. Sci. U.S.A. 94, 3765– Biol. 50, 3571–3588 ͑2005͒. 3770 ͑1997͒. 89V. Moiseenko, “Effect of heterogeneity in radiosensitivity on LQ based 65J. M. Nelson, A. L. Brooks, N. F. Metting, M. A. Khan, R. L. Buschbom, isoeffect formalism for low alpha/beta cancers,” Acta Oncol. 43, 499–502 A. Duncan, R. Miick, and L. A. Braby, “Clastogenic effects of defined ͑2004͒. numbers of 3.2 MeV alpha particles on individual CHO-K1 cells,” Ra- 90J. Lian and L. Xing, “Incorporating model parameter uncertainty into diat. Res. 145, 568–574 ͑1996͒. inverse treatment planning,” Med. Phys. 31, 2711–2720 ͑2004͒. 66K. M. Prise, O. V. Belyakov, M. Folkard, and B. D. Michael, “Studies on 91J. F. Fowler, R. Chappell, and M. Ritter, “Is alpha/beta for prostate tumors bystander effects in human fibroblasts using a charged particle micro- really low?” Int. J. Radiat. Oncol., Biol., Phys. 50, 1021–1031 ͑2001͒. beam,” Int. J. Radiat. Biol. 74, 793–798 ͑1998͒. 92J. Z. Wang, M. Guerrero, and X. A. Li, “How low is the alpha/beta ratio 67C. Mothersill and C. Seymour, “Medium from irradiated human epithelial for prostate cancer?” Int. J. Radiat. Oncol., Biol., Phys. 55, 194–203 cells but not human fibroblasts reduces the clonogenic survival of unirra- ͑2003͒. diated cells,” Int. J. Radiat. Biol. 71, 421–427 ͑1997͒. 93B. G. Wouters and J. M. Brown, “Cells at intermediate oxygen levels can 68C. Mothersill and C. B. Seymour, “Cell-cell contact during gamma irra- be more important than the hypoxic fraction in determining tumor re- diation is not required to induce a bystander effect in normal human sponse to fractionated radiotherapy,” Radiat. Res. 147, 541–550 ͑1997͒. keratinocytes: Evidence for release during irradiation of a signal control- 94M. Höckel, K. Schlenger, B. Aral, M. Mitze, U. Schaffer, and P. Vaupel, ling survival into the medium,” Radiat. Res. 149, 256–262 ͑1998͒. “Association between tumor hypoxia and malignant progression in ad- 69E. I. Azzam, S. M. de Toledo, and J. B. Little, “Direct evidence for the vanced cancer of the uterine cervix,” Cancer Res. 56, 4509–4515 ͑1996͒. participation of gap junction-mediated intercellular communication in the 95K. Sundfør, H. Lyng, and E. K. Rofstad, “Tumour hypoxia and vascular transmission of damage signals from alpha-particle irradiated to nonirra- density as predictors of metastasis in squamous cell carcinoma of the diated cells,” Proc. Natl. Acad. Sci. U.S.A. 98, 473–478 ͑2001͒. uterine cervix,” Br. J. Cancer 78, 822–827 ͑1998͒. 70E. I. Azzam, S. M. de Toledo, and J. B. Little, “Oxidative metabolism, 96D. Thorwarth, S. M. Eschmann, F. Paulsen, and M. Alber, “Hypoxia dose gap junctions and the ionizing radiation-induced bystander effect,” Onco- painting by numbers: A planning study,” Int. J. Radiat. Oncol., Biol., gene 22, 7050–7057 ͑2003͒. Phys. 68͑1͒, 291–300 ͑2007͒. 71C. Mothersill and C. Seymour, “Radiation-induced bystander effects: Past 97M. Alber, F. Paulsen, S. M. Eschmann, and H. J. Machulla, “On biologi- history and future directions,” Radiat. Res. 155, 759–767 ͑2001͒. cally conformal boost dose optimization,” Phys. Med. Biol. 48͑2͒, N31– 72E. J. Hall, “The bystander effect,” Health Phys. 85, 31–35 ͑2003͒. N35 ͑2003͒. 73J. Z. Wang, X. A. Li., W. D’Souza, and R. D. Stewart, “Impacts of 98S. M. Bentzen, “Theragnostic imaging for radiation oncology: Dose- prolonged dose-delivery time on tumor control: A note of caution for painting by numbers,” Lancet 6͑2͒, 112–117 ͑2005͒. IMRT,” Int. J. Radiat. Oncol., Biol., Phys. 57͑2͒, 543–552 ͑2003͒. 99D. J. Carlson, R. D. Stewart, and V. A. Semenenko, “Effects of oxygen on 74R. K. Sachs and D. J. Brenner, “The mechanistic basis of the linear- intrinsic radiation sensitivity—A test of the relationship between aerobic quadratic formalism,” Med. Phys. 25, 2071–2073 ͑1998͒. and hypoxic linear-quadratic ͑LQ͒ model parameters,” Med. Phys. 33, 75M. Zaider, “There is no mechanistic basis for the use of the linear- 3105–3115 ͑2006͒. quadratic expression in cellular survival analysis,” Med. Phys. 25, 791– 100J. Z. Wang, X. A. Li, and N. A. Mayr, “Dose escalation to combat hy- 792 ͑1998͒. poxia in prostate cancer, a radiobiological analysis of clinical data,” Br. J. 76M. Zaider, “Sequel to the discussion concerning the mechanistic basis of Radiol. 79, 905–911 ͑2006͒. the linear quadratic formalism,” Med. Phys. 25, 2074–2075 ͑1998͒. 101M. Guerrero and X. A. Li, “Deriving radiobiological parameters from a 77D. J. Brenner and D. E. Herbert, “The use of the linear-quadratic model in large number of clinical studies for radiotherapy treatment planning of clinical radiation oncology can be defended on the basis of empirical early-stage breast cancer,” Phys. Med. Biol. 48, 3307–3326 ͑2003͒. evidence and theoretical argument,” Med. Phys. 24, 1245–1248 ͑1997͒. 102X. S. Qi, C. J. Schultz, and X. A. Li, “An estimation of radiobiologic See also the comment in Med. Phys. 24, 1329 ͑1997͒. parameters from clinical outcomes for radiation treatment planning of 78M. Kühne, E. Riballo, N. Rief, K. Rothkamm, P. A. Jeggo, and M. Lo- brain tumor,” Int. J. Radiat. Oncol., Biol., Phys. 64, 1570–1580 ͑2006͒. brich, “A double-strand break repair defect in ATM-deficient cells con- 103Y. F. Wong, D. S. Sahota, T. H. Cheung, K. W. Lo, S. F. Yim, T. K. tributes to radiosensitivity,” Cancer Res. 64, 500–508 ͑2004͒. Chung, A. M. Chang, and D. I. Smith, “Gene expression pattern associ- 79N. Chavaudra, J. Bourhis, and N. Foray, “Quantified relationship between ated with radiotherapy sensitivity in cervical cancer,” Cancer J. 12,189– cellular radiosensitivity, DNA repair defects and chromatin relaxation: A 193 ͑2006͒. study of 19 human tumour cell lines from different origin,” Radiother. 104T. Watanabe, Y. Komuro, T. Kiyomatsu, T. Kanazawa, Y. Kazama, J. Oncol. 73, 373–382 ͑2004͒. Tanaka, T. Tanaka, Y. Yamamoto, M. Shirane, T. Muto, and H. Nagawa, 80M. N. Cornforth and J. S. Bedford, “A quantitative comparison of poten- “Prediction of sensitivity of rectal cancer cells in response to preoperative tially lethal damage repair and the rejoining of interphase chromosome radiotherapy by DNA microarray analysis of gene expression profiles,” breaks in low passage normal human fibroblasts,” Radiat. Res. 111, 385– Cancer Res. 66, 3370–3374 ͑2006͒. 405 ͑1987͒. 105S. Apisarnthanarax and K. S. C. Chao, “Current imaging paradigms in 81B. Marples, B. G. Wouters, S. J. Collis, A. J. Chalmers, and M. C. Joiner, radiation oncology,” Radiat. Res. 163, 1–25 ͑2005͒. “Low-dose hyper-radiosensitivity: A consequence of ineffective cell cycle 106S. Bujenovic, “The role of positron emission tomography in radiation arrest of radiation-damaged G2-phase cells,” Radiat. Res. 161, 247–255 treatment planning,” Semin Nucl. Med. 34, 293–299 ͑2004͒. ͑2004͒. 107H. Schoder and S. M. Larson, “Positron emission tomography for pros- 82M. C. Joiner, “Induced radioresistance: An overview and historical per- tate, bladder, and renal cancer,” Semin Nucl. Med. 34, 274–292 ͑2004͒. spective,” Int. J. Radiat. Biol. 65, 79–84 ͑1994͒. 108J. L. Ulmer, C. V. Salvan, W. M. Mueller, H. G. Krouwer, G. O. Stroe, A.

Medical Physics, Vol. 34, No. 10, October 2007 3751 R. D. Stewart and X. A. Li: Biologically guided radiation therapy 3751

Aralasmak, and R. W. Prost, “The role of diffusion tensor imaging in therapy of gliomas: An application of 1H MRSI,” J. Magn. Reson Imag- establishing the proximity of tumor borders to functional brain systems: ing 16, 464–476 ͑2002͒. Implications for preoperative risk assessments and postoperative out- 113W. R. Hendee, “Biomedical imaging research opportunities workshop II: ͑ ͒ comes,” Technol. Cancer Res. Treat. 3, 567–576 2004 . A summary of ﬁndings and recommendations,” Med. Phys. 32,2484– 109 F. Z. Yetkin and D. Mendelsohn, “Hypoxia imaging in brain tumors,” 2486 ͑2005͒. ͑ ͒ Neuroimaging Clin. N. Am. 12, 537–552 2002 . 114G. P. Chen, E. Ahunbay, C. J. Schultz, and X. A. Li, “Development of an 110R. J. Gillies, N. Raghunand, G. S. Karczmar, and Z. M. Bhujwalla, “MRI inverse optimization package to plan non-uniform dose distributions of the tumor microenvironment,” J. Magn. Reson Imaging 16, 430–450 based on spatially inhomogeneous radiosensitivity extracted from biologi- ͑2002͒. 111 cal images,” Med. Phys. 34, 1198–1205 ͑2007͒. J. Kurhanewicz, M. G. Swanson, S. J. Nelson, and D. B. Vigneron, “Com- 115 bined magnetic resonance imaging and spectroscopic imaging approach to K. M. Schmainda, S. D. Rand, A. M. Joseph, R. Lund, B. D. Ward, A. P. molecular imaging of prostate cancer,” J. Magn. Reson Imaging 16, 451– Pathak, J. L. Ulmer, M. A. Baddrudoja, and H. G. J. Krouwer, “Charac- 463 ͑2002͒. terization of a ﬁrst-pass gradient-echo spin-echo method to predict brain 112S. J. Nelson, E. Graves, A. Pirzkall, X. Li, A. Chan, D. B. Vigneron, and tumor grade and angiogenesis,” AJNR Am. J. Neuroradiol. 25, 1524– T. R. McKnight, “In vivo molecular imaging for planning radiation 1532 ͑2004͒.

Medical Physics, Vol. 34, No. 10, October 2007 Radiological interpretation 2020: Toward quantitative image assessment ͒ John M. Boonea University of California, Davis, UC Davis Medical Center, 4860 Y Street, Ellison Building Suite 3100, Sacramento, California 95817 ͑Received 6 July 2007; revised 30 August 2007; accepted for publication 31 August 2007; published 15 October 2007͒ The interpretation of medical images by radiologists is primarily and fundamentally a subjective activity, but there are a number of clinical applications such as tumor imaging where quantitative imaging ͑QI͒ metrics ͑such as tumor growth rate͒ would be valuable to the patient’s care. It is predicted that the subjective interpretive environment of the past will, over the next decade, evolve toward the increased use of quantitative metrics for evaluating patient health from images. The increasing sophistication and resolution of modern tomographic scanners promote the development of meaningful quantitative end points, determined from images which are in turn produced using well-controlled imaging protocols. For the QI environment to expand, medical physicists, physicians, other researchers and equipment vendors need to work collaboratively to develop the quantitative protocols for imaging, scanner calibrations, and robust analytical software that will lead to the routine inclusion of quantitative parameters in the diagnosis and therapeutic assessment of human health. Most importantly, quantitative metrics need to be developed which have genuine impact on patient diagnosis and welfare, and only then will QI techniques become integrated into the clinical environment. © 2007 American Association of Physicists in Medicine. ͓DOI: 10.1118/1.2789501͔

Key words: quantitative imaging, cancer, computed tomography ͑CT͒, positron emission tomography ͑PET͒, single photon emission computed tomography ͑SPECT͒, magnetic resonance imaging ͑MRI͒

I. CURRENT STATUS MRI, ultrasound, SPECT, and PET becoming the predomi- Radiological diagnosis performed by radiologists in the cur- nant modalities used in imaging today’s patients. The poten- ͑ ͒ rent era is almost completely qualitative. Qualitative is not a tial of quantitative imaging QI from tomographic data sets bad thing—the diagnostic utility of medical imaging, with is clearly superior to that of projection images. The modern qualitative interpretation by an experienced radiologist, rep- radiology department, in the academic or private practice resents one of the greatest advances in modern medicine1 of settings, is completely digital and PACS based. Digital to- the 20th century. In the 1970s, when currently practicing mographic volume data sets lend themselves more readily to senior radiologists were trained, the practice of radiology quantitative analysis than screen-film radiographs. focused primarily on screen-film radiography. For example, Radiology residents and fellows in training now have in 1975, computed tomography ͑CT͒ was fledgling, rectilin- spent considerable time during their youth with a joystick in ear scanners were only slowly being replaced by projection their hands playing video games, defending earth from the nuclear scanners using Anger logic, B-mode ultrasound im- Covenant, high jacking sports cars, or shooting up Liberty aging was grainy and analog, and magnetic resonance imag- City. This generation of radiologists is primed and ready to ing ͑MRI͒ was a crude sketch in Lauterbur’s laboratory do real time fly-bys of patient’s high resolution 3D anatomy. book. During this era, the hallmark of a radiologist’s talents Unfortunately, the performance of current $100,000 medical lay in his or her diagnostic skills in radiographic interpreta- PACS workstations in radiology departments pale in com- tion, fundamentally a qualitative experience. While some ba- parison to the graphical capabilities of modern high-end sic quantitative measures ͑such as tumor width or anatomi- video game hardware, which typically incorporate both par- cally relevant angles͒ were and are still made on radiographs allel and pipeline processing techniques to accelerate graphic using a ruler or protractor ͑in scoliosis, for example͒, the fact visualization. is that screen-film radiography does not lend itself naturally Modern imaging systems produce images which are rich to robust quantitative methods. in quantitative information. While most tomographic modalities, including ultrasound imaging and MRI, possess solid II. ROLE OF QUANTITATIVE IMAGING IN THE quantitative spatial information, CT arguably is ͑at least to- FUTURE day͒ the modality which produces image data sets which are The practice of radiology today has completely changed the richest in quantitative anatomical information. The rea- relative to 20 years ago. Radiography, even digital radiogra- sons for this are threefold: ͑1͒ CT in typical clinical practice phy, is declining as a fraction of radiologist’s workload in the has the highest spatial resolution ͑smallest voxel volume United States, with tomographic modalities such as CT, with the MTF to back it up͒ of tomographic modalities, mak-

4173 Med. Phys. 34 „11…, November 2007 0094-2405/2007/34„11…/4173/7/$23.00 © 2007 Am. Assoc. Phys. Med. 4173 4174 John M. Boone: Quantitative imaging 2020 4174 ing distance, area, and volume measurements fundamentally anatomical metrics, the lack of ionizing radiation that MRI more precise. Furthermore, linear distances ͑and thus areas offers makes it the modality of choice for many clinical ap- and volumes͒ due not suffer from geometrical distortion like plications, especially outside of cancer imaging. Depending ultrasound ͑speed of sound͒ or MRI ͑susceptibility͒ images on the pulse sequence used in MRI, the images are quantita- do—indeed, if the dimensional fidelity of a CT scan is com- tively ͑but nonlinearly͒ a function of T1 and T2 relaxation promised by something like patient motion, artifacts result phenomenon and are also dependent on the three dimen- which are easily recognized by radiologists. ͑2͒ The gray sional proton density distribution in the patient. Machine de- scale data in CT ͓Hounsfield units ͑HUs͔͒ is quantitative, pendencies such as coil sensitivity also impact the magnitude unlike any other modality in typical clinical use. The normal- of the gray scale value in MRI images. With some calibration ization of the CT projection data to incident x-ray beam in- work and judicious use of pulse sequences, MRI techniques tensity prior to backprojection results in image data which can be devised in which the gray scale is quantitatively are more reflective of the patient’s anatomy and less a func- meaningful.18,19 tion of the particulars of the modality acquisition character- 2–4 MR also has the unique ability to accurately measure vas- istics. Basic “tissue characterization” comes free in CT. cular flow, without the use of contrast agents, by capitalizing ͑ ͒ ͑ ͒ 3 Finally, the injection of iodinated or other contrast on the phase component of the RF signal. Whereas there is agents in CT provides functional information pertinent to ample use of flow effects to delineate the anatomical distri- blood flow, perfusion, vascular volume, and permeability, bution of blood vessels ͓magnetic resonance angiography and this functional data also lends itself readily to quantifi- ͑MRA͔͒, MRA for quantitative assessment of vascular flow ͓ ͑ ͔͒ cation a corollary to 2 , because the change in HUs is is not used routinely for clinical diagnosis. Calibration pro- ͑ linearly proportional to the concentration of the iodine and cedures using fluid flow phantoms may be necessary to cali- ͒ volume of contrast agent in each voxel . This makes quanti- brate and validate blood flow ͑ml/s͒ metrics. tative assessment of things like time density curves or vol- The physics of ultrasound imaging is complicated and im- ume flow more straightforward and fundamentally quantita- ages produced by this modality are characterized by direc- tive. CT is currently being exploited for clinical applications tional dependencies, due to the angular dependency of sound for its gray scale accuracy. CT is capable of quantifying the reflection and refraction at tissue interfaces. Attenuation cor- fat content in the liver,5 which is useful in determining trans- rection as a function of depth of penetration is in many cases plant appropriateness. CT is used routinely to assess the cal- ad hoc ͑e.g., time gain control curve͒. However, bulk tissue cium content in single pulmonary lesions, to determine like- properties such as the Young’s modulus can be inferred with lihood of malignancy.6,7 Bone mineral density can be sufficient calibration, and elastic20 as well as viscoelastic21 evaluated accurately using CT to determine fracture risk.8,9 properties of tissue can be measured. In cardiac and obstetric While CT currently may have a small edge in terms of ultrasound imaging, use of distance measurements are fre- anatomical ͑spatial͒ quantitative integrity, positron emission ͑ ͒ ͑ ͒ quently used, with the classic example of assessing fetal age tomography PET and to a lesser extent single photon 22,23 emission computed tomography ͑SPECT͒ have sensitivity by use of the crown-rump length. Doppler techniques are unrivaled in modern human imaging. The fundamental detec- also capable of measuring vascular flow profiles, but in cur- tion event in both PET and SPECT records the decay of a rent usage it is the relative flow that is used for diagnosis. single atom inside the patient’s body. While it is true that Doppler flow metrics are highly dependent upon the angle many thousands ͑PET͒ or millions ͑SPECT͒ of such decays that the sound beam makes with the moving medium, and are needed to produce a diagnostic image, metabolic activity thus calibration techniques for absolute flow measurements ͑18FDG PET͒ or tracer uptake ͑SPECT͒ is not only ex- would need to accommodate geometrical parameters made in tremely sensitive, but can also be quantitative when imaging each in vivo measurement. protocols are standardized and calibration techniques are ad- Despite the theoretical potential of imaging systems to hered to. The history of nuclear medicine has been rich with produce quantitative images, current scanner development quantitative imaging procedures,10,11 dating back to the has focused mostly on delivering image contrast and high 24–27 1960s,12,13 and modern nuclear imaging will almost certainly signal to noise performance. With the era of quantitative improve in terms of diagnostic utility as quantitative meth- imaging upon us, scanner manufacturers will likely want to ods are developed further ͑e.g., attenuation correction meth- include quantitative assessment in the design criteria for ods in PET/CT are just the start͒. The sensitivity and func- scanner hardware and software, and these new criteria may tional aspects of nuclear imaging suggest that quantitative pose new challenges for the medical imaging industry. For imaging techniques will have a vast role to play in a number example, proprietary postprocessing techniques are used of disease areas. across the modalities to produce better looking images, but MR imaging already provides excellent anatomical infor- in many cases these algorithms compromise the quantitative mation, and for some applications such as neuroimaging, the accuracy of the image data. It will be a challenge for equip- superior contrast resolution of MR over CT makes it useful ment vendors to reveal or at least suppress their image pro- for quantifying spatial ͑length, area, and volume͒ parameters cessing techniques such that consistent quantitative results of tumors or anatomical structures. The volumetric capabili- can be achieved across manufacturer’s platforms. This is an ties of MRI have already been exploited for a number of important concern because in hospital settings where more clinical applications.14–17 In addition, for serial follow-up of than one model of scanner exists, it is very difficult to sched-

Medical Physics, Vol. 34, No. 11, November 2007 4175 John M. Boone: Quantitative imaging 2020 4175 ule the patient to be imaged in a follow-up procedure health, and direct ͑causal͒ estimates of bone strength ͑e.g., ͑months after a previous scan͒ on exactly the same scanner. relying on bone density and architecture,41–43 coupled with an engineering model͒ will replace indirect ͑correlative͒ assessments such as bone mineral density analysis.44–46 Quan- III. THE FUTURE IS RICH WITH QI titative imaging procedures will have an impact in the assess- APPLICATIONS ment of neurological disorders and neurodegenerative The future of quantitative imaging is approaching, and diseases, for example by quantifying plaque dynamics in approaching fast. While qualitative radiological diagnosis multiple sclerosis,47–50 measuring amyloid plaque burden in will always be a significant part of what radiologists do in Alzheimer disease,51,52 and assessing cognitive response in the future, the growing requirement of evidence based medi- dementia measured using PET, fMRI, or MRS cine will create an environment where diagnoses are neces- techniques.53,54 Imaging will play an enormous role in the sarily reinforced with quantitative data, especially when the quantitative assessment of abdominal organ function-islet diagnosis leads to expensive therapeutic options. The great- cell metabolism in the pancreas, glomerular filtration rate in est driver of quantitative imaging today is in cancer therapy the kidneys,19 assessment of organ volume55 ͑with bilateral trials,28,29 where quantitative measurements of tumor charac- comparisons for paired organs͒ will prove useful in the diag- teristics ͑e.g., growth, metabolism, uptake͒ are needed to de- nosis of metabolic and infectious diseases, as well as cancer. termine tumor response to chemotherapeutic or other thera- There are numerous quantitative parameters that can be peutic actions. The cost of bringing a new drug to market is assessed on images which relate to heart function and vascu- very high, and therefore routine imaging costs are small in lar performance, such as wall motion analysis, stroke vol- comparison. It has already been demonstrated30 that in some ume, ejection fraction, and percent stenosis. The recent ad- cases quantitative imaging techniques can accurately predict vent of cardiac CT scanners suggests that some of these tumor response and therapeutic outcome, much earlier than parameters can be characterized using the four dimensional longer term outcome measures such as tumor recurrence or ͑x, y, z, and t͒ capabilities of this modality.56 death. Early predictors of a drug’s efficacy can reduce the The above examples are but the tip of the iceberg, and the time needed for clinical trials, which in turn can substantially use of the quantitative capabilities of medical imaging is reduce the cost of the trial. limited only by the creativity of the physicists and physicians While quantitative measurement of tumor response is now involved in radiology. It should be noted that QI is really a used principally in patients who are on clinical trials, ulti- superset of something already quite familiar to radiologists mately the quantitative imaging tools and communication and medical physicists—that being computer aided detection strategies developed between radiologists and oncologists31 ͑CAD͒. With CAD, a computer searches the mathematical for clinical trials will be exploited for the standard care of topography of the digital image, and when it finds specific most cancer patients, even those not participating in clinical mathematical signatures, it responds by setting a flag or trials—but why? Drug companies typically bear the cost of painting an arrow. Fundamentally, the detection event occurs clinical trials, and thus it is in their own self interest to use owing to specific quantitative properties in that region of the tools such as QI techniques to save the costs of clinical trials. image that was flagged. In CAD, however, usually a number But if the early determination of whether a patient is benefit- of quantitative metrics are determined spatially ͑e.g., edge ing from a course of therapy is both cost effective and ben- gradient, jaggedness, texture, etc.͒ and these many interme- eficial to the patient, then will not those who pay for health diate numerical parameters are fed into a higher order dis- care want the receive the same efficiencies? Absolutely. Ac- criminator such as a neural network, which processes the curate quantitative data, including that provided by imaging inputs and computes an output, and if that output exceeds procedures, represents a rich source of objective clinical data some threshold value, then a detection event is flagged. in a world in which evidence-based procedures32–36 are re- Therefore, CAD is fundamentally a self directed quantitative imbursed. Therefore, imaging has a huge potential role to imaging procedure, however, the overall metric ͑a detection play in a future landscape where medical diagnostic and event͒ is based upon statistical classifiers or a training expe- treatment decisions are governed by this higher standard. rience over a large database of image regions with known Under payer mandates such as pay for performance,37,38 classes. Although CAD is a fundamentally quantitative tool radiologists will become accustomed to performing routine that radiologists ͑especially in mammography͒ are familiar quantitative assessments on digital image data in the cancer with, for brevity, I am limiting the scope of this essay to setting, and this gradual change in mindset will be accompa- quantitative metrics that have physical meaning to the inter- nied and reinforced by ever increasing algorithmic preting physician, such as area, volume, uptake, or metabo- sophistication,39,40 which will make the generation of quan- lism. titative metrics more efficient clinically, but also will make these quantitative metrics more accurate. The most basic metric in cancer imaging is the assessment of the change in IV. INTEGRATING QI INTO RADIOLOGICAL tumor volume between scans. Beyond cancer, the use of DIAGNOSIS quantitative imaging techniques will extend to other disease Medical physicists are ideally situated to assist, promote, settings. In musculoskeletal radiology, kinetic parameters and develop techniques for increasing the utility of quantita- which describe joint motion will help to quantify joint tive imaging techniques in radiological interpretation. Physi-

Medical Physics, Vol. 34, No. 11, November 2007 4176 John M. Boone: Quantitative imaging 2020 4176 cists can and will play an important role in understanding the specific tumor type ͑e.g., hepatocellular carcinoma͒ to a spe- quantitative potential of medical imaging procedures, but cific drug, the time between the base line scan and a given converting quantifiable metrics to medically useful diagnos- follow up scan should be controlled ͑fixed to a specific value tic information will in general require collaboration with ra- with small leeway͒, such as 3 months plus or minus 1 week. diologists or other physicians. Because of the visually based A CT protocol may scan the entire abdomen of the patient manner in which radiologists-in-training learn their craft, in using thicker CT sections at lower mA s values ͑and there- many cases they may not immediately realize that an inter- fore lower radiation levels for the same noise͒. For better pretive task could benefit from quantitative data taken from accuracy, the scan protocol could use thinner sections and the image. higher mA s near the anatomical site of known tumors to The ultimate utility of quantitative imaging depends on a produce lower noise, higher fidelity images. Contrast injec- number of important factors: ͑a͒ The clinical application for tion, if used, should be consistent in terms of type, volume which quantitative information may be useful in patient care, injected, injection rate, and delay between injection and im- and how well the quantitative metric correlates to disease aging. status, ͑b͒ the standardization and consistent use of acquisi- There are obviously a whole host of other parameters that tion protocols, ͑c͒ the logistics of calibrating the scanners to can and should be considered and set, because consistency is deliver the required quantitative information, ͑d͒ the image needed between scans to achieve accurate quantitative re- analysis tools that are used to determine the quantitative met- sults. Only a few acquisition parameters are discussed above, rics, ͑e͒ the willingness of radiologists to work with these in the interest of brevity. tools and adopt the use of quantitative metrics into their diagnostic workup, and ͑f͒ the ability of the radiology infor- IV.C. Image calibration mation system ͑RIS͒ or picture archive and communication What is the variability in CT HUs over a period of system ͑PACS͒ to archive and distribute quantitative metrics months? Is it possible for your institution to really control in specific data formats for use in other databases. I will which CT scanner is used to image the patient for follow up discuss each of these factors in the context of a straightfor- studies? If not, how does the HU and spatial accuracy ͑pixel ward and concrete clinical example, that of using CT for the size͒ vary between the brand X scanner in the main hospital evaluation of tumor growth. Although the simple determina- and the brand Y scanner in the basement? Does this matter? tion of tumor dimensions on CT should in principle be Well, of course you will not know unless you measure it, and straightforward, the state of the art implementation of this in this then suggests the use of a phantom. If the protocol in- the majority of radiology practices is surprisingly primitive. volves the injection of iodine, then this suggests that the phantom should have iodinated regions for evaluation as IV.A. Clinical application well. Iodinated regions have the potential for greater vari- Cancer patients with solid tumors undergoing chemo- ability in HU response than differences in tissue density due therapy are often subjected to serial CT studies ͑with or with- differences in spectral properties and beam hardening correc- out contrast injection͒ to evaluate whether or not the size of tions between scanner types. Why does HU accuracy matter the lesion is changing over time. This type of study requires if you are just measuring edges of the tumor? The visual that tumor size be compared at different time points during perception of the “edge” of a tumor is dependent on the the treatment. While some would argue that CT is a crude Window/Level setting in CT, and thus if constant W/L values metric to determine tumor viability compared to PET or are to be used, then the HU of the tumor and its surround MRS or other imaging biomarkers, it is nevertheless the should be reproducible as well. most ubiquitous QI measure used today and therefore serves as a good example. IV.D. Image analysis tools The RECIST criteria57 call for unidimensional measure- IV.B. Acquisition protocol ments of a tumor at its widest point in-plane and there are a The imaging physicist can and should be involved in the set of other criteria required when multiple tumors are development of CT protocols for quantitative assessment. present. Although the RECIST standard should be used short Radiation dose issues should be considered in the context of term on NCI sponsored clinical trials, with the thin section the age of the patient and the type and location of the tumor. CT imaging capabilities of modern multislice CT scanners, Knowledge of the patient’s treatment plan is important, in there is a strong sentiment in the QI community based on particular whether or not the patient is considered palliative simple reasoning that volume measurements are more accu- and whether they will be receiving radiation therapy at the rate than linear measurements. tumor site, after chemotherapy. Obviously, the CT protocols Most PACS workstations have basic measurement tools for tumor assessment in pediatric patients who are consid- such as distance and area, but these are often tedious and ered curable and who are not receiving radiation therapy time consuming to use. While there are many efforts under- should be as low in dose as reasonable, while the protocols way to build easier and more automatic tumor segmentation for CT evaluation of tumors in older patients who will be tools, getting these tools onto a given PACS system is not undergoing radiation therapy may be less stringent in terms always easy, and if these tools are to be used to affect patient of radiation dose. For the evaluation of the response of a care, then only FDA approved software packages can be

Medical Physics, Vol. 34, No. 11, November 2007 4177 John M. Boone: Quantitative imaging 2020 4177 used. Radiologists will only embrace image analysis tools if text, the quantitative result ͓which could be tumor volume, they are easy to use, intuitive, allow margin editing, and have adrenal size asymmetry, or kidney glomerular filtration rate a high degree of automation to make them quick. Clearly, ͑GFR͒, etc.͔ should be displayed graphically with other con- there is a lot of work that is necessary to bring these features textual information. For example, tumor volume could be in line with the isotropic capabilities of modern CT58 and automatically plotted as a function of time ͑incorporating with the increasing clinical caseload that most radiologists previous volume measurement information͒, adrenal organ are experiencing. Adding to the challenges of consistent sizes could be bar-charted next to each other to demonstrate quantitative assessment, the variability between scanners, asymmetry graphically, and GFR could be plotted with the workstation hardware, and PACS decision support tools is 90% and 99% normal ranges shown on the graph. Placing large. The imaging community has begun the process of de- quantitative information into context to seamlessly aid in the veloping benchmarking tools for radiologist interpretation.59 interpretation is an approach that will accelerate and promote The National Cancer Institute has led efforts to develop da- the incorporation of these numerical data into routine diag- tabases which can be used for validating and standardizing nosis. Quantitative information can and should also be dis- the performance of image analysis software,60 and this is a played in real time during interventional procedures— necessary first step along the long road of demonstrating percent reduction in perfusion after a chemoembolization consistent quantitative performance across analysis packages procedure, real time MRI assessment of tissue volume ab- and the physicians who use them. lated by high intensity ultrasound, or increase in absolute blood flow after placing a vascular stent. The ultimate incentive for radiologists to incorporate QI IV.E. Radiologist attitude into their diagnostic report is financial. The U.S. government Radiologists typically reject new mandates which slow has used financial incentives to encourage the use of new them down and the evaluation and reporting of quantitative technology in the past, as evidenced by the increased Medi- results in their dictation typically takes longer than the free care reimbursement for digital mammography compared to flow of words which is the hallmark of subjective radiologi- screen film mammography, and for the additional reimburse- cal interpretation. It would be easy to say that the onus is on ment in mammography when computer aided diagnostic radiologists to adapt to the increasing number of QI tech- tools are used. Similar incentives would expedite the use of niques that are reported in the literature, but this simply QI in the appropriate disease settings. avoids the reality of modern radiology practice in the United States. I contend, in fact, that the onus is on us, medical IV.F. PACS and RIS interfaces physicists and other researchers, to develop QI techniques which are clinically meaningful and genuinely improve ra- It is incumbent upon software engineers and PACS ven- diological diagnosis, and not just complicate it. The use of dors to provide “hooks” into the display software that com- quantitative measures needs to be obviously better to the prises a PACS program which allow researchers and others clinical radiologist for adoption. Some quantitative metrics to add QI software packages to the standard PACS display will be perceived to be better than their subjective counter- capabilities. Only if QI techniques can be bundled into an parts on face value, such as the quantitative assessment of intuitive interface on the PACS console will QI techniques tumor growth30 or kidney function.61 Most QI techniques become adopted by radiologists. The software will need to be will require comprehensive evidence to convince practitio- robust and operate in a time-efficient manner. Obviously, ners that their use will benefit patient care and thus their FDA approval for these packages is required for routine practice. Therefore, I encourage all those investigating QI clinical use, but hooks into PACS software for QI research is techniques to design experiments ͑either prospective or ret- an important start toward the long term adoption of quanti- rospective͒ which demonstrate superior, clinically relevant tative measures in imaging. outcomes with statistical significance. To encourage QI prac- Reporting quantitative metrics such as SUV or tumor vol- tices into the evidence-based medicine environment, we need ume in the free text portion of a radiologists’ report is inad- to promote and deliver evidence-based research. Of course equate and impractical. Radiology information system ͑RIS͒ all research should be based on evidence, but in the context providers need to provide the ability to define special fields of QI techniques, the evidence should be in clinical terms in the radiologist report, where specific quantitative informa- that physicians understand and consider meaningful. A new tion can be located. Examples include tumor volume or tu- QI technique may be 50% more accurate in the assessment mor SUV value, for an array of tumors a patient might have. of 18FDG uptake, but a more meaningful metric to practitio- These data fields need to be accessible by other databases, so ners is to demonstrate that this new technique predicts 5 year that tumor growth rate ͑etc.͒ can be automatically computed survival 50% better. It will be easy for a radiologist to adapt for a given patient by the push of a button. For example, one a new QI technique if he or she is convinced that this quan- cancer patient could have five distinct tumors and four dif- titative approach is better for patients. ferent CT scans over time. Hand computing 15 different vol- Furthermore, quantitative information determined either ume changes from the free text reports is too time consuming automatically or semiautomatically from images needs to be and is simply not feasible for routine care. This is what da- integrated smoothly into the interpretive environment. In- tabases and computers are supposed to do, convert menial stead of simply providing a quantitative value void of con- labor to a push button procedure, but before this happens in

Medical Physics, Vol. 34, No. 11, November 2007 4178 John M. Boone: Quantitative imaging 2020 4178 the clinical setting, the data need to be placed in specific ume and area,” Neuropsychology 21, 235–241 ͑2007͒. 17 fields so software knows where to find it. This proposition F. P. Macmaster, R. El-Sheikh, A. R. Upadhyaya, J. Nutche, D. R. Rosen- berg, and M. Keshavan, “Effect of antipsychotics on pituitary gland vol- may require the development of standards. ume in treatment-naive first-episode schizophrenia: A pilot study,” Schizophr. Res. 92, 207–210 ͑2007͒. 18R. W. Katzberg, C. L. Dumoulin, M. A. Buonocore, L. R. Opsahl, R. D. V. SUMMARY Darrow, and T. W. Morris, “Noninvasive measurement of renal hemody- There are a number of activities in place toward enhanc- namic functions using gadolinium-enhanced magnetic resonance imaging,” Invest. Radiol. 29, S123–S126 ͑1994͒. ing the development of quantitative imaging techniques. 19M. H. Buonocore and R. W. Katzberg, “Estimation of extraction fraction Most of these efforts are technical in nature, as part of an ͑EF͒ and glomerular filtration rate ͑GFR͒ using MRI: Considerations de- individual scientist’s research programs. There are also a rived from a new Gd-chelate biodistribution model simulation,” IEEE number of national initiatives which are focused on the de- Trans. Med. Imaging 24, 651–666 ͑2005͒. 20A. Thomas, M. Warm, M. Hoopmann, F. Diekmann, and T. Fischer, “Tis- velopment of calibration techniques and protocol standard- sue Doppler and strain imaging for evaluating tissue elasticity of breast ization for the various modalities, led by scientists at the lesions,” Acad. Radiol. 14, 522–529 ͑2007͒. American Association of Physicists in Medicine, the Na- 21M. Sridhar, J. Liu, and M. F. Insana, “Viscoelasticity imaging using ul- tional Institute for Standards and Technology,62 and the Na- trasound: Parameters and error analysis,” Phys. Med. Biol. 52, 2425–2443 31 ͑2007͒. tional Institutes of Health. These efforts, taken collectively, 22J. E. Drumm and R. O’Rahilly, “The assessment of prenatal age from the have only gotten the ball rolling slowly. It is anticipated that crown-rump length determined ultrasonically,” Am. J. Anat. 148, 555– over time, and with the recognition and acceptance of the 560 ͑1977͒. 23 medical imaging community, the snowball effect will occur J. E. Drumm, J. Clinch, and G. MacKenzie, “The ultrasonic measurement of fetal crown-rump length as a method of assessing gestational age,” Br. and QI will be a part of every radiologist’s practice. J. Obstet. Gynaecol. 83, 417–421 ͑1976͒. 24P. F. Judy, R. G. Swensson, and M. Szulc, “Lesion detection and signal- ͒ a Electronic mail: [email protected] to-noise ratio in CT images,” Med. Phys. 8, 13–23 ͑1981͒. 1D. L. Wahner-Roedler, S. S. Chaliki, B. A. Bauer, J. B. Bundrick, L. R. 25R. M. Nishikawa and M. J. Yaffe, “Signal-to-noise properties of mammo- Bergstrom, M. C. Lee, S. S. Cha, and P. L. Elkin, “Who makes the graphic film-screen systems,” Med. Phys. 12, 32–39 ͑1985͒. diagnosis? The role of clinical skills and diagnostic test results,” J. Eval. 26W. A. Edelstein, P. A. Bottomley, and L. M. Pfeifer, “A signal-to-noise Clin. Pract. 13, 321–325 ͑2007͒. calibration procedure for NMR imaging systems,” Med. Phys. 11, 180– 2T. R. Johnson, B. Krauss, M. Sedlmair, M. Grasruck, H. Bruder, D. 185 ͑1984͒. Morhard, C. Fink, S. Weckbach, M. Lenhard, B. Schmidt, T. Flohr, M. F. 27D. P. Chakraborty and G. T. Barnes, “Signal-to-noise ratio considerations Reiser, and C. R. Becker, “Material differentiation by dual energy CT: in radiographic imaging,” Med. Phys. 10, 467–469 ͑1983͒. Initial experience,” Eur. Radiol. 17, 1510–1517 ͑2006͒. 28B. Zhao, L. H. Schwartz, C. S. Moskowitz, M. S. Ginsberg, N. A. Rizvi, 3M. M. Goodsitt, H. P. Chan, T. W. Way, S. C. Larson, E. G. Christodou- and M. G. Kris, “Lung cancer: Computerized quantification of tumor lou, and J. Kim, “Accuracy of the CT numbers of simulated lung nodules response–initial results,” Radiology 241, 892–898 ͑2006͒. imaged with multi-detector CT scanners,” Med. Phys. 33, 3006–3017 29S. Rohde, B. Turowski, J. Berkefeld, and A. F. Kovacs, “CT-based evalu- ͑2006͒. ation of tumor volume after intra-arterial chemotherapy of locally ad- 4E. O. Crawley, “In vivo tissue characterization using quantitative com- vanced carcinoma of the oral cavity: Comparison with clinical remission puted tomography: A review,” J. Med. Eng. Technol. 14, 233–242 ͑1990͒. rates,” Cardiovasc. Intervent. Radiol. 30, 85–91 ͑2007͒. 5Y. Kodama, C. Ng, T. Wu, G. Ayers, S. Curley, E. Abdalla, J. Vauthey, 30C. H. Holdsworth, R. D. Badawi, J. Manola, M. F. Kijewski, D. A. Israel, and C. Charnsangavej, “Comparison of CT methods for determining the G. D. Demetri, and A. D. Van den Abbeele, “Use of CT and FDG-PET as fat content of the liver,” AJR, Am. J. Roentgenol. 188, 1307–1312 ͑2007͒. early prognostic indicators of response to imatinib mesylate ͑Gleevec͒ in 6J. J. Erasmus, J. E. Connolly, H. P. McAdams, and V. L. Roggli, “Solitary patients with gastrointenstinal stromal tumors ͑GIST͒,” AJR, Am. J. pulmonary nodules: Part I. Morphologic evaluation for differentiation of Roentgenol. ͑in press͒. benign and malignant lesions,” Radiographics 20, 43–58 ͑2000͒. 31The IRAT network, http://www.aaci-cancer.org/irats/about network.asp, 7K. Shaffer, “Role of radiology for imaging and biopsy of solitary pulmo- accessed 2007. nary nodules,” Chest 116, 519S–522S ͑1999͒. 32J. Beuth and J. M. Schierholz, “Review. Evidence-based complementary 8C. E. Cann, “Quantitative CT for determination of bone mineral density: oncology. Innovative approaches to optimize standard therapy strategies,” A review,” Radiology 166, 509–522 ͑1988͒. In Vivo 21, 423–428 ͑2007͒. 9T. F. Lang, J. Li, S. T. Harris, and H. K. Genant, “Assessment of vertebral 33S. M. Erturk, S. Ondategui-Parra, H. Otero, and P. R. Ros, “Evidence- bone mineral density using volumetric quantitative CT,” J. Comput. As- based radiology,” J. Am. Coll. Radiol. 3, 513–519 ͑2006͒. sist. Tomogr. 23, 130–137 ͑1999͒. 34D. L. Sackett, W. M. Rosenberg, J. A. Gray, R. B. Haynes, and W. S. 10C. Marchal, R. Itti, L. Philippe, E. Boissinot, J. Moline, and M. La- Richardson, “Evidence based medicine: What it is and what it isn’t. vandier, “The radiospirometric flow-volume diagram recording technique 1996,” Clin. Orthop. Relat. Res. 455, 3–5 ͑2007͒. and comparative study with conventional spirometry,” Eur. J. Nucl. Med. 35J. P. Ioannidis, “Molecular evidence-based medicine,” Eur. J. Clin. Invest. 2, 165–171 ͑1977͒. 37, 340–349 ͑2007͒. 11B. C. Yung, S. Sostre, and J. P. Gearhart, “Normalized clearance-to- 36G. W. Sledge, Jr., “Evidence-based medicine in breast cancer,” Clin. uptake slope ratio: A method to minimize false-positive diuretic reno- Breast Cancer 7, 435 ͑2007͒. grams,” J. Nucl. Med. 34, 762–768 ͑1993͒. 37A. Fine, “Medicare evaluates pay-for-performance,” Manag. Care Q. 14, 12H. S. Winchell, “Hematology. I. Quantitative studies of iron and heme 22–23 ͑2006͒. metabolism using radioisotope kinetics,” J. Nucl. Med. 8,375͑1967͒. 38T. P. Meehan, “Pay-for-performance: A new trend in health care,” Conn. 13F. J. Pircher, E. A. Carr, Jr., and M. E. Patno, “Evaluation of quantitative Med. 71, 225–226 ͑2007͒. aspects of the radioisotope renogram,” J. Nucl. Med. 4, 117–131 ͑1963͒. 39R. Lu, P. Marziliano, and T. C. Hua, “Liver tumor volume estimation by 14R. H. Lazeron, L. M. de Sonneville, P. Scheltens, C. H. Polman, and F. semi-automatic segmentation method,” Conf. Proc. IEEE Eng. Med. Biol. Barkhof, “Cognitive slowing in multiple sclerosis is strongly associated Soc., 2005, Vol. 3, pp. 3296–3299. with brain volume reduction,” Mult. Scler. 12, 760–768 ͑2006͒. 40P. J. Yim, A. V. Vora, D. Raghavan, R. Prasad, M. McAullife, P. Ohman- 15D. Horinek, A. Varjassyova, and J. Hort, “Magnetic resonance analysis of Strickland, and J. L. Nosher, “Volumetric analysis of liver metastases in amygdalar volume in Alzheimer’s disease,” Curr. Opin. Psych. 20, 273– computed tomography with the fuzzy C-means algorithm,” J. Comput. 277 ͑2007͒. Assist. Tomogr. 30, 212–220 ͑2006͒. 16J. G. Fine, M. Semrud-Clikeman, T. Z. Keith, L. M. Stapleton, and G. W. 41M. C. Ashe, K. M. Khan, S. A. Kontulainen, P. Guy, D. Liu, T. J. Beck, Hynd, “Reading and the corpus callosum: An MRI family study of vol- and H. A. McKay, “Accuracy of pQCT for evaluating the aged human

Medical Physics, Vol. 34, No. 11, November 2007 4179 John M. Boone: Quantitative imaging 2020 4179

radius: An ashing, histomorphometry and failure load investigation,” Os- 2192–2198 ͑2006͒. teoporos. Int. 17, 1241–1251 ͑2006͒. 53D. E. Huddleston and S. A. Small, “Technology insight: imaging amyloid 42B. C. Khoo, T. J. Beck, Q. H. Qiao, P. Parakh, L. Semanick, R. L. Prince, plaques in the living brain with positron emission tomography and MRI,” K. P. Singer, and R. I. Price, “In vivo short-term precision of hip structure Nat. Clin. Pract. Neurol. 1, 96–105 ͑2005͒. analysis variables in comparison with bone mineral density using paired 54T. den Heijer, P. E. Sijens, N. D. Prins, A. Hofman, P. J. Koudstaal, M. dual-energy x-ray absorptiometry scans from multi-center clinical trials,” Oudkerk, and M. M. Breteler, “MR spectroscopy of brain white matter in Bone 37, 112–121 ͑2005͒. the prediction of dementia,” Neurology 66, 540–544 ͑2006͒. 43L. J. Melton III, T. J. Beck, S. Amin, S. Khosla, S. J. Achenbach, A. L. 55E. M. Geraghty, J. M. Boone, J. P. McGahan, and K. Jain, “Normal organ Oberg, and B. L. Riggs, “Contributions of bone density and structure to volume assessment from abdominal CT,” Abdom. Imaging 29, 482–490 fracture risk assessment in men and women,” Osteoporos. Int. 16, 460– ͑2004͒. 467 ͑2005͒. 56S. V. Raman, M. Shah, B. McCarthy, A. Garcia, and A. K. Ferketich, 44P. D. Ross, “Osteoporosis. Frequency, consequences, and risk factors,” “Multi-detector row cardiac computed tomography accurately quantifies Arch. Intern. Med. 156, 1399–1411 ͑1996͒. right and left ventricular size and function compared with cardiac mag- 45H. Kroger, M. Tuppurainen, R. Honkanen, E. Alhava, and S. Saarikoski, netic resonance,” Am. Heart J. 151, 736–744 ͑2006͒. “Bone mineral density and risk factors for osteoporosis–a population- 57P. Therasse, S. G. Arbuck, E. A. Eisenhauer, J. Wanders, R. S. Kaplan, L. based study of 1600 perimenopausal women,” Calcif. Tissue Int. 55, 1–7 Rubinstein, J. Verweij, G. M. Van, A. T. van Oosterom, M. C. Christian, ͑1994͒. and S. G. Gwyther, “New guidelines to evaluate the response to treatment 46M. E. Ooms, P. Lips, L. A. Van, and H. A. Valkenburg, “Determinants of in solid tumors. European Organization for Research and Treatment of bone mineral density and risk factors for osteoporosis in healthy elderly Cancer, National Cancer Institute of the United States, National Cancer women,” J. Bone Miner. Res. 8, 669–675 ͑1993͒. Institute of Canada,” J. Natl. Cancer Inst. 92, 205–216 ͑2000͒. 47D. H. Miller et al., “MRI outcomes in a placebo-controlled trial of natali- 58J. M. Boone, “Multidetector CT: Opportunities, challenges, and concerns zumab in relapsing MS,” Neurology 68, 1390–1401 ͑2007͒. associated with scanners with 64 or more detector rows,” Radiology 241, 48F. Fazekas, P. Soelberg-Sorensen, G. Comi, and M. Filippi, “MRI to 334–337 ͑2006͒. monitor treatment efficacy in multiple sclerosis,” J. Neuroimaging 17, 59C. R. Meyer et al., “Evaluation of lung MDCT nodule annotation across 50S–55S ͑2007͒. radiologists and methods,” Acad. Radiol. 13, 1254–1265 ͑2006͒. 49M. A. Rocca and M. Filippi, “Functional MRI in multiple sclerosis,” J. 60S. G. Armato III, G. McLennan, M. F. Nitt-Gray, C. R. Meyer, D. Neuroimaging 17, 36S–41S ͑2007͒. Yankelevitz, D. R. Aberle, C. I. Henschke, E. A. Hoffman, E. A. Kaze- 50N. De Stefano and M. Filippi, “MR spectroscopy in multiple sclerosis,” J. rooni, H. MacMahon, A. P. Reeves, B. Y. Croft, and L. P. Clarke, “Lung Neuroimaging 17, 31S–35S ͑2007͒. image database consortium: Developing a resource for the medical imag- 51L. J. Thal, K. Kantarci, E. M. Reiman, W. E. Klunk, M. W. Weiner, H. ing research community,” Radiology 232, 739–748 ͑2004͒. Zetterberg, D. Galasko, D. Pratico, S. Griffin, D. Schenk, and E. Siemers, 61M. H. Buonocore and R. W. Katzberg, “Estimation of extraction fraction “The role of biomarkers in clinical trials for Alzheimer disease,” Alzhe- ͑EF͒ and glomerular filtration rate ͑GFR͒ using MRI: Considerations de- imer Dis. Assoc. Disord. 20, 6–15 ͑2006͒. rived from a new Gd-chelate biodistribution model simulation,” IEEE 52M. Yoshita, E. Fletcher, D. Harvey, M. Ortega, O. Martinez, D. M. Mu- Trans. Med. Imaging 24, 651–666 ͑2005͒. ngas, B. R. Reed, and C. S. DeCarli, “Extent and distribution of white 62Imaging as a biomarker: Standards for change measurements in therapy, matter hyperintensities in normal aging, MCI, and AD,” Neurology 67, 2007.

Medical Physics, Vol. 34, No. 11, November 2007 From medical images to multiple-biomarker microarrays Robert F. Wagner Center for Devices and Radiological Health, FDA, 10903 New Hampshire Avenue, Building 62, Room 3126, Silver Spring, Maryland 20993-0002 ͑Received 1 August 2007; revised 9 October 2007; accepted for publication 13 October 2007; published 28 November 2007͒ A favorite cliché, often attributed to Yogi Berra, is “Prediction is difficult, especially about the future!” In this brief review, we shall recall some historical difficulties in predicting the future of diagnostic medical imaging—in particular, the modern technologies of CT and MRI—and examine the analogous situation in the emerging technology of diagnostic microarrays for the multiple- biomarker problem. All of these technologies began their lives as ill-conditioned problems, i.e., there was insufficient data to solve the central problem at hand. ͓DOI: 10.1118/1.2805252͔

I. OVERVIEW aging and microarray technologies are destined to be teamed together for the foreseeable future. In the first half of this article we will look at how well investigators in the past predicted the future of technology in II. BEFORE THERE WAS CT diagnostic medical imaging, and their vulnerability to a well- ͑ ͒ known dictum about forecasting.1 In the second half we will In the early 1970s, computed tomography CT was still a consider an analogous situation for the new kind of medical gleam in the eye of just a few leading researchers. One of the image represented by genomic and proteomic microarrays. more vigorous areas of radiologic research at that time involved the adaptation of bright color-TV-CRT phosphors for These latter emerging technologies allow for simultaneous use in x-ray intensifying screens. Together with advances in measurement—from a single tissue or blood sample—of the x-ray tube and focus design, this led to significant improve- levels of expression of many thousands of different gene or ments in blood vessel visualization in, for example, x-ray protein fragments using a novel chip design that merges mo- magnification cerebral angiography. However, the clinical lecular biology and optoelectronics. We will find some natu- need and relevance of such improvements were debated in ral parallels between diagnostic imaging and microarrays. At some cases—many radiologists seemed content with avail- the end we will identify a central theme from the assessment able imaging technologies. Few if any anticipated CT, which of conventional medical imaging that can offer insight into was barely a year over the horizon at the time. In fact, a the evolution of contemporary microarray technologies. frequently heard comment in retrospect was that if the tem- The topics covered here were selected from the research poral and spatial parameters of the coming first generation of experience of the author and his professional colleagues be- CT ͑4–5 min exposures, multimillimeter resolution in cross- cause they exemplify the difficulty of predicting the course sectional images͒ had been freely offered to radiologists at of the history of these technologies while it was being lived the time, they would have seen no use for such a system! in real time. No attempt has been made to provide a broad However, CT was to represent a qualitative change, over and history of either the very large field of medical imaging or above its quantitative parameters. that of multiple-biomarker microarray technologies. First, let us remark that a medical image is a random array III. MODERN MEDICAL IMAGING or vector: “Random” because there are multiple sources of variability or randomness, including detector noise and inter- III.A. Some critical historical moments patient and intrapatient variability, and “array” because an Let us consider some critical moments during the emer- image is obviously a multidimensional matrix. Multivariate gence of CT and magnetic resonance imaging ͑MRI͒ during statistics is therefore an essential tool for understanding the the 1970s. Recall that these technologies were both enabled amount of information that can be captured in a medical by giant steps in digital technologies, especially the mini- image. The new technology of multiple-biomarker microar- computer, the “computer in a breadbox” that for the first time rays may be thought of as a special category of medical allowed complex mathematical image reconstruction algo- imaging. In conventionally processed medical image arrays, rithms to be executed on large format images in a manage- the underlying relational structures are usually obvious be- able time and space and therefore with manageable expense. cause natural morphology and function are typically dis- While the mathematical algorithm community has natu- played directly. In the case of microarrays, computationally rally emphasized the open-ended potential for their own spe- intensive statistical techniques are necessary to discover any cialized contributions to imaging, physicists have tried to relational structure in the data and within and across samples understand not only the potential, but also the limitations, from nondiseased and diseased patients. An obvious limita- imposed on these technologies by the laws of physics and tion of microarrays is that they do not generally localize their statistics—in particular, the quantity and quality of the findings to well-specified sites in the body. So medical im- samples of input data required for clinically useful images.

4944 Med. Phys. 34 „12…, December 2007 0094-2405/2007/34„12…/4944/8/$23.00 4944 4945 Robert F. Wagner: From medical images to multiple-biomarker microarrays 4945

differences.4–7 It took some years before a widespread understanding emerged that CT was in principle quantum limited, and thus highly efficient as defined above, for low-contrast tasks. Investigators who wished to push the envelope in this field then turned their attention to the question of whether reductions in the number of views could be efficiently taken for certain high-contrast imaging applications or by the incorporation of prior information and constraints.8

III.C. The early predictions for MRI Some of the early investigators of MRI ͓or nuclear magnetic resonance ͑NMR͒ imaging as it was then called͔ were pessimistic about achieving clinically useful levels of resolution in realistic imaging times. Signal-to-noise ͑SNR͒ calculations based on elementary theories of signal detection and statistical decision making lead to the conclusion that imaging time in three dimensions depends on the inverse sixth power of the resolution required ͑or fourth power in two dimensions, among other variations of the scenario9͒.I FIG. 1. Example of an early CT image of the brain showing a large space- filling lesion. The conditioning of this inverse problem can be improved to attended an MRI brainstorming meeting at NIH in the late some extent by simply demanding lower resolution in the image, achievable 1970s. David Hoult, a pioneer in the field who was recruited most simply by blurring one’s vision. ͑Courtesy of Siemens Medical by NIH to develop an early clinical scanner for them, em- ͒ Solutions. phasized his concern that attempts to reduce the limiting resolution of MRI would face a formidable obstacle from the Both CT and MRI are, in principle, mathematically ill- constraint of the power law just cited. In a few words, if conditioned because they attempt to solve an inverse prob- image resolution was to be improved by a factor of 2, the lem of reconstructing a continuous object ͑i.e., the body͒ imaging time might have to be increased by a factor ranging from a finite number of discrete and noisy data samples.2 The from 16 to 64, and this would not be clinically practical. original and most common way of dealing with this ill- On May 4–5, 1995 I attended a meeting at the National conditioning is by relaxing the resolution requirements on Library of Medicine in celebration of the centenary of the discovery of x rays by Roentgen ͑Radiology Centennial the final result until a useful image, with disguised or hardly ͒ visible artifacts, is obtained ͑see, for example, Fig. 1͒. For Commemorative Conference . Pioneers as well as contempo- our present purposes, we define an artifact as a structure in rary experts across many fields of medical imaging presented the image not present in the original object and not due their experience of the progress in their fields. One of the solely to random photon or detector noise. presenters was a major player in the development of both CT and MRI at General Electric Corporate Research and Devel- One of the principal benchmarks used for assessing these ͑ ͒ imaging technologies is the ability to discriminate a region of opment Laboratories, Lewis S. Lonnie Edelheit, who had succeeded the beloved mentor of many of us of the previous a given size and contrast from its surround, versus the radia- ͑ ͒ tion dose or exposure and/or imaging time required for this generation, Rowland W. Red Redington. In Edelheit’s pre- task. We may refer to this benchmark of “image quality” sentation to this commemorative conference he showed a versus dose or exposure and/or imaging time as imaging ef- slide containing a copy of a letter he had written to GE ficiency. How did the early investigators view the prospects management early in the development of MRI. The letter for imaging efficiency in CT and MRI? told a story similar to that of Hoult, namely, the outlook for improved resolution in MRI was not great owing to the strong dependence of imaging time on required resolution; III.B. The early predictions for CT he was not able to encourage GE management to increase At the emergence of CT in the early- to mid-1970s, most their support for development of MRI at that point. investigators recognized this as a relatively high-dose modal- A brief historical summary of the evolution of that view ity but had only vague impressions regarding the prospects was presented by Redington in Ref. 10. Redington empha- for improving its imaging efficiency. Some early mathemati- sized that, among other points, the previous discussions on cal researchers raised hopes for reducing dose through more resolution neglected to distinguish between high- and low- elaborate approaches to image reconstruction.3 On the other contrast regimes and ignored the great soft-tissue contrast hand, several authors from the physics community, including available in MRI. His short paper also includes a discussion our own group, argued that some existing CT designs and of the difference between signal, noise, and resolution char- software algorithms were already operating close to the sta- acteristics in MRI versus in CT that guided some of our own tistical limitations imposed by quantum noise for the task of work.9 He outlined in vivo NMR spectroscopy as a potential discriminating large-area ͑ϳ1cm͒ low-contrast tissue answer to “what comes next after NMR imaging?”. And he

Medical Physics, Vol. 34, No. 12, December 2007 4946 Robert F. Wagner: From medical images to multiple-biomarker microarrays 4946 observed that it was then only a matter of time until a demand for—steady miniaturization and increase in the num- straightforward MR pulse sequence would be demonstrated ber of CT detectors, both circumferentially around the body that would produce blood flow information. Written more and axially along the body. In the early days of CT, many than 25 years ago, this still makes fascinating reading. Red- investigators thought that such an increase would automati- ington’s clear vision of the future stood out against an oth- cally lead to an increase in required x-ray dose. However, the erwise cluttered background of those times. large-area low-contrast performance may be maintained in- Edelheit’s achievements both before and since the letter to dependently of the number of detectors—it is not the number management mentioned above greatly overshadow this mis- of photons per detector that directly determines the dose/ read of the early situation that he shared with us that day. image-quality relationship in the low-contrast regime, it is Many technological tricks came out of continuing research in rather the spatial density of detected x-ray counts9—as long MRI that allowed “multiplex methods” for collecting as the number of detected counts exceeds the dark noise and multiple-slice MRI data in about the same time originally readout noise of the detector. dedicated to single-slice data. Methods for speeding up MRI A major unsurprising ͑and long-awaited͒ development has imaging continue to evolve to this day, including techniques been the emergence of technologies foreseen more than three for subsampling data space, taking advantage of samples decades ago but only made practical by advances in digital from high-contrast regions while undersampling potentially detectors, e.g., dual-energy x-ray imaging and limited-angle correlated regions of space ͑and/or time͒. The intrinsic tomography or tomosynthesis. One popular prediction gradu- thermal-noise limitations remain for low-contrast MRI sig- ally being realized is that many if not most 2D or planar nals, but for applications where there is higher contrast avail- imaging technologies will be supplanted by 3D volumetric able, such as angiography or other applications that use MR imaging technologies in the foreseeable future. The radiation contrast agents, these tricks can offer substantial reductions dose to the body may increase appreciably for some of these in imaging time. latter developments. Finally, an unconventional re-examination of the geometry of CT scanning has led to the investigation of a configu- III.D. Some contemporary efforts toward pushing the ration referred to as inverse-geometry volumetric CT.15 The envelope name derives from the fact that a large-area, scanned x-ray In the recent decade, Mistretta and colleagues have taken source is used with a detector array that is smaller than the a small step backward, and then a large step forward, in source in the transverse direction ͑but comparable in the speeding up some special tasks in MRI imaging.11 Recall axial direction͒. The authors claim that noise and resolution that—aside from the first generation of MRI imaging—the with their micro-CT system are comparable to an existing most popular approach to data collection was in terms of volumetric micro-CT system, while avoiding the cone-beam Cartesian coordinates in k- or spatial-frequency space, which artifacts that occur in the latter. Additional projected benefits is natural to MRI, at least in one dimension and extended by include reduced scatter and detector cost. Fourier-based pulse techniques to higher dimensions. Mis- To summarize, the first generations of investigators in tretta’s step backward was to revisit one of the first- both CT and MRI did not have a clear view of the require- generation approaches to MRI, namely, using the radial ge- ments for the number of image samples, e.g., photons ͑and ometry of projection-reconstruction ͑PR͒ imaging that is radiation exposure or dose͒, views, and imaging time, needed natural and standard in CT, rather than the later-generation for clinically useful images for particular imaging tasks. MRI Cartesian geometry. Much work advanced on an ad hoc basis, in particular by These investigators then began experimenting—in the means of a “beauty contest” between competing modalities context of high-contrast sparse-signal applications—with or algorithms—continuing in this mode up to the present. A collecting only a small fraction of the typically required foundational approach to many of the issues sketched above number of projections or angular samples. This offered mod- required several decades to formulate and has been published est efficiency gains in the context of 2D PR geometry but in the present decade by Barrett and Myers.2 This approach remarkable gains when the projections were distributed in all should appeal naturally to the physicists in our audience. It directions in 3D PR geometry.12 Further gains result from depends in part on physical measurement and analysis of the using training image sets to learn and incorporate the image so-called “singular vectors,” or natural imaging building signal correlation structure for time-resolved imaging.13 This blocks corresponding to a given physical configuration of work has led to images that are visually comparable or su- image detection system; this analysis leads to a separation perior to images collected using conventional approaches to between the concepts of the “measurement space” and the sampling in Cartesian geometry but with a great reduction in “null space.” The measurement space is that portion of the imaging time by reducing the number of views or angular object that is accessible to measurement by the imaging sys- samples. These investigators are in the process of applying to tem; the null space is that portion of the object that is inac- time-dependent CT imaging14 the principles learned from cessible to measurement by the imaging system. ͑A trivial their work in MRI. Some of these more recent developments example of a null space would be the zeroes of the system have come as quite a surprise to researchers in these fields. transfer function.͒ Thus, objects that differ only in their null- Another somewhat surprising feature of contemporary CT space component appear the same when imaged. Many arti- technology has been the rate of—and to some extent the facts may be thought of as “ghosts from the null space,”8 i.e.,

Medical Physics, Vol. 34, No. 12, December 2007 4947 Robert F. Wagner: From medical images to multiple-biomarker microarrays 4947 trying to solve for information that is not available from ciated with a class of breast cancers. In genomics, proteom- finite sampling of the object, together with noisy detected ics, and related technologies, however, investigators are test- data, leads to the generation of unwarranted image ing not for the presence or absence, but rather for the level of content—in the absence of prior information about the ob- expression, of a large number of genes and/or proteins, and ject. The fundamental approach of Ref. 2 combines math- patterns of expression across many genes or protein frag- ematics, statistics, and physics but still awaits application to ments. The physical measurements in the proteomic ap- many contemporary imaging scenarios—including those of proach are obtained from mass spectrometry of specially pre- Mistretta and colleagues and Schmidt et al.,15 sketched pared tissue specimens. The physical measurements in the above—a challenge previously presented by the present genomic approach will be sketched here for interested new- author,16 among others. comers. Both technologies are complicated by potential This unresolved situation regarding the fundamentals sug- variations in expression level as a function of time of day or gests seeking a practical working solution in the short term. metabolic or other natural cycle including, of course, the In a few words: How does one quantify the impact of arti- patient’s age. facts that always accompany undersampled imagery? Many The technology used in genomics to measure the level of investigators still depend on a performance measure whose expression of a large number of specified genes simulta- central component is the SNR at the pixel level. This is in neously is referred to as a microarray assay; an individual spite of the fact that decades of publications by many of the microarray is often referred to as a “DNA chip” and is about authors cited above ͑cf. Ref. 9͒ have demonstrated that pixel the size of a thumbprint. There are several different contem- SNR is a highly ambiguous figure of merit—especially porary microarray technologies.20 We provide here an intro- within the context of correlated noise and/or long-range im- ductory summary of the generic approach. A microarray con- age artifacts. A practical middle ground—beyond naïve SNR tains a location and spot for each of the specified reference but short of the more formal analysis—was investigated in genes. The spots can be prepared by synthesizing previously the early 1990s by Hanson, Myers, Wagner, and designated sections of known genetic sequence and binding a coauthors.17,18 It is based on measuring the impact of ran- quantity of this material to a substrate. The spot, together domized artifacts on diagnostic performance. Although these with some associated controls, is referred to as a “probe.” In references focus on simulated imagery, there is no funda- contemporary work, the number of probes on a chip is in the mental reason why the methods cannot be extended to clini- order of tens of thousands. A prepared sample of genetic cal images ͑or a hybrid of clinical images with simulated material from a patient’s blood or other tissue of interest, the inclusions͒—aside from the expense of collecting and read- “target”, is labeled with a fluorescent dye, and then washed ing the images. The main challenge to the investigator would over the chip. The goal of the measurement is to quantify the be to collect a random sample of realistic examples where degree of hybridization between the material in the target the anatomy challenges the physical source of the artifacts. and that in the probe. Hybridization refers to the complementary binding of the bases in the genetic code ͑A to T, G to C, IV. MICROARRAYS etc.͒. The degree of hybridization at each spot is assumed to be proportional to the number of copies of the specified RNA IV.A. Background section in the patient’s tissue sample—a measure of the level The biomedical landmark of our time has been the se- of expression of the specified gene. After hybridization, the quencing of the genomes of many organisms, in particular spots on the microarray are read out using laser light to ex- the sequencing of the human genome. As more genes and cite the fluorescence, optics and photodetection to measure proteins are identified, and those involved in disease initia- the fluorescence, and finally digitization. Microarrays are tion and progression become better understood, an increasing thus a form of molecular imaging of tissue samples extracted number of candidate diagnostic biomarkers as well as novel from patients. therapeutic agents are expected to emerge.19 The target of As in medical imaging ͑but greatly more so͒, the genom- the diagnostic and therapeutic agents may be the general ics and proteomics problems are not generally well condi- population, or it might be some specially targeted subpopu- tioned; great variability in data consistent with a wide range lations. The targeting of therapeutics based on the biological of potential ͑but not real͒ solutions to any particular diagnos- make-up of subclasses of patients is known as “pharmacoge- tic problem can arise at each of several stages of analyzing nomics” and is popularly referred to as “personalized medi- the problem. The very first stage involves quality control of cine.” The promise of the field is great and open-ended, the laboratory conditions and measurement apparatus. There yet—as was the case with the breakthrough technologies in are a multitude of issues here, well beyond our present scope. medical imaging—the scale of the promise and efficiency The next principal stage—trying to find those genes that are requirements for developing clinically useful diagnostic tools biologically significant for a particular task, among many is not yet well understood. thousands of candidates—is fraught with the general prob- Investigators emphasize that it is essential to distinguish lems of all tasks of data mining, namely, the fact that many between genetics and genomics. In genetics, one tests for the candidates are expected to stand out in a noisy sample purely presence or absence ͑or usually the mutation status͒ of one or by random chance, so-called false discovery.20 Newcomers typically only a few specified genes, e.g., the gene associated may be surprised to learn that a typical starting point for the with cystic fibrosis or the BRCA1 and BRCA2 genes asso- overall procedure is measurement of the level of expression

Medical Physics, Vol. 34, No. 12, December 2007 4948 Robert F. Wagner: From medical images to multiple-biomarker microarrays 4948 of many thousands ͑or tens of thousands͒ of genes from the the first published results on binary classification based on tissues of only a hundred ͑or at most a few hundred͒ patients. gene expression levels. The authors identified 50 “informa- That is, the sampling of data and the conditioning of the tive genes” among many thousands of candidates. They then problem are just the opposite of what one would prefer in an trained a large number of classifiers for the task of discrimi- ideal experiment. For example, in typical problems in nating acute lymphoblastic leukemia ͑ALL͒ from acute my- computer-aided diagnosis in medical imaging, one may typi- eloid leukemia ͑AML͒ based on the levels of expression of cally design a diagnostic model with one or two dozen im- these informative genes in patients’ bone marrow samples aging features using the images of several hundred patients. and found success in the training set almost independent of Investigators attempt to complement the problem of data their choice among those genes. A peculiar feature of this mining with the use of any prior knowledge or understanding work is that only 38 patients were in the training set. A they have of the biological role of particular genes. This is celebrated theorem attributable to Cover24 ͑but yet to be cel- analogous to scientist image processors in computer-aided ebrated in the biomarker community͒ indicates that the prob- diagnosis in medical imaging querying clinicians about the lem they solved at this point would be trivial—if ͑the escape relative importance of various image features, e.g., spicula- clause͒ those 50 genes were not strongly coexpressed. Ac- tions of masses, or pleomorphism of calcifications in mam- cording to this theorem, almost every possible labeling of mography. cases in two classes ͑here, ALL versus AML͒ will be perfectly separable by a simple hyperplane unless the number of IV.B. Statistical learning machines cases is a multiple greater than unity ͑when only a few fea- ͒ ͑ ͒ A crucial final stage involves the task of training a classi- tures are used or about two for such high-dimensional data fier how to weight the levels of expression of a modest num- times the number of features ͑or biomarkers͒ used. An in- ber of gene or protein fragments that survive the initial data spection of Fig. 2, however, reproduced here from their mining, using a “statistical learning machine,” e.g., a classi- work, makes it visually obvious that there is a strong corre- cal or neural-network classifier, to maximize success in clas- lation, or strong level of coexpression, of the genes in that sifying the condition of interest, e.g., cancer versus noncan- sample. The escape clause above is now operational: Those cer, or an aggressive subclass of cancer versus an indolent 50 genes apparently live on a lower-dimensional subspace. one, or a responder versus a nonresponder to a specified In that case ͑e.g., if it is only a 5D to 10D space͒, then they therapy, among others. A natural bottleneck occurs here since may have sufficient samples that the discrimination they ob- at present the accessible and affordable world provides only served is not simply a consequence of geometry in high- a finite sample of patients with known truth status who can dimensional space. We encourage authors to address this ge- be used to train the classifier, and next to test it with previ- ometry problem before making inferences from their work. ously unseen cases. This limitation of samples can lead to Although the authors did not address this issue, they were great uncertainty in the classifier itself, as well as attempts to aware of the necessity to validate their results on indepen- estimate its performance over the target population using any dent test data. They reported that they found good predict- modest number of available patients. ability in an independent test set of 34 samples. We return to In general, the uncertainty in the performance estimate this point below. decreases with increases in either or both of the number of This particular example—aside from any issues that can training samples and the number of testing samples. The is- be raised in its critique—appears to offer an example of low- sues here are conceptually identical to those one encounters hanging fruit in the following sense. In retrospect, if one when studying task-dependent trained model observers when looks at the color map of the response of the 50 genes in the assessing medical imaging systems.21 As in this latter prob- authors’ original paper in Science ͑Ref. 23 and Fig. 2 here͒, lem, the uncertainty in performance estimation also de- one sees that the individual genes on their own have very creases with increasing intrinsic separability of the popula- high, albeit not quite perfect, discriminating power. For this tions. This is analogous to the intrinsic contrast of a reason, this data set has come to be recognized as an easy particular diagnostic task in medical imaging. A further issue for the problem of statistical learning machines is that the one for classifier development, analogous to imaging of number of training samples required for a given confidence high-contrast phenomena in the technologies discussed level also increases with the number of biomarkers ͑features above. Still, it is relatively early in the acquisition of data in the classifier͒ and/or the complexity of the classifier.22 and critical review of work on this problem. Because of the great opportunity for “false discovery” of Another celebrated data set is that of Petricoin, Liotta and genes at the early stage of development of a given technol- colleagues for discriminating between the presence or ab- ogy and the limitations of available samples from patients sence of ovarian cancer using spectral lines from mass spec- 25 with known truth status, many early promises have not held trometry of protein fragments from blood samples. After up under later scrutiny, while the jury is still out on many elaborate feature selection and training, the performance of other high-profile studies. their classifier was considered to have been validated by the The work of Golub and colleagues on classification of original investigators using independent test samples. How- human acute leukemias23 has attracted a great deal of atten- ever, like many other early multiple-biomarker tests, their tion for several reasons, including the fact that it was one of results have not been reproduced and have been subjected to

Medical Physics, Vol. 34, No. 12, December 2007 4949 Robert F. Wagner: From medical images to multiple-biomarker microarrays 4949

FIG. 2. Levels of expression of 50 most informative genes ͑the labeled rows͒ from 38 patients ͑the columns͒ in two kinds of acute human leukemia ͑ALL and AML͒. Red represents genes overexpressed with respect to the mean level across patients and blue represents genes underexpressed with respect to that mean level. Notice the strong coexpression of the genes in both major regions ͑top and bottom of ﬁgure͒. These genes may live on a low-dimensional subspace of the original 50 dimensions. ͓Figure reproduced with permission from Science, Ref. 23, copyright 1999 American Association for the Advancement of Science ͑AAAS͒.͔

challenges and much debate based on potential biases in the well as a new random sample of testers? Of course, confi- way the samples were analyzed ͑see, e.g., Ref. 26 among dence intervals for the latter approach will in general be many others͒. wider than those for the former approach. In general, there are great uncertainties in the perfor- The point of view of myself and collaborators is that the mance assessment of multiple-biomarker classifiers because second, or more general, uncertainty should be specified.28,29 of the general structure of the problem and the modest sizes Classifier designers sometimes argue that their training is of available data sets. In addition to trying to reduce the “frozen.” However, it is almost always the intent of these sources of bias in the assessment process, it is also of great investigators to continue to build their database, improve interest to estimate confidence intervals on the resulting per- their statistical learning, and update their algorithms. This is formance estimates. We have been addressing this problem 27–30 motivation for the more general approach of Refs. 28 and 29. in contemporary work within our group. The former may be useful for analyzing a pilot study to guide the sizing of a larger subsequent pivotal study; the IV.C. Levels of generalizability of estimated latter can apply equally to the setting of either a pilot or a uncertainties pivotal study. An analysis of the uncertainties in a pilot study A classic question arises at this point. Should one estimate may be the only way to design a more definitive pivotal the uncertainty that one would observe if the classifier is study. fixed and on replication of the experiment only a new ran- Further motivation for our more general position can be dom sample of testers is drawn, or should one estimate the drawn from a recent exchange in the multiple-biomarker lit- uncertainty that one would observe if, on replication of the erature. Dave and colleagues31 trained a model for experiment, a new random sample of trainers is drawn as prediction-of-survival on 95 biopsy specimens from patients

Medical Physics, Vol. 34, No. 12, December 2007 4950 Robert F. Wagner: From medical images to multiple-biomarker microarrays 4950 with untreated follicular lymphoma. They tested the model cussed at the outset. In imaging, one can often improve the by validating it in an independent test set of 96 specimens conditioning of an inverse problem by simply backing off from the same population and found a highly significant as- from the resolution requirements and looking at the resulting sociation of their model with survival in the independent test images ͑cf. Fig. 1͒. To date, no such simple strategy exists set ͑pϽ0.001͒. for dimensionality reduction in the field of microarray tech- Tibshirani acknowledged the authors’ result that their nology, although many sophisticated alternatives are recipe gave a significant p-value when used on the test set emerging.37 It will also require some time to sort out the fact but went on to point out that “the result is extremely that some investigators will discard dimensions or biomark- fragile.”32 When the training and test sets are swapped, and ers found to play a critical role by other investigators. the authors’ recipe for training is applied, the authors’ model does not emerge. Additional analyses “suggest that their re- VI. CONCLUSION sult occurred by chance and is not robust or reproducible.” An appreciation of the foundational statistical issues is Thus, even what we refer to as “the traditional hygiene of essential to progress in all these fields and to attempting to independent training and test sets” fails to probe the robust- predict their future prospects. And—as in all complex ness of a model and should give us pause regarding our level decision-making tasks—much more data are required to cull of satisfaction with that simple practice. the fruitful paths from the myriad blind alleys with which almost all researchers have ample familiarity. V. SOME GENERAL FEATURES OF THE LARGER Ultimately, the whole world will be our database. In the PICTURE meantime, who will organize and analyze the currently sparse available data in a resource-efficient way that respects Many of the issues surrounding requirements for sample fundamental scientific and statistical principles? ͑Cf. Ref. numbers in the classifier problem have begun to be addressed 38.͒ It may take some time to converge on a unified founda- by investigators of model observers trained for assessing ditional approach to the theory and practice of the general agnostic imaging technologies21 and in the subfield of statis- multiple-biomarker problem—analogously to the situation in tical pattern recognition known as computer-aided diagnosis medical imaging. in medical imaging.33,34 The general problem is also inti- The bottom line of this look at the past, present, and fu- mately related to the so-called multiple-reader, multiple-case 1 ture: Niels Bohr was right all along! Prediction—especially ͑MRMC͒ paradigm used in receiver operating characteristic about the future—is difficult. But our predictions about the ͑ROC͒ analysis in medical imaging,35 where there may be a future of technologies involving random arrays have a much great difference in skill ͑training and experience, say͒ among better chance of survival if they are based on foundational trained readers ͑i.e., radiologists͒. Readers in medical imag- principles of multivariate statistics—in addition to the under- ing are analogous to training sets in the machine learning lying science. problem; cases in medical imaging are analogous to the test- 36 ing cases in the machine learning problem. But a coherent 1‘‘Prediction is difficult, especially about the future!” Y. Berra or N. Bohr? foundational approach is still at an early stage of develop- Apparently Niels Bohr is ahead in the competition for this attribution. ment. We therefore expect to see divergence of views and Other household names are also high on the list, according to searches approaches by investigators in many disparate subfields of conducted by http://letterfromhere.blogspot.com/2006/12/bohr-leads- berra-but-yogi-closing-gap.html microarray technology, arguably analogous to the situation in 2H. H. Barrett and K. J. Myers, Foundations of Image Science ͑John Wiley the first few decades of the development of contemporary and Sons, Hoboken, NJ, 2004͒. high-tech medical imaging systems. The recognition of the 3R. Gordon, “Dose reduction in computerized tomography,” Invest. Ra- diol. 11, 508–517 ͑1976͒. need for a fundamental multivariate statistical analysis for all 4 R. F. Wagner, D. G. Brown, and M. S. Pastel, “The application of infor- of these applications is still not widespread throughout the mation theory to the assessment of computed tomography,” Med. Phys. 6, land. 83–94 ͑1979͒. 5 In both medical imaging and microarray technologies a K. M. Hanson, “Detectability in computed tomographic images,” Med. Phys. 6, 441–451 ͑1979͒. central goal is to reduce the very high dimensional informa- 6K. M. Hanson, “Noise and contrast discrimination in computed tomogra- tion in the detected data to a few clinically meaningful di- phy,” in Radiology of the Skull and Brain: Technical Aspects of Computed mensions or features and ultimately to a diagnostic decision. Tomography, edited by T. H. Newton and D. G. Potts ͑C.V. Mosby, St. The task is complicated by the fact that the high-dimensional Louis, 1981͒, Vol. 5, Chap. 113, pp. 3941–3955. 7R. Stanton and O. Tretiak, “Dose reduction through variable dose CT information in either medical image arrays or applications of Scanning: Optimality of the filtered backprojection algorithm,” J. Com- microarrays includes at least two principal sources of ran- put. Assist. Tomogr. 7, 1054–1061 ͑1983͒. domness, namely, random noise from the image-detection 8K. M. Hanson, “Bayesian and related methods in reconstruction from technology and the natural randomness or variability that we incomplete data, in Image Recovery: Theory and Applications, edited by H. Stark ͑Academic Press, Orlando, 1987͒, pp. 79–125. patients bring to the table. The statistical pattern recognition 9R. F. Wagner and D. G. Brown, “Unified SNR analysis of medical imag- experience of a radiologist is typically the key to the dimen- ing systems,” Phys. Med. Biol. 30, 489–518 ͑1985͒. sionality reduction task in medical imaging, but the statistical 10R. W. Redington, “Diagnostic NMR,” IEEE Trans. Med. Imaging MI-1, ͑ ͒ patterns in microarray data are not typically visually acces- 230–233 1982 . 11D. C. Peters, T. M. Grist, F. R. Korosec, J. E. Holden, W. F. Block, K. L. sible. The field of microarray technologies does not enjoy Wedding, T. J. Carroll, and C. A. Mistretta, “Undersampled projection another of the great advantages of medical imaging dis- reconstruction applied to MR angiography,” Magn. Reson. Med. 43,91–

Medical Physics, Vol. 34, No. 12, December 2007 4951 Robert F. Wagner: From medical images to multiple-biomarker microarrays 4951

101 ͑2000͒. 26D. E. Ransohoff, “Bias as a threat to the validity of cancer molecular- 12K. K. Vigen, D. C. Peters, T. M. Grist, W. F. Block, and C. A. Mistretta, marker research,” Nat. Rev. Cancer 5, 142–149 ͑2005͒. “Undersampled projection-reconstruction imaging for time-resolved 27W. A. Yousef, R. F. Wagner, and M. H. Loew, “Comparison of nonpara- contrast-enhanced imaging,” Magn. Reson. Med. 43, 170–176 ͑2000͒. metric methods for assessing classifier performance in terms of ROC 13C. A. Mistretta, O. Wieben, J. Velikina, W. Block, J. Perry, Y. Wu, K. parameters,” in Applied Imagery Pattern Recognition Workshop, 2004: Johnson, and Y. Wu, “Highly constrained backprojection for time- Proceedings of the 33rd AIPR Conference ͑IEEE Computer Society, Los resolved MRI,” Magn. Reson. Med. 55, 30–40 ͑2006͒. Alamitos, CA, 2004͒, pp. 190–195. 14C. A. Mistretta, “Innovative physics boosts MRI speed, cuts CT dose,” 28W. A. Yousef, R. F. Wagner, and M. H. Loew, “Estimating the uncertainty Invited article for Diagnostic Imaging magazine ͑August 2007͒, pp. 33– in the estimated mean area under the ROC curve of a classifier,” Pattern 42, concluded on p. 54. Recognit. Lett. 26, 2600–2610 ͑2005͒. 15T. G. Schmidt, J. Star-Lack, N. R. Bennet, S. R. Mazin, E. G. Solomon, 29W. A. Yousef, R. F. Wagner, and M. H. Loew, “Assessing classifiers from R. Fahrig, and N. J. Pelc, “A prototype table-top inverse-geometry volu- two independent data sets using ROC analysis: A nonparametric ap- metric CT system,” Med. Phys. 33, 1867–1878 ͑2006͒. proach,” IEEE Trans. Pattern Anal. Mach. Intell. 28, 1809–1817 ͑2006͒ 16R. F. Wagner, “Lessons from my Dinners with the Giants of Modern ͑TPAMI͒. Image Science,” Radiat. Prot. Dosimetry 114, 4–10 ͑2005͒. 30W. A. Yousef, R. F. Wagner, and M. H. Loew, “The partial area under the 17K. J. Myers, R. F. Wagner, K. M. Hanson, H. H. Barrett, and J. P. Rolland, ROC curve: Its properties and nonparametric estimation for assessing “Human and quasi-Bayesian observers of images limited by quantum classifier performance,” submitted to IEEE Trans. Pattern Anal. Mach. noise, object variability, and artifacts,” Proc. SPIE 2166, 180–190 ͑1994͒. Intell., 2007. 18Details of many applications of the approach of Ref. 17 may be found in 31S. S. Dave et al., “Prediction of survival in follicular lymphoma based on manuscript or abstract form on the website of K. M. Hanson at Los molecular features of tumor-infiltrating immune cells,” N. Engl. J. Med. Alamos, http://public.lanl.gov/kmh/publications 351, 2159–2169 ͑2004͒. 19G. S. Burrill, Biotech 2006—20th Anniversary Report on the Industry. 32R. Tibshirani, “Immune signatures in follicular lymphoma,” N. Engl. J. Life Sciences: A Changing Prescription ͑Burrill and Company, San Fran- Med. 352, 1496–1497 ͑2005͒. cisco, CA, 2006͒. 33H. P. Chan, B. Sahiner, R. F. Wagner, and N. Petrick, “Classifier design 20G. J. McLachlan, K.-A. Do, and C. Ambroise, Analyzing Microarray for computer-aided diagnosis: Effects of finite sample size on the mean Gene Expression Data ͑Wiley, Hoboken, NJ, 2004͒. performance of classical and neural network classifiers,” Med. Phys. 26, 21B. D. Gallas, “Estimating the variance of the ideal linear observer’s 2654–2668 ͑1999͒. signal-detection performance from a finite number of trainers and testers,” 34B. Sahiner, H. P. Chan, N. Petrick, R. F. Wagner, and L. Hadjiiski, “Fea- presented at Medical Image Perception Conference X, Duke University, ture selection and classifier performance in computer-aided diagnosis: Durham, North Carolina ͑2003͒. Proceedings of the conference on disc The effect of finite sample size,” Med. Phys. 27, 1509–1522 ͑2000͒. available from Medical Imaging Perception Society ͑MIPS͒, or file avail- 35R. F. Wagner, C. E. Metz, and G. Campbell, “Assessment of medical able from [email protected] imaging systems and computer aids: A Tutorial Review,” Acad. Radiol. 22V. N. Vapnik, The Nature of Statistical Learning Theory ͑Springer-Verlag, 14, 723–748 ͑2007͒. New York, 1995͒. 36S. V. Beiden, M. A. Maloof, and R. F. Wagner, “A general model for 23T. R. Golub et al., “Molecular classification of cancer: Class discovery finite-sample effects in training and testing of competing classifiers,” and class prediction by gene expression monitoring,” Science 286, 531– IEEE Trans. Pattern Anal. Mach. Intell. 25, 1561–1569 ͑2003͒. 537 ͑1999͒. 37R. M. Simon, E. L. Korn, L. M. McShane, M. D. Radmacher, G. W. 24T. M. Cover, “Geometrical and statistical properties of systems of linear Wright, and Y. Zhao, Design and Analysis of DNA Microarray Investiga- inequalities with applications in pattern recognition,” IEEE Trans. Elec- tions ͑Springer-Verlag, New York, 2004͒. tron. Comput. EC-14, 326–334 ͑1965͒. 38D. Gur, R. F. Wagner, and H.-P. Chan, “On the repeated use of databases 25E. F. Petricoin et al., “Use of proteomic patterns in serum to identify for testing incremental improvement of computer-aided detection ovarian cancer,” Lancet 359, 572–577 ͑2002͒. schemes,” Acad. Radiol. 11, 103–105 ͑2004͒.

Medical Physics, Vol. 34, No. 12, December 2007 Hypofractionation in radiation therapy and its impact ͒ Lech Papieza and Robert Timmerman University of Texas Southwestern Medical Center, Dallas, Texas 75390 ͑Received 26 August 2007; revised 2 October 2007; accepted for publication 1 November 2007; published 19 December 2007͒ A brief history of the underlying principles of the conventional fractionation in radiation therapy is discussed, followed by the formulation of the hypothesis for hypofractionated stereotactic body radiation therapy ͑SBRT͒. Subsequently, consequences of the hypothesis for SBRT dose shaping and dose delivery techniques are sketched. A brief review of the advantages of SBRT therapy in light of the existing experience is then provided. Finally, the need for new technological developments is advocated to make SBRT therapies more practical, safer, and clinically more effective. It is ﬁnally concluded that hypofractionated SBRT treatment will develop into a new paradigm that will shape the future of radiation therapy by providing the means to suppress the growth of most carcinogen-induced carcinomas and by supporting the cure of the disease. © 2008 American As- sociation of Physicists in Medicine. ͓DOI: 10.1118/1.2816228͔

Key words: ablative radiation therapy, hypofractionation, SBRT

I. INTRODUCTION energies utilized. These treatments suffered also from large targeting uncertainties caused by the unavailability of ad- I.A. Historical foundation of conventional fractionation schemes equate imaging techniques and the incapacity of even mildly accurate representations of the dose distribution inside the Traditional radiation therapy delivery requires multiple frac- patient anatomy. tions of 1.5 to 3 Gy administered daily over a period of 3–7 weeks. This regimen has been established based on early I.B. The impact of the early technology experience of treatment with radiation and has been justified When energies of beams were available only in the KeV by widely accepted models of radiobiological effects of x range, the dose to healthy tissue, particularly tissue at body 1–3 rays on human tissue. However, the strategy of traditional surface, exceeded many times the dose deposited at depth fractionation in external beam radiation therapy has not been ͑10–20 cm below surface͒ where typical tumors were lo- the only one practiced historically. After the discovery of cated. This unfortunate characteristic of early dose delivery ionizing radiation, hypofractionated, or even single large technology was responsible for a huge integral dose being dose fraction treatments, were practiced. It has been ob- delivered to the patient’s skin and other healthy parts of the served that large doses per fraction were tumorcidal, espe- body when deeper situated tumors were treated. To make cially for epithelial tumors. Furthermore, early clinical expe- things worse, the early treatment techniques were also inca- rience provided valuable lessons regarding the balance pable of accurately estimating how the dose delivered was between tumor control and tissue toxicities. Early evalua- redistributed to different portions of the patient’s body. When tions of radiation therapy showed that the delivery of a large we take into further account the inability of earlier treatment dose per fraction treatments was leading to unacceptably techniques to locate the target relative to x-ray beams, we high toxicities. Therefore, quite early in the development of realize that only mechanisms of differential effects of radia- radiation therapy these schedules were abandoned because of tion on tumors and normal tissues could have made radiation complications such as fibrosis, stenosis, and vascular injury. therapy an acceptable mode of cancer treatment. Data collected at initial stages of the development of ra- This rationale for utilizing the mechanisms of differential diation therapy were irrefutable. The understanding of the effects between tumors and normal tissues, and ensuing rea- factors contributing to complications was incomplete. The sons for decreasing the dose per fraction, has been based on ability to manage the parameters underlying the unfavorable the insights from radiobiology,1–3 and in particular, from results for large dose fraction therapy was severely limited in mechanisms of repair of sublethal damage, repopulation, re- the early days of radiation therapy by immature technologies assortment within the cycle, and reoxygenation. It has been of dose delivery. However, these early experiences and their inferred from these mechanisms that by fractionating, one impact on the acceptance of particular fractionation schemes can take advantage of superior repair capabilities between have been largely forgotten by later practitioners of radiation fractions of normal tissue from the damage caused by radia- therapy. The paradigm of delivering a dose in small portions tion. In addition, the normal tissues were understood to be has been taken for granted and disconnected from the reflec- able to better repopulate between fractions, and thereby heal tion that early treatments suffered multiple dosimetric limi- or reform mucosa. As far as the tumor was concerned, expo- tations. These limitations included, among others, the inabil- sure of different phases of the cell cycle ͑some more sensi- ity to decrease exposure of normal tissues due to low beam tive to radiation than others͒ was assumed to be more likely

112 Med. Phys. 35 „1…, January 2008 0094-2405/2008/35„1…/112/7/$23.00 © 2008 Am. Assoc. Phys. Med. 112 113 L. Papiez and R. Timmerman: Radiation therapy hypofractionation 113 assured under the provision of multiple, conventional frac- ͑NSCLC͒ patients has been showing that only 20–30% of tionation. Finally, since oxygenated tissue was considered to tumor treatments with conventional fractionation techniques be more radiosensitive, the better reoxygenation of tumors stopped or recessed the growth.5–7 The focus of the estab- during multifractionated dose delivery was thought to be ad- lished radiotherapy is that it is better tolerated compared to vantageous for the therapy. surgery, consistent with the physician’s oath of “first do no The overall mechanism of positive differential effects in harm.” Unfortunately, this may come at a high cost to the eradication of tumor cells vs normal tissues in radiation patient. This stress of radiotherapy has an aura of rationality therapy based on multifractionation regimes has been called when the therapy is deemed to be only marginally effective. the “therapeutic window.” However, the therapeutic window When treating cancer one has to assume, however, that the benefits have not always been well documented and some- potential recurrence is deadly and thus a recurrence has to be times actually may not have worked very well for the thera- treated as the ultimate toxicity. Facing these risks and assum- peutic advantage. In particular, all the above-described ing that radiation therapy may be the treatment of last resort, mechanisms could, under specific conditions, act to the dis- the most appropriate paradigm of radiation therapy should be advantage of radiation therapy. For example, tumors have a establishment of the most appropriate balance between ben- capacity to repair and tumors may repopulate too. In turn, efit and harm from the therapy. normal tissues can also become more sensitive throughout The radical reevaluation of radiotherapy objectives with the course of radiotherapy. Thus, under certain circumstances the goal of changing it from regional adjuvant therapy ͑e.g., and for certain types of cancers and treatment sites, fraction- breast, rectum, sarcoma͒ to curative therapy based on high ation may have actually been detrimental rather than advan- local control rates ͑comparable to surgery͒ requires dramatic tageous for the success of radiation therapy treatment. changes in the dose prescription. It is clear that this change cannot be accomplished through traditional dose escalation. I.C. The conventional fractionation vs Gamma Knife Far-reaching improvements in local control would evidently experience require a massive increase in the number of fractions in traditional dose escalation schemes, extending treatments to The first attempt to revive hypofractionation in the era of 9–10 weeks. From previous experience, it is known, how- ͑ modern radiation therapy arose when high-energy beams in ever, that extended over multiple weeks, treatment leads to ͒ the MeV energy range began to be available and were de- only marginal improvement in therapy results.8 One may livered with Gamma Knife ͑GK͒ radiosurgery. The original 4 speculate that the increased accumulation of tumor regrowth device was conceived by a neurosurgeon who was rightly and repair in conventional fractionated radiotherapy in fact inspired by the thought that MeV radiation can be used as a negates the effectiveness of increased tumor exposure. It surgical tool for the removal of tumorcidal tissue. In conse- seems, therefore, that the one practical method of increasing quence, the idea of focusing radiation on the target from the efficacy of curative radiotherapy is to apply ablative, many sources simultaneously, while keeping the dose small high dose per fraction schemes of therapy delivery. The to the healthy tissues of the brain, was born. The focusing of question appears, however, if the toxicity of such ablative a high dose, together with precise targeting of a dose assisted therapies may be tolerable. These questions may be resolved by stereotactically defined localization of tumor tissue in the only by clinical data, particularly when new technologies and brain, made it possible to realize the idea of tumor ablation new techniques of treatment planning and treatment delivery with limited toxicity to other parts of the brain. Despite the are undertaken to minimize the effects of toxicity based on reservations of the radiation therapy community regarding justifiable hypothesizing from existing data. Fortunately, the application of Gamma Knife technology and one fraction some of these data already exist, and a considerable amount treatment regime to cranial radiotherapy, the results of the of these data indicate that toxicity of ablative therapies are in treatment of brain metastasis and brain tumors in general has fact well tolerated. been characterized over time as favorable. Thus, the question The hypothesis of limiting radiotherapy toxicity at abla- appeared whether the radiosurgical approach in the brain tive dose levels must first take into account the fact that the could also work in other organs of the body. To answer this tissue biological response will be different for hypofraction- question, however, one was obliged to design tools to move ated regimes and for traditional fractionation.9–11 The hypof- radiosurgical techniques to extracranial sites. In particular, ractionated mode of treatment has an ablative character, and this transfer of experience would require targeting extracra- as such, leads to direct obliteration of cancerous cells. How- ͑ nial sites in the same manner as in cranial therapy stereo- ever, it has to be assumed that the same fate would befall ͒ tactically . These tools appeared first in the early 1990s. healthy tissue if it were exposed to equally high levels of radiation as the tumor itself. The situation is similar to radio- II. METHODS surgical treatments performed with the Gamma Knife. Thus, the outcome of hypofractionated approach more II.A. Hypothesis—the need for large dose fractions closely follows the model of surgery than conventionally It has been observed over many years of practice that fractionated radiotherapy. The inevitable damage to healthy conventional radiotherapy is miserably ineffective for gross tissue may be tolerated only if the volumes of obliterated disease, especially for common carcinogen-induced carcino- cells constitute a small portion of the total volume of the mas. The long-term follow-up of nonsmall cell lung cancer organ affected, i.e., as long as surviving tissues of the organ

Medical Physics, Vol. 35, No. 1, January 2008 114 L. Papiez and R. Timmerman: Radiation therapy hypofractionation 114 that experienced partial ablation are capable of replacing the mor and its margin͒ and large portions of below threshold function of the lost fraction of the organ. This strategy, when dose exposed organs ͑lung, liver, etc.͒ are safe from applied to extracranial targets, is called stereotactic body ra- radiation-induced toxicity. diation therapy, or SBRT. The basic assumptions are that: Justifications for the hypofractionation and the design of ͑a͒ The volumes of obliterated healthy tissues are minimal. treatment parameters for extracranial stereotactic radiation ͑b͒ In these larger portions of treated organs where a tumor therapy discussed above are not sufficient for clinical prac- is absent but where radiation is still delivered, the dose tice. There is ample necessity for clinical data to support is below a threshold level, guaranteeing the full recov- these conjectures. Those data were collected in the early ery of these tissues from radiation impact. 1990s, first in Karolinska Hospital in Stockholm, where ͑c͒ It is expected that different types of tissue will react Blomgren and Lax first applied, on a regular basis, extracra- 12–19 differently to injuries caused by ablation resulting from nial radiosurgery treatments. Following on the experi- large doses per fraction treatment. Some small volumes ence of Gamma Knife radiosurgery, they aimed to use ster- of tissues ͑parallel functioning tissues͒ can be removed eotactic guidance and well-focused dose distributions for without dramatic impact on the organ functioning. For extracranial targets. To this end, they designed the stereotac- other tissue affected by treatment ͑serially functioning tic body immobilization frame that played a role similar to tissues͒, the effect of ablation of even a relatively small the head helmet in cranial radiosurgery. The role of frame number of cells may be critically detrimental for organ was to functioning. • Immobilize the patient’s body to increase the accuracy The large dose per fraction model assumes that a tumor of patient positioning and patient body stability during and the healthy tissue directly surrounding the tumor will be treatment; eradicated ͑as happens during surgery͒. This approach to • Decrease the respiratory motions of internal organs in therapy makes it necessary, however, to differentiate between order to make structures and organs in the body more types of tissues exposed to injury during irradiation. In par- static during therapy; and ticular, it can be expected that irradiation effects may cause • Stereotactically target tumors. different reactions in parallel functioning tissues versus serially functioning tissues.2,3 Tissues made up of predominantly Radiotherapy treatment parameters required by hypofrac- structurally defined functional subunits ͑FSU͒ are called par- tionated SBRT were not possible before development of the allel functioning tissues ͑peripheral lung, peripheral liver, pe- relevant technology of radiation delivery. Stereotactic target- ripheral kidney, etc.͒ and are characterized by independent ing for extracranial targets and the ability to plan and deliver redundancy. Thus, a parallel organ’s dysfunction is related focused on-target dose distributions are minimal require- mostly to the fraction of the organ volume exceeding the ments to facilitating SBRT. These provisions were first made threshold dose. On the other hand, tissues made up of pre- possible around 1990. This was the time when the first treat- dominantly structurally undefined FSU’s are called serial ments of this type were accomplished at Karolinska, and less functioning tissues ͑mucosa of GI tract, ducts, bronchus, spi- frequently, at other centers. The original SBRT treatments nal cord, etc.͒ and are characterized by “chain” functioning. relied on setting the target to Cartesian coordinates of the The serial organ dysfunction is related mostly to the number frame system and employing non-coplanar beam arrange- of surviving clonagens and the linear distance they must ments for focusing the radiation on the target.16,38 Addition- travel to “rescue” damaged areas. The consequence for hy- ally, the treatment of chest and abdominal areas employed pofractionated SBRT is that the treatment has to avoid exces- abdominal compression for the reduction of respiratory- sive volume irradiation of parallel organs and keep the dose induced motion of body organs at the time of treatment de- level in serial organ below the threshold level to preserve a 12–46 livery. sufficient amount of clonagens. It should be noted that by modern standards of using 4D CT imaging, IMRT dose shaping, and IGRT-reliant targeting II.B. SBRT hypofractionated therapy—early clinical for radiation therapy delivery, the original tools of SBRT experience were not particularly sophisticated. However, the treatment As the goal of SBRT is the ablation of tissue of the target outcomes from these early days of SBRT therapy were still 12–41 and its close surroundings, the primary importance is as- very encouraging. This can only mean that recent tech- signed to accurate targeting. Radiobiological distinctions be- nologies, though helpful to increase SBRT precision and ef- tween cancerous and healthy tissue are in this case of sec- ficiency, are not compulsory to properly execute hypofrac- ondary concern. Thus, when designing SBRT treatments, one tionated treatments for specific classes of cancer therapy. is led to the conclusion that the target and its close vicinity Essential, however, for the early success of SBRT therapy should be exposed to high doses while regions of the organ was the vigilant attention to detail during simulation, plan- containing the tumor, not in direct contact with the target, ning, and treatment delivery. Well-executed patient immobi- should be exposed to a level of dose below the threshold. lization and accurate repositioning of the patient’s body in This irradiation pattern assumes then that the ablation of tis- the frame before each treatment, together with careful trans- sue is restricted to the target and its close surroundings ͑tu- formation of coordinates of the target from the planning

Medical Physics, Vol. 35, No. 1, January 2008 115 L. Papiez and R. Timmerman: Radiation therapy hypofractionation 115 stage to treatment setup, were able to adequately compensate explained below, the definitive sophistication of integrated for the unavailability of 4D CT and IGRT tools. IMRT and IGRT methods for the delivery of SBRT therapy In addition, the management of respiratory organ motions has not been achieved yet. at times when techniques such as gating, tracking, or breath The other aspect of integrated IMRT and IGRT technol- hold were unavailable was done simply and efficiently by ogy in SBRT delivery is the unquestionable benefit that these suppression of diaphragm motion by abdominal compres- technologies bring to the efficiency of this treatment tech- sion. This simple method allowed for the successful decrease nique. Multiple tasks related to the precision of the patient of margins ͑to below 1 cm in any direction͒, accommodating body setup, as well as the matching of body structures to all target definition uncertainties and target motions. Obser- treatment beam positions, are ultimately difficult to achieve vation of the extent of the target motion, or motion of target unless automated and software-controlled beam shaping ad- surrogate under fluoro, competently allowed verification of justments are performed in real time. This superiority of dose the adequacy of margins. Finally, planning has been judged delivery can be accomplished only through appropriate inte- by the conformity of the prescribed dose surface with the gration of technologies that allow recognizing patient body PTV volume surface and by the quality of the dose descent geometries with treatment delivery modifications in real into healthy tissue. The quality of the dose distribution time. Generally, multiple x-ray, optical, and electromagnetic judged by the dose gradient approach mandated the multiple detectors are employed to register anatomical structures with non-coplanar beam arrangements.37 The dose quality also their motion.. Then, software algorithms have to be devel- has been judged by the careful avoidance of any beams’ oped for analyzing data in real time and responding with passage through serially functioning organs near the target. continuous treatment adjustments. The active involvement in The personal involvement of the clinician at each step of the treatment modification in real time by equipment operators process was deemed indispensable, as well as committed as- ͑therapists͒ and treatment parameter-evaluating personnel sistance from trained physicists, dosimetrists, and radiation ͑physicians, physicists͒ has to be eliminated in this scenario therapists. The early practice of hypofractionated SBRT to make the treatment efficient and precise at the same time. therapy in Europe,12–28 Asia,29–32 and North America33–43 has been universally distinguished by this specifically careful attitude to the innovative therapy. As noted above, the overall III. DISCUSSION commitment of resources to SBRT treatment per fraction may be considerably larger than in the case of traditionally III.A. SBRT—vision for future fractionated radiation therapy. However, hypofractionated SBRT is not yet a completely mature treatment technique. treatment means that only 1–5 treatment sessions will be It requires considerable growth to achieve its full potential. used per course of therapy, rather than the 20–35 treatment Among the numerous developments needed for the enhance- sessions needed for conventionally fractionated treatments.44 ment of the technique, three may have the most immediate The exceptional outcomes of SBRT treatments leave no and significant impact: doubt, however, that the additional toil per fraction is worth the effort. ͑1͒ The main obstacle for safe application of the SBRT treatment technique is the unavailability of data that allow unambiguous determination of the parameters for II.C. SBRT—treatment techniques and radiation fractionation schemes and dose prescriptions; therapy technology ͑2͒ The next impediment for regular application of SBRT is The precision of the setup and delivery required for hy- the imprecision of the dose actually delivered at treat- pofractionated therapies makes technologies of IMRT and ment relative to the dose planned for the therapy. The IGRT ͑though not indispensable as explained above͒ well tightness of the margins and the intent of precise dose suited for efficiently carrying out SBRT treatments. In turn, shaping in the treatment volume makes the dose inaccu- the SBRT therapy may be specifically well suited for show- racy in SBRT a more concerning problem than in con- ing the value of these new technologies to cancer therapy. ventionally fractionated therapy. The main source of the The clinical gains resulting from IMRT and IGRT may be delivery imprecision is the respiratory-induced motion difficult to prove for standard fractionations. For traditional of tissue at treatment.45 This is particularly significant radiation therapy, advances in local control are not expected for IMRT treatments of chest and abdominal targets. to be dramatic when IMRT and IGRT are implemented, and ͑3͒ Finally, the most basic barrier for confident employment improved survival data would be notoriously difficult to of SBRT to a large and diverse patient population and demonstrate. However, in the case of SBRT treatment, the for diverse cases of cancer therapy is the lack of in- combination of radical dose fractionation and the ability to depth understanding of the tissue response to treatment contain the toxicity, inured by superior accuracy of techno- in both short-term and long-term perspective. Interaction logically advanced delivery, will allow more ready measure- between large dose fractions depends on the individual ment of the improvements in local control and in survival characteristics of the tumor, patient genetic make-up, rates. Therefore, the overall results of SBRT delivery, when and immune system stimulation or suppression during supported by IMRT and IGRT technology, should establish radiotherapy. The information about these mechanisms these technologies’ clinical credibility. However, as will be is very limited at this time.

Medical Physics, Vol. 35, No. 1, January 2008 116 L. Papiez and R. Timmerman: Radiation therapy hypofractionation 116

Point ͑1͒ above refers to the determination of the optimal errors and make the a posteriori evaluation of relationships fractionation scheme, including the level of dose prescribed between dose and tissue response unreliable. The second as- to targets and organs, dose uniformity, and dose distribution pect of imprecise imposition of dose clouds over targets and gradient ͑in and around structures͒, and the number of frac- organs at risk are related to the inability to control the deliv- tions used. The number of fractions in SBRT ranges custom- ery of radiation in the presence of the tissue motion. Recent arily from 1 to 5 per course of treatment. The dose per frac- developments in the area of dose delivery in IMRT therapy tion varies considerably in different fractionation schemes, to moving body anatomy show that tissue motion at treat- though it almost never exceeds 30 Gy, even for single frac- ment can actually improve the quality of the dose distribution radiotherapy, and usually does not fall below 7 Gy for tion in the patient body relative to treatments delivered to 46 hypofractionated treatments. The fractionation and geometri- static body anatomy. The intriguing possibility of the dose cal parameters of the prescribed dose are customarily delivery improvement in the presence of the motion of body nonuniform.12–43 This inconsistent approach derives from the anatomy during treatment creates the exceptional opportu- fact that SBRT has been initiated in few centers around the nity of enhancement of SBRT treatment delivery and re- world simultaneously and few efforts have been made so far quires further, careful investigations. This feature of motion- to harmonize the rationalization and treatment practice. The adapted therapy provides a particularly valuable opportunity ͑ available data that could differentiate between the validity of of containing the dose in organs at risk especially, in serially ͒ one approach over the other are still sparse. Therefore, more functioning tissue organs . The potential ability to control the studies are currently being designed with the goal of answer- upper bound of the dose for serially functioning organs may ing questions on optimal SBRT planning and conduct. The give the most valuable tool for extending SBRT treatment to common goals in these studies are sites that otherwise would not have been approachable due to unavoidable toxicity in organs bordering on treated targets. —Local control of 90% or more ͑at 5 years, actuarial͒, Finally, point ͑3͒ can be seen as influencing the range of —Survival 60–80% at 5 years ͑actuarial͒, application of SBRT as well as its efficacy. By the very na- —Grade III or higher toxicity Ͻ15–20%, ture of hypofractionation, the in-treatment modification of —Ideally less invasive than surgery, therapy has limited applications in SBRT. The treatment time —Ideally more convenient than surgery and convention- interval is brief and thus, modification of the plan at treat- ally fractionated radiotherapy, ment ͑increase or decrease of dose, reshaping of dose distri- —Ideally less costly than any alternative treatment. bution, modification of agents and medicaments applied in parallel to, or post-, therapy͒ has only limited prospect of Moreover, these studies all need to be proven by prospective being applied. Recent advancements in molecular imaging testing, built on by experience, and based on guidelines of an and biometrics indicate that molecular testing as well as bio- ͑ 43͒ established QA program e.g., RTOG 0236 study . The chemical matching before treatment ͑or post-first/second overall purpose of these studies will be to find a balance fraction͒ would allow customization of SBRT to the treat- between benefit and harm from the range of SBRT therapies. ment parameters. Factors such as the dose per fraction, over- Generally, the first step will be to start with a phase I dose all dose, dose geometrical shape in the target, and in the escalation toxicity study where the only variable affecting target vicinity, can influence the SBRT technique with a sub- the outcome will be dose. The escalation will last until ex- stantial benefit to a patient. This in turn can minimize the ceeding a predetermined level of severe toxicity ͑usually risks of therapy delivery and enhance its local and global 15–20%͒, determining in this fashion the highest ͑maxi- worth in terms of near-term as well as long-term goal. mum͒ tolerable dose ͑MTD͒. Then, in the phase II study the In conclusion, we can summarize these reflections with MTD from the phase I study will designate how more pa- the claim that the great impact of SBRT on the future of tients are to be treated to confirm the toxicity with a larger radiotherapy, and cancer therapy in general, seems inevi- sample ͑Ͻ15–20% severe͒. Finally, at phase III, the studies table. This assertion is based on the already proven success will be randomized in order to eliminate the selection bias. of the novel paradigm of SBRT hypofractionation. Moreover, Point ͑2͒ has two aspects. The first is related to the uncer- it is based on improved future benefits that may be predicted tainty of the evaluation of the dose that is actually delivered from integration and fine-tuning of the latest technologies to the target and the organs at risk during SBRT treatments. with this treatment technique. The expected local control of This uncertainty makes it difficult to correlate results of tumors with SBRT, in lung and in other chest and abdominal treatments with the dose. Consequently, the precise recom- organs, can be safely predicted from existing data as reach- mendations for dosimetry for treatments of various sites with ing the range of 80–90%.12–43 Moreover, properly executed SBRT are not yet clearly resolved. These difficulties are re- hypofractionated radiotherapy should create the opportunity lated to limited control of tissue motion that influenced the for stimulating the immune system and allow repeating the dose delivery in the past, as well as to inferior dosimetry treatments. Thus, SBRT will likely achieve the level of sur- calculation algorithms, especially those calculations that ig- gical efficiency, without the associated surgery toxicity, mak- nored the scattering contribution from uneven density of tis- ing sequential treatment of multiple metastases possible. Ul- sue in exposed volumes. For dose calculations in the pres- timately, individualized SBRT therapies based on molecular ence of large volumes of different than water-equivalent imaging diagnostics and genetic predictors, will permit mul- density tissue, these algorithms can lead to relatively large tiple applications of curative and prophylactic SBRT treat-

Medical Physics, Vol. 35, No. 1, January 2008 117 L. Papiez and R. Timmerman: Radiation therapy hypofractionation 117 ments with the aim of local control of tumor growth as well for stage I non-small cell lung cancer,” Lung Cancer 48, 107–114 ͑2005͒. 23 as prevention of metastasis formations. The new radiation P. Fritz et al., “Stereotactic, single-dose irradiation of stage I non-small cell lung cancer and lung metastases,” Radiat. Oncol. 1,30͑2006͒. therapy paradigm of hypofractionated SBRT, particularly 24H. Hof et al., “Stereotactic single-dose radiotherapy of stage I non-small- when enhanced by other modalities, and new applications of cell lung cancer ͑NSCLC͒,” Int. J. Radiat. Oncol., Biol., Phys. 56, 335– 341 ͑2003͒. radiosensitizers and radio protectors, should bring the pro- 25 spective of turning many chest and abdominal cancers into a U. Haedinger, W. Thiele, and J. Wulf, “Extracranial stereotactic radiotherapy: Evaluation of PTV coverage and dose conformity,” Med. Phys. chronic disease. 12, 221–229 ͑2002͒. 26U. Haedinger, J. Wulf, U. Oppitz, B. Olshausen, W. Thiele, and M. ͒ a Electronic mail: [email protected] Flentje, “Stereotactic treatment of extracranial targets: Evaluation of plan- 1B. G. Douglas and J. F. Fowler, “The effect of multiple small doses of x ning target volume ͑PTV͒ to compensate for target mobility due to target rays on skin reactions in the mouse and a basic interpretation,” Radiat. motion and inaccuracy of patient positioning *1,”Int. J. Radiat. Oncol., Res. 66, 401–426 ͑1976͒. Biol., Phys. 48, 346–347 ͑2000͒. 2A. B. Wolbarst, L. M. Chin, and G. K. Svensson, “Optimization of radia- 27U. Haedinger, J. Wulf, U. Oppitz, W. Thiele, and M. Flentje, “Extracra- tion therapy: Integral-response of a model biological system,” Int. J. Ra- nial stereotactic radiotherapy: Evaluation of the PTV to compensate target diat. Oncol., Biol., Phys. 8, 1761–1769 ͑1982͒. mobility and set-up inaccuracy over the complete target volume measured 3R. J. Yaes and A. Kalend, “Local stem cell depletion model for radiation by DVH from repeated CT-simulation,” Int. J. Radiat. Oncol., Biol., Phys. myelitis,” Int. J. Radiat. Oncol., Biol., Phys. 14, 1247–1259 ͑1988͒. 51, 45–46 ͑2001͒. 4L. Leksell, “The stereotaxic method and radiosurgery of the brain,” Acta 28M. Nevinny-Stickel, R. A. Sweeney, R. J. Bale, A. Posch, T. Auberger, Chir. Scand. 102, 316–319 ͑1951͒. and P. Lukas, “Reproducibility of patient positioning for fractionated ex- 5B. G. Haffty et al., “Results of radical radiation therapy in clinical stage tracranial stereotactic radiotherapy using a double-vacuum technique,” I, technically operable non-small cell lung cancer,” Int. J. Radiat. Oncol., Strahlenther. Onkol. 180, 117–122 ͑2004͒. Biol., Phys. 15, 69–73 ͑1988͒. 29T. Xia et al., “Promising clinical outcome of stereotactic body radiation 6L. Kaskowitz et al., “Radiation therapy alone for stage I non-small cell therapy for patients with inoperable Stage I/II non-small-cell lung can- lung cancer,” Int. J. Radiat. Oncol., Biol., Phys. 27, 517–523 ͑1993͒. cer,” Int. J. Radiat. Oncol., Biol., Phys. 66, 117–125 ͑2006͒. 7D. E. Dosoretz et al., “Radiation therapy in the management of medically 30Y. Nagata et al., “Clinical outcomes of a phase I/II study of 48 Gy of inoperable carcinoma of the lung: Results and implications for future stereotactic body radiotherapy in 4 fractions for primary lung cancer us- treatment strategies,” Int. J. Radiat. Oncol., Biol., Phys. 24, 3–9 ͑1992͒. ing a stereotactic body frame,” Int. J. Radiat. Oncol., Biol., Phys. 63, 8J. A. Hayman et al., “Dose escalation in non-small cell lung cancer using 1427–1431 ͑2005͒. three-dimensional conformal radiation therapy: Update of a phase I trial,” 31R. Hara et al., “Clinical outcomes of single-fraction stereotactic radiation J. Clin. Oncol. 19, 127–136 ͑2001͒. therapy of lung tumors,” Cancer 106, 1347–1352 ͑2006͒. 9T. T. Puck and P. I. Marcus, “Action of x-rays on mammalian cells,” J. 32H. Onishi et al., “Stereotactic hypofractionated high-dose irradiation for Exp. Med. 103, 653–666 ͑1956͒. stage I nonsmall cell lung carcinoma: Clinical outcomes in 245 subjects 10B. Fertil, I. Reydellet, and P. J. Deschavanne, “A benchmark of cell sur- in a Japanese multi-institutional study,” Cancer 101, 1623–1631 ͑2004͒. vival models using survival curves for human cells after completion of 33R. Timmerman et al., “Extracranial stereotactic radioablation: Results of repair of potentially lethal damage,” Radiat. Res. 138, 61–69 ͑1994͒. a phase I study in medically inoperable stage I non-small cell lung can- 11L. B. Marks, “Extrapolating hypofractionated radiation schemes from ra- cer,” Chest 124, 1946–1955 ͑2003͒. diosurgery data: Regarding Hall et al., IJROBP 21:819–824; 1991 and 34L. E. Gaspar and T. E. Schefter, “Analysis of extracranial stereotactic Halland Brenner, XJROBP 25:381–385; 1993,” Int. J. Radiat. Oncol. radiosurgery via equivalent uniform dose and tumor control probability: Biol. Phys. 28, 829–837 ͑1995͒. Practical ramifications and translational implications,” Int. J. Radiat. On- 12H. Blomgren, I. Lax, I. Naslund, and R. Svanstrom, “Stereotactic high col., Biol., Phys. 54, 225 ͑2002͒. dose fraction radiation therapy of extracranial tumors using an accelera- 35B. D. Kavanagh, R. D. Timmerman, S. H. Benedict, Q. Wu, T. E. tor. Clinical experience of the first 31 patients,” Acta Oncol. ͑Madr.͒ 34, Schefter, K. Stuhr, S. McCourt, F. Newman, R. M. Cardinale, and L. E 861–870 ͑1995͒. Gaspar, “How should we describe the radioblologic effect of extracranial 13H. Blomgren, I. Lax, H. Goranson, T. Kraepelien, B. Nilsson, I. Naslund, stereotactic radlosurgery: Equivalent uniform dose or tumor control prob- R. Svanstrom, and A. Tilikidis, “Radiosurgery for tumors in the body: ability?” Med. Phys. 30, 321–324 ͑2003͒. Clinical experience using a new method,” J. Radiosurgery 1, 63–74 36C. R. Kelsey, T. Schefter, R. Nash, P. Russ, A. E. Baron, C. Zeng, and L. ͑1998͒. F. Gaspar, “Retrospective clinicopathologic correlation of gross tumor 14H. Blomgren, I. Lax, and I. Näslund, “Extracranial stereotactic radiosur- size of hepatocellular carcinoma: Implications for extracranial stereotactic gery. Clinical results,” Int. J. Radiat. Oncol., Biol., Phys. 36, 253 ͑1996͒; radiosurgery,” Int. J. Radiat. Oncol., Biol., Phys. 57, S283 ͑2003͒. I. Lax, H. Blomgren, D. Larson, and I. Naslund, “Extracranial stereotactic 37L. Papiez, R. Timmerman, C. DesRosiers, and M. Randall, “Extracranial radiosurgery of localized targets,” J. Radiosurgery 1, 135–148 ͑1998͒. stereotactic radioablation: Physical principles,” Acta Oncol. 42, 882–894 15H. Blomgren, I. Lax, and I. Näslund, “Radiosurgery for tumors in the ͑2003͒. body,” Int. J. Radiat. Oncol., Biol., Phys. 39, 328 ͑1997͒. 38J. E. Reiff, M. Werner-Wasik, P. R. Anne, R. K. Valicenti, and J. M. 16I. Lax, H. Blomgren, and I. Näslund, “Extracranial stereotactic Galvin, “Interfraction variations of the isocenter relative to coordinates of radiosurgery—method,” Int. J. Radiat. Oncol., Biol., Phys. 36, 258 a stereotactic body frame for the treatment of extracranial lesions,” Int. J. ͑1996͒. Radiat. Oncol., Biol., Phys. 48,345͑2000͒. 17I. Lax, “Stereotactic radiotherapy of liver tumors,” J. Radiosurgery 1, 39J. E. Reiff, M. Werner-Wasik, B. E. Garofola, R. K. Valicenti, P. R. Anne, 239–240 ͑1998͒. A. P. Dicker, W. J. Curran, Jr., and J. M. Galvin, “The efficacy of a 18I. Lax, H. Blomgren, I. Naslund, and R. Svanstrom, “Stereotactic radio- stereotactic body frame in an adaptive radiotherapy program,” Int. J. Ra- therapy of malignancies in the abdomen,” Acta Oncol. ͑Madr.͒ 33, 677– diat. Oncol., Biol., Phys. 51, 172–173 ͑2001͒. 683 ͑1994͒. 40R. D. Timmerman, L. Papiez, R. McGarry, L. Likes, C. DesRosiers, S. 19J. Wulf, K. Baier, G. Mueller, and M. P. Flentje, “Dose-response in ster- Frost, and M. Williams, “Extracranial stereotactic radioablation: Results eotactic irradiation of lung tumors,” Radiother. Oncol. 77,83–87͑2005͒. of a phase I study in stage I non-small cell lung cancer,” Int. J. Radiat. 20J. Nyman, K. A. Johansson, and U. Hulten, “Stereotactic hypofractionated Oncol., Biol., Phys. 57, S280–S281 ͑2003͒. radiotherapy for stage I non-small cell lung cancer—mature results for 41R. Timmerman, L. Papiez, R. McGarry, L. Likes, C. DesRosiers, S. Frost, medically inoperable patients,” Lung Cancer 51, 97–103 ͑2006͒. and M. Williams, “Extracranial stereotactic radioablation: Results of a 21P. Baumann et al., “Factors important for efficacy of stereotactic body phase I study in medically inoperable stage I non-small cell lung cancer,” radiotherapy of medically inoperable stage I lung cancer. A retrospective Chest 124, 1946–1955 ͑2003͒. analysis of patients treated in the Nordic countries,” Acta Oncol. 45, 42R. Timmerman, L. Papiez, and M. Suntharalingam, “Extracranial stereo- 787–795 ͑2006͒. tactic radiation delivery: Expansion of technology beyond the brain,” 22F. B. Zimmermann et al., “Stereotactic hypofractionated radiation therapy Technol. Cancer Res. Treat. 2, 153–160 ͑2003͒.

Medical Physics, Vol. 35, No. 1, January 2008 118 L. Papiez and R. Timmerman: Radiation therapy hypofractionation 118

43R. Timmerman, R. McGarry, C. Yiannoutsos, L. Papiez, K. Tudor, J. Oncol. 45, 779–786 ͑2006͒. DeLuca, M. Ewing, R. Abdulrahman, C. DesRosiers, M. Williams, and J. 45Treating Tumors that Move with Respiration, edited by H. Urschel, L. Fletcher, “Excessive toxicity when treating central tumors in a phase II Kresl, J. Luketich, L. Papiez, and R. Timmerman ͑Springer, Berlin, 2007͒. study of stereotactic body radiation therapy for medically inoperable 46L. Papiez, R. McMahon, and R. Timmerman, “4D IMRT planning and 24 ͑ ͒ early-stage lung cancer,” J. Clin. Oncol. , 4833–4839 2006 . delivery—Formulation and preliminary results,” in The Radiotherapy Dy- 44R. Timmerman, J. Galvin, J. Michalski, W. Straube, G. Ibbott, E. Martin, namic, XVth International Conference on the Use of Computers in Ra- R. Abdulrahman, S. Swann, J. Fowler, and H. Choy, “Accreditation and ͑ quality assurance for radiation therapy oncology group: Multicenter clini- diation Therapy, Vol. 1, edited by J. P. Bissonnette and D. Bahig Univer- ͒ cal trials using stereotactic body radiation therapy in lung cancer,” Acta sity of Toronto, Toronto, 2007 , p. 298.

Medical Physics, Vol. 35, No. 1, January 2008 Small fields: Nonequilibrium radiation dosimetry ͒ Indra J. Dasa Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 George X. Ding Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 Anders Ahnesjö Department of Oncology, Radiology and Clinical Immunology, Section of Oncology, Uppsala University, S-751 85 Uppsala & Nucletron AB, S-751 47 Uppsala, Sweden ͑Received 31 July 2007; revised 24 September 2007; accepted for publication 18 October 2007; published 20 December 2007͒ Advances in radiation treatment with beamlet-based intensity modulation, image-guided radiation therapy, and stereotactic radiosurgery ͑including specialized equipments like CyberKnife, Gamma Knife, tomotherapy, and high-resolution multileaf collimating systems͒ have resulted in the use of reduced treatment fields to a subcentimeter scale. Compared to the traditional radiotherapy with fields Ն4ϫ4cm2, this can result in significant uncertainty in the accuracy of clinical dosimetry. The dosimetry of small fields is challenging due to nonequilibrium conditions created as a consequence of the secondary electron track lengths and the source size projected through the collimating system that are comparable to the treatment field size. It is further complicated by the prolonged electron tracks in the presence of low-density inhomogeneities. Also, radiation detectors introduced into such fields usually perturb the level of disequilibrium. Hence, the dosimetric accuracy previously achieved for standard radiotherapy applications is at risk for both absolute and relative dose determination. This article summarizes the present knowledge and gives an insight into the future procedures to handle the nonequilibrium radiation dosimetry problems. It is anticipated that new miniature detectors with controlled perturbations and corrections will be available to meet the demand for accurate measurements. It is also expected that the Monte Carlo techniques will increasingly be used in assessing the accuracy, verification, and calculation of dose, and will aid perturbation calculations of detectors used in small and highly conformal radiation beams. © 2008 American Association of Physicists in Medicine. ͓DOI: 10.1118/1.2815356͔

Key words: small ﬁeld dosimetry, nonequilibrium conditions, Monte Carlo

I. INTRODUCTION beam energy, the composition of the medium, and particularly the density of the medium. With a large variety of ra- With image guidance and improved treatment delivery tech- diation detectors marketed by various manufacturers cover- niques at the core of modern radiation therapy, the treatment ing all sizes ͑from mini to micro͒, types ͑ionization chamber, ϫ 2 fields that traditionally spanned from 4 4cm up to 40 semiconductor, chemical, film, etc.͒, and shapes ͑thimble, ϫ 2 40 cm are now being reduced down to a subcentimeter spherical, plane parallel͒, the choice of a suitable detector for range in advanced and specialized radiation treatments such small field dosimetry could be a challenging and rather con- as beamlet-based intensity modulated radiation therapy fusing task without proper guidelines. It is not too uncom- ͑IMRT͒, image-guided radiation therapy ͑IGRT͒, tomo- mon in clinical practice to compare measurements with vari- therapy, stereotactic radiosurgery ͑SRS͒ with high-resolution ous detectors and choose the detector that yields the highest multileaf collimator, Gamma Knife, and CyberKnife. In par- output for a given field size, or to select a measured value ticular, the SRS, Gamma Knife, and CyberKnife rely on very that is common to several detectors, without proper consid- small field sizes on the order of a few millimeters to treat tumors and spare normal structures. IMRT requires the addi- eration of the possible perturbations and corrections for each tion of small fields with nonequilibrium conditions to treat of the detectors. Such approaches do not provide the scien- target volumes using optimization routines. Several dosimet- tific basis needed to achieve the confidence for dosimetric ric challenges due to this trend are lack of charged particle accuracy commonly set for clinical practices. To deal with 10–17 equilibrium ͑CPE͒,1,2 partial blocking of the beam source these difficulties, a growing number of authors have re- giving rise to pronounced and overlapping penumbra,3–6 the ported the comparison of measured data with Monte Carlo availability of small detectors for sizes comparable to the simulation. However, at the present time Monte Carlo simu- field dimensions,7,8 and variations of the electron spectrum lations cannot be assumed to invariably provide a gold stan- inducing changes in stopping power ratios.9,10 dard without appropriate experimental validation. These de- Electronic equilibrium is a phenomenon associated with velopments challenge the conventional way of performing the range of secondary particles and hence dependent on the dosimetric measurement and treatment planning. The pur-

FIG. 1. With field sizes large enough to yield charged particle equilibrium ͑CPE͒ and fully viewed sources, the full width at half maximum ͑FWHM͒ of dose profiles yields correctly determined field sizes since the field borders will be approximately at the level of 50% of the dose level of CPE, as shown in panel ͑a͒. When the field size is of the same order as the charged particle lateral diffusion distance, the penumbra from opposing field edges overlap, causing a small error in field size determination from FWHM data ͓panel ͑b͔͒, but completely break down for very small fields since the resulting curve has a lower maximum and hence its half value will be pushed outward from the correct position, resulting in an overestimated field size as shown in panel ͑c͒.

pose of this paper is to illustrate the problem, provide pos- mum ͑FWHM͒ break down, resulting in overestimated field sible solutions, and predict future trends in small field radia- sizes as shown ͑Fig. 1͒. It has been demonstrated by Ding et tion dosimetry. al.21 that the beam output ͑planar fluence profile͒ can be significantly influenced by the auxilary collimator ͑jaw͒ set- II. PROBLEMS tings used to achieve the small field sizes. This is reflected in Fig. 2, indicating the profile patterns for the 6 MV beam for II.A. What is small? 6ϫ6 and 24ϫ24 mm2 fields with various jaw settings. For The definition of a small field in radiation dosimetry is nonfocused multileaf collimators the light fields are not con- currently very subjective and ad hoc. There is no clear congruent with the radiation field due to the curved nature of the sensus definition as to what constitutes a small field. Com- leaves permitting variable amounts of radiation through dif- monly, a field size of less than 3ϫ3cm2 is considered out- ferent thicknesses of the leaves.22 This positional depen- side the conventional treatment field size that needs special dence, varying from one side of the field to the other, further attention both in dose measurements and in dose calcula- complicates the precise metrics of small field sizes. tions. A more scientific approach is needed to set the criteria which define a small field condition based on the beam en- II.C. Electron ranges and loss of CPE ergy and the density of the medium. There are essentially three “equilibrium factors” that determine the scale if a ra- The electrons produced from megavoltage photon beams diation field is to be considered as small or not: ͑i͒ the size of have a considerable range that gets prolonged in a low- the viewable parts of the beam source as projected from the density medium. Compared to the field size, the lateral range ͑ ͒ of the electrons is the critical parameter to the CPE, rather detector location through the beam aperture; ii the size of 23 the detector used in measurements; and ͑iii͒ the electron than the forward range of the electrons. Li et al. described range in the irradiated medium. These factors are discussed the lateral range of electrons which are energy dependent. below. Shown in Fig. 3 are primary dose profiles in water across a collimating edge for different beam energies, specified by ͑ ͒ 24,25 II.B. Effects of the radiation source size their quality index TPR20/10 . This provides the information of penumbra ranges in unit density media that set the By collimating a beam from a source of finite width, it is dimensions of when small field conditions apply based on clear that below a certain field size, only a part of the source overlapping electron distribution zones from different field area can be viewed from a detector’s point of view. The edges.26 output will then be lower than compared to field sizes at which the entire source can be viewed from the detector’s II.D. Measurement field of view.3,4,6,18–20 The output changes differently depending on position contributing to the phenomena yielding a For photon beams, measured data are used in dose calcu- blurred and widened profile as illustrated in Fig. 1.Ifthe lation to provide the absolute dose normalization at a refer- entire source cannot be viewed from the center of the field, ence field, and through a beam modeling procedure indi- then the geometrical penumbra is extended all over the field rectly drive dose calculations based on relative data such as 3,4,19 ͑ ͒ ͑ ͒ cross section. Under such conditions traditional methods total scatter factor Scp , tissue maximum ratio TMR , perfor field size determination such as full width at half maxi- cent depth dose ͑PDD͒, and off-axis ratio ͑OAR͒. The refer-

Medical Physics, Vol. 35, No. 1, January 2008 208 Das, Ding, and Ahnesjö: Small ﬁelds: Nonequilibrium radiation dosimetry 208

FIG. 3. The graph shows the primary dose profile in water across a collimating edge for different beam energies, specified by their quality index ͑ ͒ TPR20/10 , ranging from 0.68 to 0.80 at an interval of 0.2. Ideal “spot source” fluence profiles are assumed with only the electron transport that contributes to the penumbra width.

r t r D ͑r͒ D ͑E,r͒ W¯ S t = ͩ t ͪͩ ͪ ͩͩ ͪ ͪ , ͑2͒ ͑ ͒ ͑ ͒ ␳ Dt ref Dt ref e ref a ref where Q is the detector reading of charge, m is mass of the air in an ion chamber, W/e is ionization potential of air, r is ͑ /␳͒t the field dimension, ref is reference field size, and S a is the mass collision stopping power ratio of tissue ͑t͒ to air ͑a͒.28–30 All of the parameters in Eq. ͑2͒ are energy dependent; hence, the dose in small fields compared to the reference or calibration field ͑10ϫ10 cm2͒ is uncertain due to FIG. 2. The effects of source size and beam shaping geometry on the output spectral variations. The measured ionization readings Q͑E,r͒ 2 2 of a small field, ͑a͒ 6ϫ6mm and ͑b͒ 24ϫ24 mm . Both field sizes are are influenced by many factors as shown below: defined by the micro multi-leave collimator ͑mMLC͒ and the variation are caused by different settings of auxilary jaws. ͑Reproduced with permission ͑ ͒ ͑ ͒ Q E,r = QmPionPreplPwallPcecPpcf, 3 from Ding et al., Ref. 21.͒ where Qm is measured reading, Pion in the ion recombination, Prepl is the replacement correction factor, Pwall is wall correc- ence dose calibration is performed according to the dosime- tion factor, Pcec is the central electrode correction factor, and 24,25,27 try protocols with a well-defined beam geometry, Ppcf is the perturbation correction factor as described in where beam quality and dosimetric parameters are known to TG-21 ͑Ref. 25͒ and by Nahum.2 Usually the ratio of these a high degree of accuracy. Dose measurements with ioniza- correction factors as shown in Eq. ͑2͒ is ignored in routine tion chambers rely on the assumptions of cavity theory. clinical practices where CPE exists, but they cannot gener- When the size of the cavity is smaller than the range of ally be ignored for small fields as noted by Seuntjens and charged particles originated in the medium, the cavity is Verhaegen31 and Sauer and Wilbert.8 It was observed that for treated as nonperturbing. In such a situation, the dose to the a small volume mini-ion chamber ͑Exradin A14P͒ the pertur- medium is related to the dose to the air in the cavity by the bation factor is larger than unity by about 36%, 30%, and stopping power ratios of medium to air. However, with de- 18% for circular field diameter of 1.5, 3, and 5 mm, respec- creasing field size, neither the CPE nor the conditions for the tively. As noted by several other investigators,8,16,32 these cavity theory can be fulfilled due to the lateral range of the large differences are mainly due to nonequilibrium condi- electrons. For a small field when the CPE does not exist, the tions which are dependent on the type and design of the presence of a detector can change the local level of the CPE, detector. The magnitude is significantly larger in low-density adding more perturbations to complicate the problem. media. In a heterogeneous medium, these factors ͑in particu- ͒ Under electronic equilibrium, cavity theory describes a lar Prepl are not easy to predict because of the uniqueness of method to calculate the dose ͑D͒ in a medium based on measurement conditions in small fields.33,34 The Monte Carlo measured charge in the cavity, simulation has been shown to be an effective tool to study 33,34 t these effects. A significant amount of work is still needed Q W¯ S D = ͩ ͪͩ ͪͩ ͪ , ͑1͒ to calculate factors for the field size, beam energy, and de- t ␳ m e a tector geometry.

Medical Physics, Vol. 35, No. 1, January 2008 209 Das, Ding, and Ahnesjö: Small ﬁelds: Nonequilibrium radiation dosimetry 209

The second factor in Eq. ͑2͒ is usually ignored since W/e from the RPC values have been observed, indicating the se- is treated as relatively constant, even though it might depend riousness of the dosimetric problem. The accurate dosimetry slightly on beam energy.35,36 This assumption is based on for small field remains a problem until an appropriate and small changes in the spectrum versus field size. The third consistent procedure is available and widely accepted by a factor in Eq. ͑2͒ is of significant interest. However, it is often majority of users to calibrate nonstandard beams. ignored in clinical settings.37,38 The photon spectrum does change9,39 with field size and location off axis; however, the stopping power ratio is shown to be relatively insensitive for II.G. Low-density inhomogeneity low-energy photon beams within the accuracy of the mea- In low-density medium like the lung, small fields are sub- ͑Ͻ ͒ 9,10,13–15,40–43 surements 1% . However, for high-energy ject to significant perturbations that are energy- and density 44 beams it cannot be ignored. With a clear knowledge of the dependent. Treatment planning algorithms that use simple photon and electron spectra in small fields, the terms 2 and 3 one-dimensional density scaling fail to provide accurate dose ͑ ͒ 45–51 in Eq. 2 can therefore be better estimated in the future distributions as noted in several publications. Advanced evaluation. Another measurement-related problem is the ex- treatment planning algorithms in general provide more accu- perimental determination of field size. When small field con- rate dose calculations in treatment planning.34,52–54 However, ditions prevail, overlapping penumbra cause traditional in clinical trials, a consistent approach in radiation dosimetry methods for field size determination based on full width at is necessary. In order to make the outcome comparison ͑ ͒ half maximum FWHM metrics to break down, resulting in meaningful, new treatment protocols have yet to take advan- overestimated field sizes as shown in Fig. 1. tage of these more accurate treatment planning algorithms, which are now available in many commercial 3D treatment II.E. Corrections and perturbations planning systems. The main problem associated with the dosimetry of small fields is the very presence of the detector itself that produces 33,34 III. PRESENT KNOWLEDGE a perturbation hard to quantify in a reliable way. This is because the detector is normally different from the medium III.A. Experiment in both composition and density. The major source of the With advances in technology, radiation detectors have effect comes from the perturbation of the charged particle evolved and improved in quality. Various manufacturers of- fluence, which depends not only on the detector geometry fer a wide range of radiation detectors including ion cham- but also on the medium in which the measurement is per- ber, solid-state detector, diode, TLD, scintillator, chemical, formed, as well as on the beam energy and field size. There- Fricke, film, alanine, and others. These detectors can be cat- fore, it is difficult to use standard correction methods in the egorized as standard, mini-, and micro-detectors depending dosimetric measurement of the small field in heterogeneous on the sizes Ϸ10−1, Ϸ10−2, and Ϸ10−3 cm3, respectively. media because, in addition to other known corrections,25 the An assortment of ion chambers and other radiation detec- value of P in Eq. ͑3͒ is field size- and phantom geometry- repl tors is available that can be used for a specific task in dosim- dependent. etry. Ionization chambers have been widely used in radiation dosimetry due to their near independence of energy, dose, II.F. Absolute dose and dose rate. They provide a reproducible direct reading and For accurate patient treatment, knowledge of the absolute can be calibrated to a national standard to calculate the dose. dose in a reference beam is required. This is performed Ion chambers are relatively inexpensive, readily available, through TG21 ͑Ref. 25͒ or TG-51 ͑Ref. 27͒ protocols in and are manufactured in various shapes ͑cylindrical, spheri- North American, and the IAEA protocol24 or other dosimetry cal, and parallel plate͒ and sizes for various protocols developed in other countries. These protocols pro- applications.12,17,39,43,55–58 For special procedures such as vide the methodology to perform dosimetry in a reference SRS, Gamma knife, CyberKnife, tomotherapy, and IMRT, field, usually 10ϫ10 cm2, where the radiological param- the wide availability of radiation detectors questions the se- eters in the reference conditions are available. For some lection and proper use of detectors, which has been ad- treatment modalities used in SRS treatments, such as Gamma dressed by various investigators.7,10,12–15,39,59–67 Figure 4 Knife, CyberKnife, and tomotherapy, the reference beam shows the measured dose at central axis in the form of rela- ͑ ϫ 2͒ condition field size of 10 10 cm does not exist. In such tive dose, Scp , for 6 and 15 MV beams measured from vari- a situation there is no simple method to provide absolute or ous detectors. A rapid drop in dose with a certain detector is reference dosimetry. It is often indirectly performed by trans- observed when the field size is decreased. This figure repre- ferring, extrapolating, or intercomparing among various de- sents only the ratio of reading without any correction, as tectors, usually film, TLD, or a small volume ion chamber. noted in Eq. ͑3͒. The effect is more magnified for high- The procedure for such a transfer is usually dependent on the energy beams, possibly due to a nonequilibrium condition, choice of an individual physicist and the measurement equip- perturbation corrections as noted in Eq. ͑3͒, and volume ment used. The Radiological Physics Center ͑RPC͒ in Hous- averaging.61 With various detectors, the small field produces ton has undertaken the task of intercomparing doses from challenges in dose measurements with a greater probability participating institutions. Significant deviations in dosimetry of significant error.

Medical Physics, Vol. 35, No. 1, January 2008 210 Das, Ding, and Ahnesjö: Small ﬁelds: Nonequilibrium radiation dosimetry 210

͑ ͒ FIG. 4. Total scatter factor Scp versus field size measured with various available radiation detectors for ͑a͒ 6MV and ͑b͒ 15 MV beams. The data are plotted without the consideration of any corrections or perturbations and simply the ratio of reading in a field size to the reference field.

Semiconductor diode detectors are being widely used for effect should be used. Often diode detector measurements patient dosimetry for both photon and electron beams. Diode are compared with an ion chamber to provide confidence in detectors have small sensitive volumes and are categorized small field dosimetry. The stereotactic photon diode ͑SFD͒ as mini- and micro-detectors. Characteristics include quick with nearly micron-size sensitive volume has become an at- ͑ response time microseconds compared to milliseconds of an tractive choice for small field dosimetry.23,72–74 ͒ ion chamber , excellent spatial resolution, absence of exter- Diamond detectors are solid-state detectors with large signal bias, and high sensitivity. In addition, stopping power nals and the sensitive volume is relatively small ͑1.0 ratios for diodes are nearly energy independent, but the pres- −6.0 mm3͒, which makes them ideal for small field dosim- ence of low-energy photons causes problems due to the in- 75 creased photoelectron cross sections in silicon compared to etry and for beam profile measurements. When ionizing radiation is absorbed, it induces a temporary change in the water. The response of the diode detectors depends on tem- 76–80 perature, dose rate ͑SSD or wedge͒, and energy.68–70 De- electrical conductivity of the material. The response of a pending on the design of the diode, some may have angular diamond detector is directly proportional to the absorbed dependence as well. In order to achieve the required accu- dose rate. Diamond detectors do not exhibit any directional racy recommended by AAPM,71 these effects should be cor- dependence and they are tissue-equivalent. Diamond detec- rected, or a diode with a minimum dose rate and energy tors do exhibit a small dependence on dose rate, but a cor-

Medical Physics, Vol. 35, No. 1, January 2008 211 Das, Ding, and Ahnesjö: Small fields: Nonequilibrium radiation dosimetry 211 rection can be applied for the measurements. The detector is III.B. Theoretical and analytical approach hard to manufacture and hence more expensive than other To derive accurate beam profiles from large volume solid-state detectors. chamber measurements, deconvolution and extrapolation ͑ ͒͑ ͒ 59,61,90,97–102 Thermoluminescent dosimetry TLD Ref. 81 has been methods have been used. The confidence in do- used for point dose measurements and in vivo dosimetry. The simetry is greater with larger fields; hence, various math- TLD material comes in several different forms, such as rods, ematical approaches have been proposed for getting either chips, and powder. Rods and chips are reusable once they the relative or absolute dose.103–105 Sauer et al.8 and Cheng et have been properly annealed. TLD exhibits an energy depen- al.72 provided an extrapolation method and mathematical ex- dence as well as a dose dependence. The accuracy is limited pressions for output in small fields accurately. to the irradiation and measuring techniques. It is usually suitable for cross reference of point dose in small fields and III.C. Monte Carlo simulation IMRT. Monte Carlo ͑MC͒ approaches are rapidly finding a niche Film is used for relative dose measurement. There are two where measurements are not possible or rather difficult. Vari- 82 83 types of films: silver halides and Gafchromic. Silver ha- ous reports have highlighted the feasibility of MC for small lide films require processing, whereas Gafchromic films are field dosimetry.9,34,106–110 Monte Carlo simulation provides self-developing. TG-69 provided an overview82 of silver ha- an opportunity to investigate most of the correction factors as lide films. Gafchromic film has some superior characteris- discussed in Eq. ͑3͒. It also provides a standard against other tics; however, its use is limited to relative dosimetry.84 Even techniques for the measurement of relative dose and possibly though film exhibits strong energy dependence, it does pro- absolute dose within acceptable accuracy. Monte Carlo simu- vide a planar dose maps in small fields16,18,85 that is superior lation also provides the opportunity to understand dosimetry to other detectors. in low-density materials where measurements are difficult 45,46,48–51,54 Metal-oxide silicon semiconductor field-effect transistor with nonequilibrium conditions. There are two ap- ͑MOSFET͒ dosimeters have been investigated for their use proaches in using Monte Carlo techniques to improve the in clinical dosimetry86 and IMRT verification.87 Due to their accuracy of radiation dosimetry. One is to obtain correction factors for detectors used in the measurements. The other is small size, MOSFETs are ideal for small field dosimetry in to calculate the dosimetry quantities directly equivalent to low-density medium,33 brachytherapy, and in vivo dosimetry. performing a measurement in an ideal condition. However, The MOSFET detectors are relatively small in size with an the use of Monte Carlo needs to be verified with respect to ϫ 2 active area of 0.2 0.2 mm . It is energy independent in beam modeling parameters ͑e.g., source size and energy, MV beams. Also, it is relatively independent of dose rate and etc.͒. temperature. It has been noted that MOSFET dosimeters are similar to conventional dosimeters in reproducibility, linear- IV. FUTURE DIRECTIONS ity, energy, and angular responses.86 However, the MOSET detector is used mainly for specialized point dose measure- IV.A. Absolute dose ments and has a short life. It also requires repeated calibra- There is a growing trend and availability of specialized tion for accurate dose measurements. treatment machines that cannot provide the standard 10 Bang gel detectors88 are tissue-equivalent and provide a ϫ10 cm2 field for reference calibration as required by stan- 3D dose map with high spatial resolution. They are energy dard dosimetry protocols. With advances in treatment de- independent over a wide range of energies, making them vices delivering subcentimeters treatment fields, there is a ideal for measuring three-dimensional dose distributions. Pa- need for absolute dosimetry protocol. The normal use of ppas et al.89,90 provided satisfactory data for small SRS cone some of these machines is to produce dose distributions for with gel detectors. The downside to gel dosimetry is that it targets large enough to establish CPE, but from the superpo- takes considerable fabrication time for the proper working sition of smaller fields. Hence, to calibrate these machines conditions. Bang gel readout is based on imaging techniques under working conditions representative of their normal operating mode, dosimetry protocols need to be reviewed and that are susceptible to imaging artifacts. The new research formulated to accommodate these new modalities. The Inter- using MAGIC gel has shown some promising results in its national Atomic Energy Agency ͑IAEA͒ and American As- usefulness in dosimetry of SRS and IMRT.91 sociation of Physicists in Medicine ͑AAPM͒ have formed a Radiophotoluminescent glass plates have been used suc- 13,66,67 joint task group to address the absolute dose issue in small cessfully to measure dose in SRS and Cyberknife. fields. As a result, an international protocol will be provided Scintillator detectors in various forms have also provided for beam quality specification in small fields, detector- 92–94 dosimetry in small and elongated fields. Alanine pallets specific correction, and perturbation factors. Any detector- have been attempted to measure dose in small fields using related problem with responses to the superposition of time- 95,96 the electron spin resonance ͑ESR͒ method; however, separated small field condition subfields should be addressed such devices are limited and may not be used clinically ex- and investigated so as to provide beam calibration protocols cept to verify the point dose at a central location or in a with the same accuracy as present standard beam protocols, national laboratory. i.e., approximately ±2%.

Medical Physics, Vol. 35, No. 1, January 2008 212 Das, Ding, and Ahnesjö: Small ﬁelds: Nonequilibrium radiation dosimetry 212

IV.B. Better detectors calibrated in a reference condition per incident electron at target in the linear accelerator. Since the geometry of the Advances in radiation detectors and specialized treatment accelerator head can be modeled in detail, the output or the techniques have fueled the need for better and suitable de- entire realistic beam of any field size can be accurately detectors. Many types of detectors have been used in small termined by radiation transport calculations. Therefore, the fields and cross compared with other 10,13,14,17,41,43,55,56,62,73,74,84,89,90,93,94,96,111–113 nonequilibrium dosimetry for the small field in heteroge- detectors; how- neous media can be investigated and well understood. The ever, the particular perturbation corrections are not known in Monte Carlo technique will not only play a crucial role in the detail. It is expected that calculation-aided dosimetry will be small beam output calibration but will also contribute to in- available where specific correction and perturbation factors creased accuracy in patient dose calculations. These types of are either precalculated for irradiation geometry or calculated calculations will play an increasing role in dose verification, online using state-of-the-art radiation transport codes, e.g., beam analysis, and for direct calculation of dose distribution Monte Carlo. With improved manufacturing techniques with in treatment planning and treatment delivery. the emphasis on making reproducible detectors, it is likely that empirical corrections in hardware ͑e.g., energy- compensated shielding on diodes͒ will be replaced by calculated correction factors. This type of calculation-aided detec- V. CONCLUSIONS tor could provide energy, dose, and dose rate independence It is expected that the accuracy of small field dosimetry suitable for small field dosimetry. under a nonequilibrium condition can be significantly improved based on the following developments: IV.C. Treatment planning, beam modeling, and dose • New protocols for absolute dosimetry in small and non- calculations equilibrium condition will be developed to provide pro- Apart from the accuracy in measured data, the treatment cedures for accurate absorbed dose calibrations for new planning systems ͑TPS͒ should provide proper modeling to treatment modalities such as Gamma Knife, Cy- adequately predict the dose distribution in nonequilibrium berKnife, tomotherapy, and other devices that do not conditions and with inhomogeneous medium. Properly de- have standard reference field sizes. This will effectively signed multisource modeling using either accurate measured reduce the uncertainty and variations among different data3,4,6 or Monte Carlo derived data, together with accurate centers in the absolute reference dose calibration. dose calculation algorithms that handle non-CPE conditions, • Small volume detectors ͑ion chambers, diodes, and oth- will provide acceptable dose distribution. To meet the de- ers͒ will be developed that have minimum perturbations mand, the TPS vendors should take responsibility for provid- due to its presence and composition. Also, such detec- ing suitable implementations of either convolution/ tors will have minimum energy, dose, and dose rate superposition algorithms,26 Monte Carlo, or any other dependence. methods known to be capable of handling small field condi- • The accuracy of small field dosimetry will be greatly tions. Collaboration with clinicians and treatment planners improved by Monte Carlo simulations, especially under will provide planning methodology for lung tumors with re- extreme conditions, for small fields ͑such as beam size 2 spect to the use of margins and immobilization techniques as Ͻ3ϫ3cm with inhomogeneity͒. Current measure- dense tumors increase CPE and hence dose, compared to the ment uncertainty ͑Ͼ5%͒ will be reduced. Monte Carlo surrounding low-density lung tissue. calculations will be able to accurately relate the dose to a small field irradiated in an inhomogeneous media to the dose of reference conditions in which the radiation IV.D. Monte Carlo techniques and radiation transport beam is calibrated. This will ensure that the uncertainty calculations of the dose determination in a small treatment field un- The accurate determination of dose distributions plays an der extreme conditions remains similar in magnitude to essential role in the success of radiotherapy. Explicit radia- the uncertainty of a large reference field where the tion transport calculations based on Monte Carlo or other beam is calibrated. techniques will increasingly play an important role in non- • Monte Carlo simulations will provide correction param- equilibrium dosimetry. With the aid of calculations in the eters, such as correction factors for specific detectors future, the measurement accuracy should be greatly im- and for specific measurement conditions, and the stop- proved for these cases. It has been shown that, even when the ping power ratio as a function of field size and beam experimental measurements were correct, conclusions drawn energy. These additional data will be available for rou- from the measured data could be incorrect because the re- tine use and will greatly reduce the measurement uncer- sults were misinterpreted due to the lack of knowledge of the tainty under the nonequilibrium radiation conditions. perturbation from the presence of a detector.34,114 In addition, • More accurate implementation of model-based calcula- the Monte Carlo simulated beams can be calibrated against tion algorithms as well as direct Monte Carlo methods measurements under controlled conditions where the mea- will be available in commercial treatment planning sys- surements can be determined accurately. For example, a tems for accurate dose calculation under the nonequilib- Monte Carlo simulated incident megavoltage beam can be rium radiation conditions.

Medical Physics, Vol. 35, No. 1, January 2008 213 Das, Ding, and Ahnesjö: Small ﬁelds: Nonequilibrium radiation dosimetry 213

͒ a Author to whom correspondence should be addressed. Electronic mail: tors using miniphantoms and brass caps,” Med. Phys. 22, 1167–1170 [email protected]; ͑1995͒. ͒ b Telephone: 215-662-6472; Fax: 215-349-5978. 24I. A. E. A. Report No. 398, “Absorbed Dose Determination in External 1F. H. Attix, Introduction to Radiological Physics and Radiation Dosime- Beam Radiotherapy: An International Code of Practice for Dosimetry on try ͑Wiley & Sons, New York, 1986͒. Standards of Absorbed Dose to Water,” Technical Reports Series No. 398, 2A. E. Nahum, “Perturbation effects in dosimetry. I. Kilovoltage x-rays International Atomic Energy Agency, 2000. and electrons,” Phys. Med. Biol. 41, 1531–1580 ͑1996͒. 25Task Group-21, Radiation Therapy Committee, AAPM, “A protocol for 3M. B. Sharpe, D. A. Jaffray, J. J. Battista, and P. Munro, “Extrafocal the determination of absorbed dose from high-energy photon and electron radiation: A unified approach to the prediction of beam penumbra and beams,” Med. Phys. 10, 741–771 ͑1983͒. output factors for megavoltage x-ray beams,” Med. Phys. 22, 2065–2074 26T. Nyholm, J. Olofsson, A. Ahnesjo, and M. Karlsson, “Modeling lateral ͑1995͒. beam quality variations in pencil kernel based photon dose calculations,” 4T. C. Zhu and B. E. Bjarngard, “The head-scatter factor for small field Phys. Med. Biol. 51, 4111–4118 ͑2006͒. sizes,” Med. Phys. 21, 65–68 ͑1994͒. 27P. R. Almond, “AAPM’s TG-51 protocol for clinical reference dosimetry 5T. C. Zhu and B. E. Bjarngard, “The fraction of photons undergoing head of high-energy photon and electron beams,” Med. Phys. 26, 1847–1870 scatter in x-ray beams,” Phys. Med. Biol. 40, 1127–1134 ͑1995͒. ͑1999͒. 6T. C. Zhu, B. E. Bjarngard, and H. Shackford, “X-ray source and the 28P. Andreo and A. Brahme, “Stopping power data for high-energy photon output factor,” Med. Phys. 22, 793–798 ͑1995͒. beams,” Phys. Med. Biol. 31, 839–858 ͑1986͒. 7P. Francescon, S. Cora, C. Cavedon, P. Scalchi, S. Reccanello, and F. 29P. Andreo, J. R. Cunningham, K. Hohlfeld, and H. Svensson, Absorbed Colombo, “Use of a new type of radiochromic film, a new parallel-plate Dose Determination in Photon and Electron Beams, An International micro-chamber, MOSFETs, and TLC 800 microcubes in the dosimetry of Code of Practice, Technical Report Series No. 277 ͑International Atomic small beams,” Med. Phys. 25, 503–511 ͑1998͒. Energy Agency, Vienna, 1987͒. 8O. A. Sauer and J. Wilbert, “Measurement of output factors for small 30P. Andreo and A. E. Nahum, “Stopping-power ratio for a photon spectrum photon beams,” Med. Phys. 34, 1983–1988 ͑2007͒. as a weighted sum of the values for monoenergetic photon beams,” Phys. 9F. Verhaegen, I. J. Das, and H. Palmans, “Monte Carlo dosimetry study of Med. Biol. 30, 1055–1065 ͑1985͒. 6 MV stereotactic radiosurgery unit,” Phys. Med. Biol. 43, 2755–2768 31J. Seuntjens and F. Verhaegen, “Comments on ‘Ionization chamber do- ͑1998͒. simetry of small photon fields: A Monte Carlo study on stopping-power 10F. Sánchez-Doblado, P. Andreo, R. Capote, A. Leal, M. Perucha, R. Ar- ratios for radiosurgery and IMRT beams’,” Phys. Med. Biol. 48, L43–45 rans, L. Nunez, E. Mainegra, J. I. Lagares, and E. Carrasco, “Ionization ͑2003͒. chamber dosimetry of small photon fields: A Monte Carlo study on 32S. Li, A. Rashid, S. He, and D. Djajaputra, “A new approach in dose stopping-power ratios for radiosurgery and IMRT beams,” Phys. Med. measurement and error analysis for narrow photon beams ͑beamlets͒ Biol. 48, 2081–2099 ͑2003͒. shaped by different multileaf collimators using a small detector,” Med. 11F. Crop, N. Reynaert, G. Pittomvils, L. Paelinck, W. De Gersem, C. De Phys. 31, 2020–2032 ͑2004͒. Wagter, L. Vakaet, W. De Neve, and H. Thierens, “Monte Carlo modeling 33G. X. Ding, D. M. Duggan, B. Lu, D. E. Hallahan, A. Cmelak, A. Mal- of the ModuLeaf miniature MLC for small field dosimetry and quality colm, J. Newton, D. Mathew, and C. W. Coffey, “Impact of inhomoge- assurance of the clinical treatment planning system,” Phys. Med. Biol. 52, neity corrections on dose coverage in treatment of lung cancer using 3275–3290 ͑2007͒. stereotactic body radiation therapy,” Med. Phys. 34, 2985–2994 ͑2007͒. 12F. Sánchez-Doblado, R. Capote, A. Leal, J. V. Rosello, J. I. Lagares, R. 34G. X. Ding, D. M. Duggan, and C. W. Coffey, “Comment on ‘Testing of Arrans, and G. H. Hartmann, “Micro ionization chamber for reference analytical anisotropic algorithm for photon dose calculation’ ͓Med. Phys. dosimetry in IMRT verification: Clinical implications on OAR dosimetric 33, 4130–4148 ͑2006͔͒,” Med. Phys. 34, 3414 ͑2007͒. errors,” Phys. Med. Biol. 50, 959–970 ͑2005͒. 35ICRU 31, “Average energy required to produce an ion pair,” ICRU Re- 13F. Araki, T. Ikegami, T. Ishidoya, and H. D. Kubo, “Measurements of port 31, International Commission on Radiation Units and Measurements, Gamma-Knife helmet output factors using a radiophotoluminescent glass Washington, D.C., 1979͒. rod dosimeter and a diode detector,” Med. Phys. 30, 1976–1981 ͑2003͒. 36R. Huber, D. Combecher, and G. Burger, “Measurement of average en- 14F. Araki, “Monte Carlo study of a Cyberknife stereotactic radiosurgery ergy required to produce an ion pair ͑W value͒ for low energy ions in system,” Med. Phys. 33, 2955–2963 ͑2006͒. several gases,” Radiat. Res. 101, 237–251 ͑1985͒. 15R. Capote, F. Sánchez-Doblado, A. Leal, J. I. Lagares, R. Arrans, and G. 37I. J. Das, M. B. Downes, B. W. Corn, W. J. Curran, M. W. Wasik, and D. H. Hartmann, “An EGSnrc Monte Carlo study of the microionization W. Andrews, “Characteristics of a dedicated linear accelerator-based ste- chamber for reference dosimetry of narrow irregular IMRT beamlets,” reotactic radiosurgery-radiotherapy unit,” Radiother. Oncol. 38,61–68 Med. Phys. 31, 2416–2422 ͑2004͒. ͑1996͒. 16K. A. Paskalev, J. P. Seuntjens, H. J. Patrocinio, and E. B. Podgorsak, 38S. C. Sharma, J. T. Ott, J. B. Williams, and D. Dickow, “Commissioning “Physical aspects of dynamic stereotactic radiosurgery with very small and acceptance testing of a CyberKnife linear accelerator,” J. Appl. Clin. photon beams ͑1.5 and 3 mm in diameter͒,” Med. Phys. 30, 111–118 Med. Phys. 8, 119–125 ͑2007͒. ͑2003͒. 39A. Mack, S. G. Scheib, J. Major, S. Gianolini, G. Pazmandi, H. Feist, H. 17F. Haryanto, M. Fippel, W. Laub, O. Dohm, and F. Nusslin, “Investigation Czempiel, and H. J. Kreiner, “Precision dosimetry for narrow photon of photon beam output factors for conformal radiation therapy-Monte beams used in radiosurgery-determination of Gamma Knife output fac- Carlo simulations and measurements,” Phys. Med. Biol. 47, N133–N143 tors,” Med. Phys. 29, 2080–2089 ͑2002͒. ͑2002͒. 40P. Björk, T. Knöös, and P. Nilsson, “Measurements of output factors with 18X. R. Zhu, J. J. Allen, J. Shi, and W. E. Simon, “Total scatter factors and different detector types and Monte Carlo calculations of stopping-power tissue maximum ratios for small radiosurgery fields: Comparison of diode ratios for degraded electron beams,” Phys. Med. Biol. 49, 4493–4506 detectors, a parallel-plate ion chamber, and radiographic film,” Med. ͑2004͒. Phys. 27, 472–477 ͑2000͒. 41A. L. McNiven, M. Mulligan, T. Kron, and J. J. Battista, “The response of 19T. C. Zhu and K. Manbeck, “CT reconstruction of the x-ray source profile prototype plane-parallel ionization chambers in small megavoltage x-ray of a medical accelerator,” Proc. SPIE 2132, 242–253 ͑1994͒. fields,” Med. Phys. 33, 3997–4004 ͑2006͒. 20P. Munro, J. A. Rawlinson, and A. Fenster, “Therapy imaging: Source 42G. G. Zhang, D. W. O. Rogers, J. E. Cygler, and T. R. Mackie, “Effects of sizes of radiotherapy beams,” Med. Phys. 15, 517–524 ͑1988͒. changes in stopping-power ratios with field size on electron beam relative 21G. X. Ding, D. M. Duggan, and C. W. Coffey, “Commissioning stereo- output factors,” Med. Phys. 25, 1711–1716 ͑1998͒. tactic radiosurgery beams using both experimental and theoretical meth- 43H. Bouchard and J. Seuntjens, “Ionization chamber-based reference do- ods,” Phys. Med. Biol. 51, 2549–2566 ͑2006͒. simetry of intensity modulated radiation beams,” Med. Phys. 31,2454– 22A. L. Boyer, T. G. Ochran, C. E. Nyerick, T. J. Waldron, and C. J. 2465 ͑2004͒. Huntzinger, “Clinical dosimetry for implementation of a multileaf colli- 44A. Wu, R. D. Zwicker, A. M. Kalend, and Z. Zheng, “Comments on dose mator,” Med. Phys. 19, 1255–1261 ͑1992͒. measurements for a narrow beam in radiosurgery,” Med. Phys. 20, 777– 23X. A. Li, M. Soubra, J. Szanto, and L. H. Gerig, “Lateral electron equi- 779 ͑1993͒. librium and electron contamination in measurements of head-scatter fac- 45A. O. Jones, I. J. Das, and F. L. Jones, “A Monte Carlo study of IMRT

Medical Physics, Vol. 35, No. 1, January 2008 214 Das, Ding, and Ahnesjö: Small ﬁelds: Nonequilibrium radiation dosimetry 214

beamlets in homogeneous media,” Med. Phys. 30, 296–300 ͑2003͒. 70A. S. Saini and T. C. Zhu, “Dose rate and SDD dependence of commer- 46A. O. Jones and I. J. Das, “Comparison of inhomogeneity correction cially available diode detectors,” Med. Phys. 31, 914–924 ͑2004͒. algorithms in small photon fields,” Med. Phys. 32, 766–776 ͑2005͒. 71TG-62, Diode In Vivo Dosimetry for Patients Receiving External Beam 47J. Y. Cheung, B. K. Ng, and K. N. Yu, “Dose enhancement close to Radiation Therapy: Report of the AAPM Radiation Therapy Committee platinum implants for the 4, 6, and 10 MV stereotactic radiosurgery,” Task Group No. 62 ͑Medical Physics Publishing, Madison, WI, 2005͒. Med. Phys. 31, 2787–2791 ͑2004͒. 72C. W. Cheng, S. H. Cho, M. Taylor, and I. J. Das, “Determination of zero 48H. Saitoh, T. Fujisaki, R. Sakai, and E. Kunieda, “Dose distribution of field size percent depth doses and tissue maximum ratios for stereotactic narrow beam irradiation for small lung tumor,” Int. J. Radiat. Oncol. Biol. radiosurgery and IMRT dosimetry: Comparison between experimental Phys. 53, 1380–1387 ͑2002͒. measurements and Monte Carlo simulation,” Med. Phys. 34, 3149–3157 49H. A. Al-Hallaq, C. S. Reft, and J. C. Roeske, “The dosimetric effects of ͑2007͒. tissue heterogeneities in intensity-modulated radiation therapy ͑IMRT͒ of 73C. McKerracher and D. I. Thwaites, “Assessment of new small-field de- the head and neck,” Phys. Med. Biol. 51, 1145–1156 ͑2006͒. tectors against standard-field detectors for practical stereotactic beam data 50L. Paelinck, N. Reynaert, H. Thierens, W. De Neve, and C. De Wagter, acquisition,” Phys. Med. Biol. 44, 2143–2160 ͑1999͒. “Experimental verification of lung dose with radiochromic film: Compari- 74C. McKerracher and D. I. Thwaites, “Notes on the construction of solid- son with Monte Carlo simulations and commercially available treatment state detectors,” Radiother. Oncol. 79, 348–351 ͑2006͒. planning systems,” Phys. Med. Biol. 50, 2055–2069 ͑2005͒. 75P. Björk, T. Knöös, and P. Nilsson, “Comparative dosimetry of diode and 51T. Krieger and O. A. Sauer, “Monte Carlo- versus pencil-beam-/ diamond detectors in electron beams for intraoperative radiation therapy,” collapsed-cone-dose calculation in a heterogeneous multi-layer phantom,” Med. Phys. 27, 2580–2588 ͑2000͒. Phys. Med. Biol. 50, 859–868 ͑2005͒. 76M. Heydarian, P. W. Hoban, W. A. Beckham, I. A. Borchardt, and A. H. 52M. M. Aspradakis, R. H. Morrison, N. D. Richmond, and A. Steele, Beddoe, “Evaluation of a PTW diamond detector for electron beam mea- “Experimental verification of convolution/superposition photon dose cal- surements,” Phys. Med. Biol. 38, 1035–1042 ͑1993͒. culations for radiotherapy treatment planning,” Phys. Med. Biol. 48, 77P. W. Hoban, M. Heydarian, W. A. Beckham, and A. H. Beddoe, “Dose 2873–2893 ͑2003͒. rate dependence of a PTW diamond detector in the dosimetry of a 6 MV 53A. Ahnesjö, “Collapsed cone convolution of radiant energy for photon Photon beam,” Phys. Med. Biol. 39, 1219–1229 ͑1994͒. dose calculation in heterogeneous media,” Med. Phys. 16, 577–592 78V. S. Khrunov, S. S. Martynov, S. M. Vatnisky, I. A. Ermakov, A. M. ͑1989͒. Chervjakov, D. L. Karlin, V. I. Fominych, and Y. V. Tarbeyev, “Diamond 54I. J. Chetty, P. M. Charland, N. Tyagi, and D. McShan, “Photon beam detectors in relative dosimetry of photon, electron and proton radiation relative dose validation of the DPM Monte Carlo code in lung-equivalent fields,” Radiat. Prot. Dosimetry 33, 155–157 ͑1990͒. media,” Med. Phys. 30, 563–573 ͑2003͒. 79W. U. Laub, T. W. Kaulich, and F. Nusslin, “Energy and dose rate depen- 55C. F. Serago, P. V. Houdek, G. H. Hartmann, D. S. Saini, M. S. Serago, dence of a diamond detector in the dosimetry of 4–25 MV photon and A. Kaydee, “Tissue maximum ratios ͑and other parameters͒ of small beams,” Med. Phys. 24, 535–536 ͑1997͒. circular 4, 6, 10, 15 and 24 MV x-ray beams for radiosurgery,” Phys. 80S. Vatnitsky and H. Järvinen, “Application of natural diamond detector Med. Biol. 37, 1943–1956 ͑1992͒. for the measurement of relative dose distributions in radiotherapy,” Phys. 56P. Francescon, S. Cora, and P. Chiovati, “Dose verification of an IMRT Med. Biol. 38, 173–184 ͑1993͒. treatment planning system with BEAM, EGS-based Monte Carlo code,” 81Y. S. Horowitz, “The theoretical and microdosimetric basis of thermolu- Med. Phys. 30, 144–157 ͑2003͒. minescence and applications to dosimetry,” Phys. Med. Biol. 26, 765–824 57J. C. L. Chow, M. Seguin, and A. Alexander, “Dosimetric effect of col- ͑1981͒. limating jaws for small multileaf collimated fields,” Med. Phys. 32, 759– 82S. Pai, I. J. Das, J. F. Dempsey, K. L. Lam, T. J. LoSasso, A. J. Olch, J. 765 ͑2005͒. R. Palta, L. E. Reinstein, D. Ritt, and E. E. Wilcox, “TG-69: Radio- 58H.-R. Lee, M. Pankuch, and J. Chu, “Evaluation and characterization of graphic film for megavoltage beam dosimetry,” Med. Phys. 34,2228– parallel plate microchamber’s functionalities in small beam dosimetry,” 2258 ͑2007͒. Med. Phys. 29, 2489–2496 ͑2002͒. 83A. Niroomand-Rad, C. R. Blackwell, B. M. Coursey, K. P. Gall, J. M. 59R. K. Rice, J. L. Hansen, G. K. Svensson, and R. L. Siddon, “Measure- Galvin, W. L. McLaughlin, A. S. Meigooni, R. Nath, J. E. Rodgers, and ments of dose distributions in small beams of 6 MV x-rays,” Phys. Med. C. G. Soares, “Radiographic film dosimetry: Recommendations of AAPM Biol. 32, 1087–1099 ͑1987͒. Radiation Therapy Committee Task Group 55,” Med. Phys. 25, 2093– 60B. E. Bjärngard, J.-S. Tsai, and R. K. Rice, “Doses on the central axes of 2115 ͑1998͒. narrow 6-MV x-ray beams,” Med. Phys. 17, 794–799 ͑1990͒. 84W. L. McLaughlin, C. G. Soares, J. A. Sayeg, E. C. McCullough, R. W. 61W. U. Laub and T. Wong, “The volume effect of detectors in the dosim- Kline, A. Wu, and A. H. Maitz, “The use of a radiochromic detector for etry of small fields used in IMRT,” Med. Phys. 30, 341–347 ͑2003͒. the determination of stereotactic radiosurgery dose characteristics,” Med. 62C. Martens, C. De Wagter, and W. De Neve, “The value of the PinPoint Phys. 21, 379–388 ͑1994͒. ion chamber for characterization of small field segments used in intensity- 85R. Ramani, A. W. Lightstone, D. L. Mason, and P. F. O’Brien, “The use modulated radiotherapy,” Phys. Med. Biol. 45, 2519–2530 ͑2000͒. of radiochromic film in treatment verification of dynamic stereotactic ra- 63I. J. Das, M. B. Downes, A. Kassaee, and Z. Tochner, “Choice of radia- diosurgery,” Med. Phys. 21, 389–392 ͑1994͒. tion detector in dosimetry of stereotactic radiosurgery-radiotherapy,” J. 86R. Ramani, S. Russell, and P. F. O’Brien, “Clinical dosimetry using Radiosurg. 3, 177–185 ͑2000͒. MOSFETs,” Int. J. Radiat. Oncol. Biol. Phys. 37, 959–964 ͑1997͒. 64L. B. Leybovich, A. Sethi, and N. Dogan, “Comparison of ionization 87C. F. Chuang, L. Verhey, and P. Xia, “Investigation of the use of chambers of various volumes for IMRT absolute dose verification,” Med. MOSFET for clinical IMRT dosimetric verification,” Med. Phys. 29, Phys. 30, 119–123 ͑2003͒. 1109–1115 ͑2002͒. 65J. W. Sohn, J. F. Dempsey, T. S. Suh, and D. A. Low, “Analysis of 88G. S. Ibbott, M. J. Maryanski, P. Eastman, S. D. Holcomb, Y. Zhang, R. various beamlet sizes for IMRT with 6 MV photons,” Med. Phys. 30, G. Avison, M. Sanders, and J. C. Gore, “Three-dimensional visualization 2432–2439 ͑2003͒. and measurement of conformal dose distributions using magnetic reso- 66F. Aaki, T. Ishidoya, T. Ikegami, N. Moribe, and Y. Yamashita, “Appli- nance imaging of BANG polymer gel dosimeters,” Int. J. Radiat. Oncol. cation of a radiophotoluminescent glass plate dosimeter for small field Biol. Phys. 38, 1097–1103 ͑1997͒. dosimetry,” Med. Phys. 32, 1548–1554 ͑2005͒. 89E. Pappas, L. Petrokokkinos, A. Angelopoulos, T. G. Maris, M. Kozicki, 67F. Araki, N. Moribe, T. Shimonobou, and Y. Yamashita, “Dosimetric I. Dalezios, and V. Kouloulias, “Relative output factor measurements of a properties of radiophotoluminescent glass rod detector in high-energy 5 mm diameter radiosurgical photon beam using polymer gel dosimetry,” photon beams from a linear accelerator and cyber-knife,” Med. Phys. 31, Med. Phys. 32, 1513–1520 ͑2005͒. 1980–1986 ͑2004͒. 90E. Pappas, T. G. Maris, A. Papadakis, F. Zacharopoulou, J. Damilakis, N. 68G. Rikner and E. Grusell, “General specifications for silicon semiconduc- Papanikolaou, and N. Gourtsoyiannis, “Experimental determination of the tors for use in radiation dosimetry,” Phys. Med. Biol. 32, 1109–1117 effect of detector size on profile measurements in narrow photon beams,” ͑1987͒. Med. Phys. 33, 3700–3710 ͑2006͒. 69A. S. Saini and T. C. Zhu, “Temperature dependence of commercially 91H. Whitney, G. X. Ding, C. W. Coffey and J. C. Gore, “Gel dosimetry for available diode detectors,” Med. Phys. 29, 622–630 ͑2002͒. measuring a complex 3D dose distribution in stereotactic radiosurgery,”

Medical Physics, Vol. 35, No. 1, January 2008 215 Das, Ding, and Ahnesjö: Small ﬁelds: Nonequilibrium radiation dosimetry 215

Med. Phys. 34, 2393 ͑abstract͒͑2007͒. 103P. Nizin, G. X. Qian, and H. Rashid, “Zero-field dose data for 60C and 92A. S. Beddar, “A new scintillator detector system for the quality assur- other high-energy photon beams in water,” Med. Phys. 20, 1353–1360 ance of Co-60 and high-energy therapy machines,” Phys. Med. Biol. 39, ͑1993͒. 253–263 ͑1994͒. 104P. S. Nizin and R. B. Mooij, “An approximation of central-axis absorbed 93 D. Letourneau, J. Pouliot, and R. Roy, “Miniature scintillating detector dose in narrow photon beams,” Med. Phys. 24, 1775–1780 ͑1997͒. for small field radiation therapy,” Med. Phys. 26, 2555–2561 ͑1999͒. 105P. S. Nizin and R. B. Mooij, “Tissue-air ratios for narrow 60C gamma-ray 94 M. Westermark, J. Arndt, B. Nilsson, and A. Brahme, “Comparative do- beams,” Med. Phys. 25, 1458–1463 ͑1998͒. simetry in narrow high-energy photon beams,” Phys. Med. Biol. 45, 685– 106P. K. Kijewski, B. E. Bjarngard, and P. L. Petti, “Monte Carlo calculations ͑ ͒ 702 2000 . 60 13 95 of scatter dose for small field sizes in a C beam,” Med. Phys. ,74–77 F. Chen, C. F. O. Graeff, and O. Baff, “K-band EPR dosimetry: Small- ͑1986͒. field beam profile determination with miniature alanine dosimeter,” Appl. 107G. X. Ding, D. M. Duggan, and C. W. Coffey, “Commissioning stereo- Radiat. Isot. 62, 267–271 ͑2005͒. 96 tactic radiosurgery beams using both experimental and theoretical meth- S. Duane, D. Nicholas, H. Palmans, B. Schaeken, J. Sephton, P. Sharpe, ods,” Phys. Med. Biol. 51, 2549–2566 ͑2006͒. R. Thomas, M. Tomsej, K. Tournel, D. Verellen, and S. Vynckier, “Ala- 108G. X. Ding, “Dose discrepancies between Monte Carlo calculations and nine and ion chamber dosimetry in helical tomotherapy,” Radiother. On- measurements in the buildup region for a high-energy photon beam,” col. 81,S45͑2006͒. Med. Phys. 29, 2459–2463 ͑2002͒. 97R. K. Rice, J. L. Hansen, L. M. Chin, B. J. Mijnheer, and B. E. Bjärngard, 109G. X. Ding, “Using Monte Carlo simulations to commission photon beam “The influence of ionization chamber and phantom design on the mea- output factors-A feasibility study,” Phys. Med. Biol. 48, 3865–3874 surement of lung dose in photon beam,” Med. Phys. 15, 884–890 ͑1988͒. 98 ͑2003͒. C. H. Sibata, H. C. Mota, A. S. Beddar, P. D. Higgins, and K. H. Shin, 110 “Influence of detector size in photon beam profile measurements,” Phys. A. Ahnesjö, “Collimator scatter in photon therapy beams,” Med. Phys. ͑ ͒ 22, 267–278 ͑1995͒. Med. Biol. 36, 621–631 1991 . 111 99G. Bednarz, S. Huq, and U. F. Rosenow, “Deconvolution of detector size A. Mack, G. Mack, D. Weltz, S. G. Scheib, H. Bottcher, and V. Seifert, effect for output factor measurement for narrow Gamma Knife radiosur- “High precision film dosimetry with GAFCHROMIC films for quality gery beams,” Phys. Med. Biol. 47, 3643–3649 ͑2002͒. assurance especially when using small fields,” Med. Phys. 30, 2399–2409 100P. D. Higgins, C. H. Sibata, L. Siskind, and J. W. Sohn, “Deconvolution ͑2003͒. 112 of detector size effect for small field measurement,” Med. Phys. 22, M. Stasi, B. Baiotto, G. Barboni, and G. Scielzo, “The behavior of several 1663–1666 ͑1995͒. microionization chambers in small intensity modulated radiotherapy 101F. Garcia-Vicente, J. M. Delgado, and C. Peraza, “Experimental determi- fields,” Med. Phys. 31, 2792–2795 ͑2004͒. 113 nation of the convolution kernel for the study of the spatial response of a C. McKerracher and D. I. Thwaites, “Verification of the dose to the iso- detector,” Med. Phys. 25, 202–207 ͑1998͒. centre in stereotactic plans,” Radiother. Oncol. 64, 97–107 ͑2002͒. 102W. Ulmer and W. Kaissl, “The inverse problem of a Gaussian convolution 114F. Sanchez-Doblado, G. H. Hartmann, J. Pena, R. Capote, M. Paiusco, B. and its application to the finite size of the measurement chambers/ Rhein, A. Leal, and J. I. Lagares, “Uncertainty estimation in intensity- detectors in photon and proton dosimetry,” Phys. Med. Biol. 48, 707–727 modulated radiotherapy absolute dosimetry verification,” Int. J. Radiat. ͑2003͒. Oncol. Biol. Phys. 68, 301–310 ͑2007͒.

Medical Physics, Vol. 35, No. 1, January 2008 Endovascular image-guided interventions „EIGIs… ͒ ͒ ͒ Stephen Rudin,a Daniel R. Bednarek,b and Kenneth R. Hoffmannc Toshiba Stroke Research Center, University at Buffalo, State University of New York, Biomedical Research Building, Room 445, 3435 Main Street, Buffalo, New York 14214 ͑Received 24 September 2007; accepted for publication 13 November 2007; published 26 December 2007͒ Minimally invasive interventions are rapidly replacing invasive surgical procedures for the most prevalent human disease conditions. X-ray image-guided interventions carried out using the insertion and navigation of catheters through the vasculature are increasing in number and sophistication. In this article, we offer our vision for the future of this dynamic field of endovascular image- guided interventions in the form of predictions about ͑1͒ improvements in high-resolution detectors for more accurate guidance, ͑2͒ the implementation of high-resolution region of interest computed tomography for evaluation and planning, ͑3͒ the implementation of dose tracking systems to control patient radiation risk, ͑4͒ the development of increasingly sophisticated interventional devices, ͑5͒ the use of quantitative treatment planning with patient-specific computer fluid dynamic simulations, and ͑6͒ the new expanding role of the medical physicist. We discuss how we envision our predictions will come to fruition and result in the universal goal of improved patient care. © 2008 American Association of Physicists in Medicine. ͓DOI: 10.1118/1.2821702͔

Key words: endovascular, image-guided intervention, detectors, cone beam CT, computer ﬂuid dynamics ͑CFD͒

I. INTRODUCTION system, radiation dose, interventional equipment and devices, procedure characteristics and treatment planning, and The three greatest killers in the developed world are heart personnel involved. We will first give an overview of the disease, cancer, and stroke or neurovascular disease, with the current state of EIGI and then make predictions about each last being the greatest cause of disability. After drug treat- feature category, providing the rationale and evidence for ment, the primary interventional therapy for vascular dis- each prediction and the strategy we suggest for making each eases and an important treatment modality for cancer are forecast become a reality in a 7–10 year time frame. endovascular image-guided interventions ͑EIGIs͒. EIGIs generally involve the insertion of a catheter into the femoral artery, which is then threaded under fluoroscopic guidance II. CURRENT STATUS through the vasculature to the site of the pathology to be Before an EIGI procedure is scheduled, diagnostic proce- treated. The pathology may be a portion of a vessel that is dures to find and analyze the pathological region are done stenosed, or totally occluded, either by chronic plaque for- preferably using noninvasive imaging modalities, such as mation or by acute clot localization. The pathology may also multislice computed tomography ͑MSCT͒ or magnetic reso- be a portion of a vessel that is weakened and bulges to form nance imaging ͑MRI͒, and followed up by higher-resolution an aneurysm, which may hemorrhage. Finally, it may be a minimally invasive angiographic procedures done in dedi- hypervascular region such as a tumor bed or an arterio- cated angiographic or special procedure x-ray suites.5,6 Typi- venous malformation. The EIGI may involve delivery of a cally, EIGI procedures, if indicated, are then done under real- drug or embolic material through the catheter, or may be the time x-ray image guidance in such a special procedure suite.7 delivery of a device such as a stent that may be used to keep Thus, such a suite may be used for the initial diagnostic a stenosed vessel open. During the course of the intervention, study and subsequently for the intervention. Rotating anode rapid-sequence fluoroscopic x-ray imaging is usually relied x-ray tubes, that have become more robust but have changed on for guidance. little in decades in overall design, are used as the source of x Increasingly, EIGIs are replacing invasive surgical proce- rays; however, dynamic x-ray detector designs are in the pro- dures because of the reduced mortality, morbidity, and dis- cess of changing from the decades old x-ray image intensifier comfort to the patient.1 For example, surgical clipping of ͑XII͒ to the new flat panel detector ͑FPD͒.8 The indirect FPD aneurysms, which just a few years ago was the standard of and the XII designs both use an x-ray absorbing structured care, is now being replaced by the deployment of embolic CsI phosphor, but differ greatly thereafter. The XII converts material, such as detachable coils delivered through a cath- the phosphor’s light to electrons that are accelerated. This eter under fluoroscopic guidance into the aneurysm, thus re- electron distribution is focused on an output phosphor to placing an invasive external approach most likely through produce an intensified image of light photons and thus create the skull with a minimally invasive endovascular a gain in brightness.9 In contrast, an indirect FPD uses an intervention.2–4 In this work, we will discuss the basic fea- array of solid state photodiodes with thin film transistor tures and current status of EIGI in terms of the imaging ͑TFT͒ switches and, currently, no additional gain to generate

301 Med. Phys. 35 „1…, January 2008 0094-2405/2008/35„1…/301/9/$23.00 © 2008 Am. Assoc. Phys. Med. 301 302 Rudin, Bednarek, and Hoffmann: Endovascular image-guided interventions 302 electronic signals that are directly digitized by circuitry off to and inserted material, such as embolizing coils or glues, have the side of the x-ray sensitive region. Direct FPDs employ a advanced somewhat over the years,31 they are still rather photoconductor, such as amorphous selenium, to absorb the simple in design and mostly passive in nature having few if x rays and directly produce a charge, which is read out by an any electronic, computerized, or motorized components. array of TFTs. While the XIIs have a number of Even specialized active devices, such as the rotational disadvantages—such as glare, pincushion distortion due to atherectomy Rotablator ͑Boston Scientific Corp, Natick, the curved x-ray sensitive phosphor, S distortion due to the MA͒, are basically simple rapidly rotating wires with dia- earth’s magnetic field, and large physical volume—they have mond burrs at the distal tip for grinding down plaque.32 Nev- the advantages of inherently large and variable gain, adjust- ertheless, these mostly passive or simple devices deployed able magnification hence pixel size, and flexible optical out- under EIGI procedures have had a major impact already in put that is usable with a variety of optical image receptors or substituting for surgically invasive procedures, such as aneu- cameras.9 However, the transition to FPDs for dynamic x-ray rysm clipping or open-heart coronary bypass procedures. imaging has been somewhat disappointing, due to the sub- Currently, unlike in radiation therapy, quantitative treat- stantial FPD additive instrumentation noise that is similar in ment planning is lacking in preparation for EIGI procedures. magnitude to the signal obtained in the lower range of stan- Also, although CBCT is now available, it is not used to dard fluoroscopic exposures. This noise quantity when ex- quantitatively plan a procedure, such as to determine in ad- pressed in units of exposure may be referred to as the instru- vance what guidewires, catheters, and endovascular devices mentation noise equivalent exposure ͑INEE͒.10 Other can be passed through vessels using computer analysis of the disadvantages of FPDs have been the image lag or mechanical properties of the vessels as well as a library of persistence,11,12 ghosting due to charge retention in the pho- such properties for the devices combined with the derived todiode TFT array,12,13 and the substantial artifacts that re- tortuosity and other characteristics of the vessel. It is gener- quire corrections prior to image display. The advantages of ally believed that blood flow has a major impact on the ini- FPDs, however, are their smaller physical size and lack of tiation of vessel pathologies,33,34 as well as the outcomes of distortion, which enable improved cone-beam computed to- subsequent EIGIs,35,36 yet there is very little done clinically mography ͑CBCT͒ to be accomplished with the same angio- to quantitatively determine the detailed flow or to predict the graphic gantry used for the diagnostic or EIGI procedures.14 effect on blood flow of a proposed intervention from infor- For both detector systems that are currently in use, image mation gained with computer fluid dynamic ͑CFD͒ calcula- quality may not be optimal especially in fine detail EIGIs. tions in time to have any clinical impact. The details of interventional devices, such as stent struts, and Because of the present rather improvised state of clinical small vessels, such as perforators in the brain, typically can- EIGI procedures, the personnel active during such proce- not be visualized because of the limited spatial resolution dures consists of a mixture of clinicians and technologists, capabilities of current conventional detectors, although the but rarely includes medical physicists or engineers. This con- development of some specialized CCD-based microangio- trasts with radiation therapy procedures where the treatment graphic detectors has begun.15 team generally includes a medical physicist. As EIGI procedures become more widespread and more complex, there is a continuing concern regarding lengthy III. PREDICTION, EVIDENCE/RATIONALE, AND procedure times and the associated radiation doses, which STRATEGY FOR IMPLEMENTATION can be some of the highest of medical radiological 16,17 We predict that in 7–10 years there will be dramatic studies. Currently, there are dose reduction techniques changes in the field of EIGI procedures in all areas: Imaging available, such as spectral shaping performed automatically equipment and doses, devices, methods of planning, as well using selected metallic filters and the option for reducing as the role of the medical physicist. In what follows we list frame rates during fluoroscopic and angiographic acquisi- our predictions in each of these areas of EIGI, provide our tions. However, other techniques, such as spatially modulat- rationale supported by evidence from current research trends, ing the beam for optimal dose utilization18–21 and recording 22,23 and suggest strategies for how these forecasted advances and displaying the details of patient dose deposition, are may come to fruition. not commonly used. Even though EIGI procedures can be lengthy and com- III.A. Imaging systems and dose plex, the actual EIGI devices that are used remain only somewhat more complex in design than those that were used III.A.1. Prediction 1 when the field began.24 Guidewires may vary in characteris- Higher resolution, lower noise, and real-time image tics, such as torsion rigidity, flexibility, and kink resistance, receptors—at first for the region of interest (ROI) near the due to the characteristics of the materials and windings used, intervention and then across the full field of view (FOV)_ and catheters may similarly vary depending upon the mate- will become the standard of care for many EIGI procedures. rial and construction of the wall.25–30 However, they are ba- The rationale for this prediction is that, increasingly, sically still passive cylinders and tubes that are actuated by MSCT and MRI are taking over the task of vascular diagno- pulling, pushing, rotating, or, in the case of balloons, inflat- sis with angiographic special procedure rooms being devoted ing, all simple mechanical actions initiated at the proximal increasingly to EIGI. The fact that MSCT and magnetic reso- end outside the patient. Also, while devices, such as stents, nance angiography ͑MRA͒ procedures require only a venous

Medical Physics, Vol. 35, No. 1, January 2008 303 Rudin, Bednarek, and Hoffmann: Endovascular image-guided interventions 303

FIG. 2. Fluoroscopic road-mapped frames done at 74 kVp and 50 mA of 3 mm diameter and 15 mm long coronary stent systems ͑Multi-link Vision, Guidant Corp, Santa Clara, CA͒. End markers indicate extent of expanded balloon on delivery catheter. Stents are deployed in carotid arteries of the same rabbit. ͑A͒ Using 2 ms pulsed XII imaging with temporal ﬁltering ͑standard on commercial systems͒, stent deployed in right carotid. ͑B͒ Using 8 ms pulsed HSMAF imaging with no temporal ﬁltering, stent deployed in left carotid showing improved visualization of details of stent struts and vessel edges.

FIG. 1. Improved resolution with new SSXII ͑right͒ compared with XII ͑left͒. ͑A͒ and ͑B͒ Bar pattern images taken at 70 kVp with 2 in. PMMA resenting the signal through the TFT lines, where the noise is filtration added with the same exposure for each detector. ͑C͒ and ͑D͒ Im- added and then onto the sides of the sensor where it can be ages of a neurovascular phantom containing thin wires ͑left to right: amplified and digitized. Were this achievable in practice, the ␮ ␮ ␮ ͒ ␮ 100 m Au, 25 m Cu, 50 mPt,100 m iodine contrast media-filled problem for FPDs of reducing the size of the pixels would tube and a new asymmetric vascular stent having a blood flow diverting low-porosity polyurethane patch ͑indicated by four Pt markers͒ designed for still remain. Alternate detector designs actively being pur- closing off flow into an aneurysm were taken at 74 kVp with 21.4 mm Al sued by the authors consist of a high-sensitivity microangio- added filtration ͑RQA 5 Spectrum͒ with the same exposure. ͑A͒ Bar pattern graphic fluoroscope ͑HSMAF͒10 and a detector called the ͑ ͒ with only 3.1 Lp/mm visible for XII in 5 in. magnification mode. B Bar solid state x-ray image intensifier ͑SSXII͒. The HSMAF em- pattern with 10 Lp/mm clearly visible for SSXII. ͑C͒ With the XII, wires are less clear: Cu wire and Pt wire bends are unseen and stent struts and patch ploys a light image intensifier between the CsI phosphor and markers are not clearly visible. ͑D͒ With the SSXII, Cu wire is barely a digital videocamera with a fiber optic taper ͑FOT͒ input. visualized but Pt wire bends and stent struts and patch markers are clearly This detector has a small FOV sufficient to be used for EIGI visible. and is capable of real-time fluoroscopy as well as very-high- resolution angiography. The SSXII consists of an array of electron multiplying charge-coupled devices ͑EMCCDs͒,43,44 puncture for injection of the contrast media and that image each viewing a portion of the CsI phosphor through its own quality is improving to the point where definitive diagnoses FOT coupling.45 EMCCDs have all the advantages of stan- are possible in many cases make this trend plausible. Once a dard CCDs: high speed, low noise, high resolution, and stan- diagnosis has localized the site of pathology, there may not dard solid state production techniques. However, in addition, be a need for superior image quality except over the site of they have a row of hundreds of multiplying elements each the intervention. Superior resolution is needed in the ROI for with a small gain of a few percent. When cascaded together both real-time fluoroscopy to actively guide the ongoing in- in this row, they can result in a total gain from 1 to 2000 tervention and also for superior angiography to evaluate the times, depending upon the variable gain voltage setting of progress of the intervention throughout the procedure and to only around 20 V. The mosaic array of the SSXII also has the help determine when a satisfactory endpoint has been advantage of being extensible in FOV by adding modules. reached. The INEE achievable for both such detectors is a fraction of To achieve this improvement especially over the ROI of the exposure typical of low-dose fluoroscopy, hence they the interventional site, either a vast improvement in current have the desirable feature of being quantum limited through- FPDs or new alternative detectors with the desired character- out their range of operation. Additionally, unlike FPDs they istics will be required. For example, large area CCDs have have no lag or ghosting and are available with small pixel been considered.37 Methods for reducing the effect of instru- sizes. The potential advantages of SSXII and HSMAF detec- mentation noise on FPDs have been proposed; one such pro- tors compared with conventional detectors are illustrated by posal being to provide inherently increased signal using a some examples in Figs. 1 and 2. A quantitative evaluation direct x-ray converter material having avalanche gain.38 For using linear cascade analysis46 can be made of these new indirect FPDs, methods include using a-Se avalanche photo- high-resolution detectors45,47; however, recent additions to conductors in place of a-Si photodiodes39,40 and placing an these analytical methods will include the effects of other im- amplifier at each pixel of the FPD.41,42 These methods enable portant factors that affect total system performance, such as signal amplification prior to sending the charge packet rep- focal spot blurring and scatter in the patient.48,49

Medical Physics, Vol. 35, No. 1, January 2008 304 Rudin, Bednarek, and Hoffmann: Endovascular image-guided interventions 304

III.A.2. Prediction 2 uniform dose application due to ROI techniques, recording High-resolution CBCT will become available for the ROI the dose distribution will become increasingly important. of the interventional site with 3D roadmapping and auto- As discussed in the section on ROI-CBCT, future patient dose may be made highly nonuniform using collimation and mated indication of the catheter or guidewire tip superim- 57 posed. semi-radio-opaque metallic filters. To implement a more The rationale for this prediction is that once a vascular comprehensive dose tracking system, our group uses the pathology has been diagnosed, superior image quality is digital signals available from new angiographic c-arm gan- needed only over the site of the intervention and not over the tries, together with software that calculates and conveniently displays the cumulative entrance skin dose distribution as full volume FOV. Currently, there is some effort in both aca- 58,59 demic and commercial organizations to develop 3D road- well as dose rate in real time. This enables a clinician to mapping capability. The syngo iPilot product50 ͑Siemens obtain feedback on the consequences of their actions and to ͒ modify the procedure to reduce the risk of deterministic ef- Medical Solutions USA, Inc., Malvern, PA or the Dynamic 17 3D Roadmap product51 ͑Philips Medical Systems, N.A, fects, such as erythema, epilation, and dermal necrosis. In Bothell, WA͒ are such implementations with current detector the future, such tracking of the beam should also be able to technology. Clearly, the higher the resolution available at the allow real-time accounting of effective dose and the in- interventional site, the greater the potential for a successful creased risk of stochastic effects, such as cancer, which may intervention. be especially important in procedures that include exposure To achieve this goal, higher-resolution ROI detectors, of the breast or thyroid. such as those in Prediction 1 above, mounted on stable de- One way to reduce the risk of entrance skin effects is to tector holders added to angiographic CBCT-capable gantries change the entrance skin exposure location and thus to will be required. The associated software will also be “spread the surface dose”. Through determination of the 3D needed. Our group has shown that most of the artifacts due vasculature, future systems may guide the interventionist in to FOV truncation ͑that one expects when the CT FOV is selecting an optional projection to spread the dose when a smaller than the object being imaged͒ can be eliminated by deterministic threshold dose is being reached, while main- combining the ROI data with a lower-.resolution full FOV taining the needed interventional site image view to continue CT image sequence. This provides sufficient information the procedure. about those parts of the object that move in and out of the Since serious deterministic effects may not be evident un- ROI of the projection views but which are not actually lo- til weeks after the procedure, it is important to be able to cated within the ROI or volume of interest of the 3D correlate the cause with the effect for proper treatment. The 52,53 patient record should contain information about the distribu- object. These high-resolution ROI-CBCT images can 60,61 then be used as the basis for enhanced treatment planning by tion of dose on the skin as recommended by the FDA. calculating the simulation of the transport of a device Using the results of a dose tracking system, the electronic through the vasculature53,54 and for improved flow informa- medical record will be able to log this information for future tion, as will be discussed next. reference with the risk level indicated. The dose from subsequent procedures will be able to be added to that already recorded to provide a measure of cumulative risk. It is pos- tulated that advances in radiobiological knowledge will al- III.A.3. Prediction 3 low modeling of cellular repair occurring between proce- There will be greater accounting of patient dose distribu- dures so a more accurate estimate of cumulative risk from tion during EIGI with techniques to minimize integral dose repeated exams can be obtained. This will further allow in- as well as deterministic effects. dividual risk factors that increase radiation sensitivity ͑such Although patient dose for EIGI procedures can be some as collagen vascular disease, diabetes mellitus, and certain of the largest of all medical procedures, it is highly nonuni- pharmaceuticals and chemicals62͒ to be taken into account. form; hence, any determination of potential biological effects will depend upon a detailed knowledge of the dose distribu- III.B. Endovascular devices tion. Although the European Union ͑EU͒ requires the measurement of dose-area product and the International Electro- III.B.1. Prediction 4 technical Commission Standard ͑IEC 60601–2-43, 2000͒ and Endovascular devices will become finer, more patient- the U.S. Food and Drug Administration ͑FDA͒ require that specific, more biocompatible, and more complex with the be- fluoroscopic equipment include, during the procedure, the ginning of remotely actuated active components using shape display of air kerma rate and cumulative air kerma at an memory alloys (SMA), micromachines, microfluidics, and mi- interventional reference point.55,56 This is only a first step in croelectronics; higher-resolution imaging will be relied upon an accurate accounting of patient dose in EIGI. A past at- to assist in accurate device deployment. tempt to provide more detailed patient entrance surface dose Since minimally invasive EIGI procedures, even with the distributions in the form of a commercial product ͑Car- current crop of simple and somewhat passive devices, are egraph, Siemens Medical Systems Corp., Malvern, PA͒ was rapidly replacing many invasive surgical procedures, it apparently discontinued; however, as EIGI procedures be- would appear to make sense that this trend would continue come more complex, potentially longer, and with more non- and be combined with advances in miniaturization. With

Medical Physics, Vol. 35, No. 1, January 2008 305 Rudin, Bednarek, and Hoffmann: Endovascular image-guided interventions 305 more accurate models of a specific patient vascular pathol- electrically activated shaped memory alloys ͑SMAs͒80 could ogy obtained from CBCT, more patient-specific devices can be developed to supply the remote mechanical force needed be created and deployed; however, care should be taken that for remote actuation. Functions, such as bending a guidewire new endovascular devices are designed with constituent ma- or catheter to change its direction and guiding it into a de- terials that are compatible with future imaging procedures sired vessel branch, could then be accomplished with more that might be required for the patient presently being treated, complex accommodations to the vessel geometry occurring so there is no negative effect such as artifact generation on when sealed catheter microjoints and robust electrical leads the images obtained. are developed. Alternatively for rotary motion, basic micro- As new more biocompatible materials are developed, de- machines that could be electrically activated would also have vices such as bioabsorbable stents under investigation63–66 to be developed. Thus, rotational motion now used in cardio- should come into common usage. The initial development of vascular applications for shaving plaque or for forming an remote actuation is also happening. For example, external intravascular ultrasound ͑IVUS͒ image could then be re- magnetic fields are actively being used in the cardiovascular placed with electrically activated rotating distal devices, area for accurately guiding new ablation probes for electro- which could be smaller and able to travel deeper into smaller physiology ͑EP͒ treatment,67–69 and are being proposed in vessels. Remote actuation would also enable IVUS for the the neurovascular arena for guiding the accurate deployment neurovasculature, which is presently not possible because of of new flow diversion stents ͓Fig. 1͑D͔͒ for treatment of the size and rigidity of current probes. Finally, although aneurysms.70 The use of the existing magnetic field in MRI probably somewhat further into the future, there is the pos- systems is being reported for steering catheters.71 There is sibility for achieving very high spatial resolution using opti- the beginning commercial availability of remote catheter cal coherence tomography ͑OCT͒ imaging81 if it can be ap- steering systems, such as the one by Hansen Medical plied intravascularly for viewing close to the surfaces of ͑Hansen Medical Inc., Mountain View, CA͒72,73 designed for vessel lumens and endovascular devices. There is also the EP. However, these appear to be implemented with wires tied possibility of using nanotechnology for creating ultrasmall to external motors and hence are hard to project to the full endovascular sensors ͑e.g., nanotube transistors for ionizing range of EIGI, which may require navigation through a tor- radiation measurement82 and nanoavalanche photodiodes for tuous vessel. Other robotic systems have also been photon detectors39͒ that might be used for guiding interven- reported.74 Remote actuation using inductive heating of tions. shape memory polymers is also being considered.75 There are also a number of new more complex devices under de- III.C. Procedure and treatment planning velopment for the treatment of acute ischemic stroke, such as ultrasonic clot busters, and complex catheter heads with high III.C.1. Prediction 5 speed saline streams to implement suction and hence reduce Treatment planning for EIGI procedures will be more ex- clots.76 New technologies in radio-frequency ablation includ- tensive and involve simulations to verify the optimal selec- ing “software for image registration and fusion, thermal tion of devices and equipment for delivery as well as flow modeling, electromagnetic tracking, semiautomated robotic calculations before, during, and after the intervention to needle guidance, and multimodality imaging77” may also be check the intervention as it proceeds. adaptable to EIGI. The rationale for this prediction is that as more detailed To achieve the full potential for new patient-specific, bio- 3D morphological information about a vascular pathology compatible, active EIGI devices, basic components of the becomes available from improved imaging studies and as process for creating these devices will have to be worked computer power continues to increase in availability at re- out. First, improved morphological models of the patient- duced cost, the use of simulations has begun83 and should specific pathology will be achieved using the high-resolution naturally continue to blossom. Evidence for this happening ROI-CBCT imaging methods described previously and using in other areas, such as in radiation treatment planning, is computer models parameterizing the desired interventional apparent. Patient-specific dose delivery regimens and result- effect such as flow modification. ͑See, for example, the CFD ing distributions are computer simulated with clinical CT calculations described next.͒ An actual physical model of the sequences as a basic part of the input data. For EIGI, how- pathology might then be constructed using rapid-prototyping ever, there are two parts to a treatment plan that will have to techniques,78,79 and if the clinical circumstances permit, a be simulated: The device delivery based upon vessel mor- patient-specific device could be tested on the physical model phology and mechanical device properties, and the blood before actual clinical use. Next, if possible and if appropri- flow results as determined using CFD calculations. ate, a new biocompatible material will be selected so that the The implementation of increasingly sophisticated EIGI device can be absorbed once the desired intervention has treatment plans will probably occur gradually. Current re- been achieved, although reaching this goal may take longer search into simulations for device transport through tortuous than the envisioned time period. Finally, the basic manufac- vasculature has begun; for example, with the tracking of a turing process for generating the required functional ele- rigid stent of given dimensions and determining tolerances ments of a new EIGI device will have to be further devel- for passage along the parent vessel.53 Increasingly sophisti- oped. For example, although it is doubtful that self-propelled cated models84 of the human vasculature, which include not yet tethered devices will be commercialized in 7–10 years, only the morphology as derived from CT sequences for pa-

Medical Physics, Vol. 35, No. 1, January 2008 306 Rudin, Bednarek, and Hoffmann: Endovascular image-guided interventions 306

the course of the EIGI to assist the interventionalist in making better decisions while the procedure is occurring. To further increase computer capability, it may be necessary to have a fast digital link to a super-computer facility to enable these complex calculations to be done so that actionable information is available during the EIGI.

III.D. Personnel involved III.D.1. Prediction 6 The medical physicist will take a more active role in individual clinical EIGI procedures as well as in the training of interventionalists using simulation systems. If the future of EIGI procedures is as predicted herein, with more patient intensive treatment planning, the analogy of the medical physicist’s role to that in radiation therapy treatment planning will be more plausible. As EIGI interventions become more technologically sophisticated, there will be a need for a professional clinical physicist to help in the selection of devices and delivery systems through simula-

FIG. 3. CFD result showing streamlines and local shear stress distributions tions and quantitative analysis, as well as in overseeing the for a patient-specific aneurysm untreated and treated with an asymmetric appropriate interpretation and use of CFD results for indi- vascular stent ͑Ref. 87͒. Notice effect of flow diversion on streamlines and vidual patient interventions. These responsibilities, of course, wall shear stress ͑WSS͒ distribution. ͑A͒ Streamlines, untreated; ͑B͒ streamlines, treated; ͑C͒ wall shear stress, untreated; ͑D͒ wall shear stress, treated. will be in addition to the primary continuing responsibility for the specification and quality assurance of all imaging systems. tients to be treated but also that of vessel flexibility and in Just as the therapy physicist is trained and certified in that the more distant future the inclusion of biological compo- branch of medical physics, the vascular medical physicist nents to the model85—such as vessel wall cellular and mo- will have to be certified in EIGI physics as well. This implies lecular properties and constituents—will make treatment the necessity for new or augmented curricula in medical planning more accurate. There will be improved selection physics training programs. While much of the basic hemo- criteria for devices and delivery equipment as well as indi- dynamics and the CFD calculations may be presently in the cations of potential vessel wall damage if nonoptimal deliv- domain of biomechanical engineers, we expect that future eries must be made. The second important part of the EIGI EIGI teams will consist of many medical professionals to treatment plan consisting of CFD simulation of the blood enable this rapidly advancing field to reach its vast potential. flow will depend upon continued progress being made in However, it is our expectation that the vascular clinical adapting the processes of solving the Navier–Stokes equation medical physicist will be uniquely qualified to integrate the to the conditions of EIGIs and validating these results.86–90 physics of imaging with the relevant aspects of biomechani- The verification link between actual blood flow situations, cal engineering involving interventional devices to be able to angiograms—where the flow of contrast media rather than oversee the technical aspects of EIGI facilities as well as to blood is recorded, and CFD calculation results, must be ac- head their scientific and engineering training programs for complished. At present, this validation process is being ac- medical personnel. Not only will there be a new syllabus of EIGI physics related concepts to teach, but we expect that tively pursued using phantom experiments with both blood 94–99 equivalent optical dye and denser more viscous radiographic simulation-based training of the physicians who perform contrast media.91,53 Once there is confidence that the CFD EIGI procedures will become the standard. The intervention- results are valid, initial flow conditions established by MRA ist will be able to practice and develop the necessary skills or ultrasound studies will be used together with the morphol- for catheter navigation and device deployment in a program- ogy determined by CBCT sequences as inputs to the CFD mable simulated environment with tactile and visual feed- calculations. The treatment plan might then consist of simu- back. The EIGI medical physicist with the collaboration of lating the deployment of a flow modifying device, such as a computer scientists will play a key role in both the use and stent, for treatment of stenoses or the deployment of a spe- the development of such systems. cialized flow diverting stent92,87,93 for treatment of aneurysms. Not only could velocity distributions and flow stream- IV. CONCLUSIONS lines be simulated, but also wall shear stress—a possible In the 1966 movie Fantastic Voyage, there was an account predictor of pathology—could be estimated as well ͑Fig. 3͒. of what future endovascular brain surgery could be like. It As models get more sophisticated and computer power involved the shrinking of a submarine with a team of people increases, it may be advantageous to do both the delivery and that was injected into a patient and instructed to take a route the CFD parts of the simulation almost in real time during through the vasculature to the brain to remove a blood clot in

Medical Physics, Vol. 35, No. 1, January 2008 307 Rudin, Bednarek, and Hoffmann: Endovascular image-guided interventions 307 a vessel. While we do not quite predict such a capability, we pp. 231–254. 10 believe there will be considerable movement in the direction S. Rudin, G. Yadava, G. Josan, A. Kuhls, H. Rangwala, Y. Wu, C. Ionita, and D. R. Bednarek, “New light-amplifier-based detector designs for high of miniaturization and remote actuation and guidance. We spatial resolution and high sensitivity CBCT mammography,” Proc. SPIE have made some specific forecasts regarding this rapidly ad- 6142, R1–R11 ͑2006͒. vancing and exciting field of EIGI. We have predicted that 11P. R. Granfors, R. Aufrichtig, G. E. Possin, B. W. Giambattista, Z. S. ϫ 2 imaging detectors will be markedly improved to better guide Huang, J. Liu, and B. Ma, “Performance of a 41 41 cm amorphous silicon flat panel x-ray detector designed for angiographic and R&F im- the use of newer and more complex interventional devices aging applications,” Med. Phys. 30, 2715–2726 ͑2003͒. and delivery equipment using radiation more appropriately. 12A. K. Bloomquist, M. J. Yaffe, G. E. Mawdsley, D. M. Hunter, and D. J. We have described how we believe treatment planning for Beideck, “Lag and ghosting in a clinical flat-panel selenium digital mam- ͑ ͒ EIGI will be enhanced from the present rather informal mography system,” Med. Phys. 33, 2998–3005 2006 . 13J. H. Siewerdsen and D. A. Jaffray, “A ghost story: Spatio-temporal re- qualitative planning to an increasingly sophisticated quanti- sponse characteristics of an indirect-detection flat-panel imager,” Med. tative procedure, involving a new labor-intensive role for Phys. 26, 1624–1641 ͑1999͒. medical physicists somewhat akin to the role that medical 14C. Schmidgunst, D. Ritter, and E. Lang, “Calibration model of a dual gain physicists play in radiation treatment planning. Ultimately, flat panel detector for 2D and 3D x-ray imaging,” Med. Phys. 34, 3649– 3666 ͑2007͒. we expect that advances in EIGI will lead to greatly im- 15A. Ganguly, S. Rudin, D. R. Bednarek, K. R. Hoffmann, and I. Kypri- proved patient procedures in which the medical physicist anou, “Micro-angiography for neuro vascular imaging, Part 1: Experi- will play a crucial role. mental measurements and feasibility,” Med. Phys. 30, 3018–3028 ͑2003͒. 16Food and Drug Administration, FDA Public Health Advisory, “Avoidance of serious x-ray induced skin injuries to patients during fluoroscopically- guided procedures,” September 30, 1994, Center for Devices and Radio- ACKNOWLEDGMENTS logical Health, Rockville, Maryland ͑available at http://www.fda.gov/ cdrh/fluor.html͒. We thank the members of the University at Buffalo- 17 Toshiba Stroke Research Center including Dr. Ciprian N. L. K. Wagner, M. D. McNeese, M. V. Marx, and E. L. Siegel, “Severe skin reactions from interventional fluoroscopy: Case report and review of Ionita for supplying the angiographic images, Andrew the literature,” Radiology 213, 773–776 ͑1999͒. Kuhls-Gilcrist for the SSXII image comparison, and Dr. Hui 18S. Rudin and D. R. Bednarek, “Region of interest fluoroscopy,” Med. Meng’s group for supplying the CFD images. The work was Phys. 19, 1183–1189 ͑1992͒. 19S. Rudin, D. R. Bednarek, L. R. Guterman, A. Wakhloo, L. N. Hopkins, supported in part by the National Institutes of Health under L. Fletcher, and P. Massoumzadeh, “Implementation of region of interest Grant Nos. EB002873, NS43024, NS47242, HL52567, and fluoroscopy using the road mapping mode of a real-time digital radio- EB02916, the National Science Foundation under Grant No. graphic unit,” Radiographics 15, 1465–1470 ͑1995͒. 20 BES-0302389, the UB Interdisciplinary Research Develop- S. Rudin, L. R. Guterman, W. Granger, D. R. Bednarek, and L. N. Hop- ͑ ͒ kins, “Neuro-interventional radiologic application of region of interest ment Fund IRDF , and an equipment grant from Toshiba ͑ROI͒ imaging techniques,” Radiology 199, 870–873 ͑1996͒. Medical Systems Corp. 21S. Rudin, D. R. Bednarek, M. Kezerashvili, W. Granger, J. Serghany, L. R. Guterman, L. N. Hopkins, P. Massoumzadeh, B. Szymanski, and R. ͒ a Author to whom correspondence should be addressed. Electronic mail: Loftus, “Clinical application of region of interest ͑ROI͒ radiologic imag- [email protected] ing techniques,” Radiographics 16, 895–902 ͑1996͒. ͒ b Electronic mail:[email protected] 22N. A. Gkanatsios, W. Huda, K. R. Peters, and J. A. Freeman, “Evaluation ͒ c Electronic mail: [email protected] of an on-line patient exposure meter in neuroradiology,” Radiology 203, 1R. T. Higashida, B. J. Lahue, M. T. Torbey, L. N. Hopkins, E. Leip, and 837–842 ͑1997͒. D. F. Hanley, “Treatment of unruptured intracranial aneurysms: A nation- 23S. Balter, D. W. Fletcher, H. M. Kuan, D. Miller, D. Richter, H. Seissl, wide assessment of effectiveness,” AJNR Am. J. Neuroradiol. 28, 146– and T. B. Shope, “Techniques to estimate radiation dose to skin during 151 ͑2007͒. fluoroscopically guided procedures,” in Intravascular Brachytherapy/ 2C. J. Koebbe, E. Veznedaroglu, P. Jabbour, and R. H. Rosenwasser, En- Fluoroscopically-Guided Interventions, edited by S. Balter, R. Chan, and dovascular management of intracranial aneurysms: current experience T. Shope ͑AAPM Summer School Proceedings, Madison, Wisconsin, and future advances,” Neurosurgery 59, S3-93–S3-102 ͑2006͒. 2002͒, pp. 731–764. 3C. J. Koebbe, A. Pandey, E. Veznedaroglu, and R. H. Rosenwasser, “The 24C. T. Dotter and M. P. Judkins, “Transluminal treatment of arteriosclerotic evolution and future directions of endovascular therapy,” Clin. Neuro- obstruction. Description of a new technic and a preliminary report of its surg. 53, 191–195 ͑2006͒͑review͒. application, 1964,” Radiology 172, 904–920 ͑1989͒͑classical article͒. 4D. Fiorella and H. H. Woo, “Emerging endovascular therapies for symp- 25H. Ceschinski, H. Henkes, H. C. Weinert, W. Weber, D. Kuhne, and H. tomatic intracranial atherosclerotic disease,” Stroke 38, 2391–2396 Monstadt, “Torquability of microcatheter guidewires: the resulting tor- ͑2007͒. sional moment,” Biomed. Mater. Eng. 10, 31–42 ͑2000͒. 5O. Saborowski and M. Saeed, “An overview on the advances in cardio- 26J. Carey, A. Fahim, and M. Munro, “Design of braided composite and vascular interventional MR imaging,” Magn. Reson. Mater. Phys. Biol. cardiovascular catheters based on required axial, flexural and torsional Med. 20, 117–127 ͑2007͒. rigidities,” J. Biomed. Mater. Res., Part B: Appl. Biomater. 70B, 73–81 6S. D. Flamm, “Cross-sectional imaging studies: What can we learn and ͑2004͒. what do we need to know,” Semin. Vasc. Surg. 20, 108–114 ͑2007͒. 27J. Carey, D. Emery, and P. McCracken, “Buckling test as a new approach 7P. L. Rauch, “A tour of the interventional vascular imaging suite,” in to testing flexural rigidities of angiographic catheters,” J. Biomed. Mater. Intravascular Brachytherapy Fluoroscopically Guided Interventions, Res., Part B: Appl. Biomater. 76B, 211–218 ͑2006͒. AAPM Monograph No. 28 ͑AAPM, College Park, Maryland, 2002͒, pp. 28P. Bloss, W. Rothe, P. Wunsche, C. Werner, A. Rothe, G. D. Kneissl, W. 547–616. Burger, and E. Rehberg, “Investigations of the pushability behavior of 8J. A. Rowlands and J. Yorkston, “Flat panel detectors for digital radiog- cardiovascular angiographic catheters,” Biomed. Mater. Eng. 13, 327–343 raphy,” in Handbook of Medical Imaging, Vol. 1, Physics and Psycho- ͑2003͒. physics, edited by J. Beutel, H. L. Kundel, and R. L. Van Metter ͑SPIE, 29G. H. Zoarski, J. M. Mathis, and J. R. Hebel, “Performance characteristics Bellingham, Washington, 2000͒, Chap. 4. of microcatheter systems in a standard tortuous pathway,” AJNR Am. J. 9J. T. Bushberg, J. A. Siebert, E. M. Leidholdt, and J. M. Boone, “Fluo- Neuroradiol. 19, 1571–1576 ͑1998͒. roscopy,” in The Essential Physics of Medical Imaging, 2nd ed. ͑Lippin- 30J. M. Anderson, “The future of biomedical materials,” J. Mater. Sci. cott Williams and Wilkins, Philadelphia, Pennsylvania, 2002͒, Chap. 9, Mater. Med. 17, 1025–8 ͑2006͒͑review͒.

Medical Physics, Vol. 35, No. 1, January 2008 308 Rudin, Bednarek, and Hoffmann: Endovascular image-guided interventions 308

31S. H. Kim, B. A. Campanella, A. I. Qureshi, A. J. Ringer, A. S. Boulos, view ͑FFOV͒ and truncated CT for a human head phantom,” Proc. SPIE D. K. Lopes, L. R. Guterman, and L. N. Hopkins, in Management of 5745, 583–590 ͑2005͒. Cerebral Aneurysms, edited by P. D. Le Roux, H. R. Winn, and D. W. 53K. R. Hoffmann, S. Rudin, H. Meng, L. N. Hopkins, L. Guterman, and E. Newell ͑Saunders, Philadelphia, 2004͒, pp. 883–902. Levy, in Multidimensional Image Processing, Analysis, and Display,ed- 32W. L. Ginete, “Rotational Atherectomy: Current Perspectives,” ited by S. G. Armato and M. S. Brown ͑RSNA, Oak Brook, Illinois, www.med.umn.edu/img/assets/7172/Rotational_Atherectomy_073004 2005͒, pp. 173–184. .swf 54S. Schafer, V. Singh, K. R. Hoffmann, P. B. Noël, and J. Xu, “Planning 33Flow-Dependent Regulation of Vascular Function, edited by J. A. Bevan, image-guided endovascular interventions: guidewire simulation using G. Kaley, and G. M. Rubanyi ͑Oxford University Press, New York, shortest path algorithms,” Proc. SPIE 6509, C1-C10 ͑2007͒. 1995͒. 55International Electrotechnical Commission, Report 60601–2-43, “Medical 34P. F. Davies, J. A. Spaan, and R. Krams, “Shear stress biology of the electrical equipment Part 2-43: Particular requirements for the safety of endothelium,” Ann. Biomed. Eng., Special Issue: International Biofluid x-ray equipment for interventional procedures,” Geneva, Switzerland, Mechanics Symposium 33͑12͒, 1714–1718 ͑2005͒. 2000. 35S. G. Imbesi and C. W. Kerber, “Analysis of slipstream flow in a wid- 56U. S. Food and Drug Administration ͑FDA͒, HHS: Electronic Products– enecked basilar artery aneurysm: Evaluation of potential treatment regi- Federal performance standard for diagnostic x-ray systems and their ma- mens,” AJNR Am. J. Neuroradiol. 22, 721–724 ͑2001͒. jor components, Federal Register, June 10, 2005 ͑Vol. 70, Number 111͒, 36A. K. Wakhloo, B. B. Lieber, J. Seong, C. Sadasivan, M. J. Gounis, L. pp. 33997–34042. Miskolczi, and J. S. Sandhu, “Hemodynamics of carotid artery atheroscle- 57P. Massoumzadeh, S. Rudin, and D. R. Bednarek, “Filter material selec- rotic occlusive disease,” J. Vasc. Interv. Radiol. 15, S111–21 ͑2004͒͑re- tion for region of interest radiologic imaging,” Med. Phys. 25, 161–171 view͒. ͑1998͒. 37S. Vedantham, A. Karellas, and S. Suryanarayanan, “Solid-state fluoro- 58P. M. Dinu, D. R. Bednarek, D. Wobschall, R. Peterson, C. N. Ionita, S. scopic imager for high resolution angiography. Physical characteristic of Rudin, M. Zeng, K. Chugh, and K. R. Hoffmann, “X-ray beam tracking an 8 cmϫ8 cm experimental prototype,” Med. Phys. 31, 1462–1472 system for a fluoroscopic c-arm unit,” Med. Phys. 30,1424͑2003͒. ͑2004͒. 59K. Chugh, P. M. Dinu, D. R. Bednarek, D. Wobschall, S. Rudin, K. R. 38D. C. Hunt, K. Tanioka, and J. A. Rowlands, “X-ray imaging using ava- Hoffmann, R. Peterson, and M. Zeng, “A computer-graphic display for lanche multiplication in amorphous selenium: investigation of depth de- real-time operator feedback during interventional x-ray procedures,” pendent avalanche noise,” Med. Phys. 34, 976–986 ͑2007͒. Proc. SPIE 5367, 464–473 ͑2004͒. 39O. Hayden, R. Agarwal, and C. M. Lieber, “Nanoscale avalanche photo- 60Food and Drug Administration, Important Information for Physicians and diodes for highly sensitive and spatially resolved photon detection,” Nat. other Health Care Professionals, “Recording information in the patient’s Mater. 5, 352–356 ͑2006͒. medical record that identifies the potential for serious x-ray-induced skin 40W. Zhao, D. Li, A. Reznik, B. Lui, D. C. Hunt, K. Tanioka, and J. A. injuries following fluoroscopically-guided procedures,” September 15, Rowlands, “Indirect flat-panel detector with avalanche gain: design and 1995, Center for Devices and Radiological Health, Rockville Maryland operation of the avalanche photoconductor,” Proc. SPIE 5745, 352–360 ͑available at http://www.fda.gov/cdrh/xrayinj.html͒. ͑2005͒. 61D. L. Miller, S. Balter, L. K. Wagner, J. Cardella, T. W. Clark, C. D. 41M. H. Izadi, K. S. Karim, A. Nathan, and J. A. Rowlands, “Low-noise Neithamer, Jr., M. S. Schwartzberg, T. L. Swan, R. B. Tobwin, K. S. architecture for advanced diagnostic medical x-ray imaging applications,” Rholl, and D. Sacks, “SIR standards of Practice Committee, “Quality Proc. SPIE 6142, T1–T11 ͑2006͒. improvement guidelines for recording patient radiation dose in the medi- 42F. Taghibakhsh and K. S. Karim, “Amplified pixel sensor architectures for cal record,” J. Vasc. Interv. Radiol. 15, 423–429 ͑2004͒. low dose computed tomography using silicon thin film technology,” Proc. 62L. K. Wagner, in Intravascular Brachytherapy / Fluoroscopically-Guided SPIE 6510, W1–W8 ͑2007͒. Interventions, edited by S. Balter, R. Chan, and T. Shope ͑AAPM Sum- 43J. Hynecek, “Impactron–A new solid state image intensifier,” IEEE Trans. mer School Proceedings, Madison, Wisconsin, 2002͒, pp. 195–218. Electron Devices 48, 2238–2241 ͑2001͒. 63J. A. Ormiston, M. W. I. Webster, and G. Armstrong, “First-in-human 44M. S. Robbins and B. J. Hadwen, “The noise performance of electron implantation of a fully bioabsorbable drug-eluting stent: the BVS poly-L- multiplying charge-coupled devices,” IEEE Trans. Electron Devices 50, lactic acid everolimus eluting coronary stent,” Catheter. Cardiovasc. In- 1227–1232 ͑2003͒. terv. 69, 128–131 ͑2007͒. 45A. T. Kuhls, G. Yadava, V. Patel, D. R. Bednarek, and S. Rudin, “Progress 64R. Erbel et al., “Temporary scaffolding of coronary arteries with bioab- in electron-multiplying CCD ͑EMCCD͒ based, high-resolution, high- sorbable magnesium stents: a prospective, non-randomised multicentre sensitivity x-ray detector for fluoroscopy and radiography,” Proc. SPIE trial,” Lancet 369, 1869–1875 ͑2007͒. 6510, C1–C11 ͑2007͒. 65J. Ormiston and M. Webster, “Absorbable coronary stents. ͓comment͔,” 46I. A. Cunningham, “Applied linear systems theory,” in Handbook of Lancet 369, 1839–1840 ͑2007͒. Medical Imaging, Vol. 1. Physics and Psychophysics, edited by J. Beutel, 66S. Saito, “New horizon of bioabsorbable stent. ͓comment͔,” Catheter. H. L. Kundel, and R. L. Van Metter ͑SPIE, Bellingham, Washington, Cardiovasc. Interv. 66, 595–596 ͑2005͒͑editorial͒. 2000͒,Chap.2. 67http://www.stereotaxis.com/ 47A. Ganguly, S. Rudin, D. R. Bednarek, and K. R. Hoffmann, “Micro 68M. P. Armacost, J. Adair, T. Munger, R. Viswanathan, F. M. Creighton, angiography for Neuro vascular imaging, part 2: Cascade model analy- D. T. Curd, and R. Sehra, “Accurate and reproducible target navigation sis,” Med. Phys. 30, 3029–3039 ͑2003͒. with the stereotaxis Niobe Magnetic Navigation System,” J. Cardiovasc. 48I. Kyprianou, S. Rudin, D. R. Bednarek, and K. R. Hoffmann, “General- Electrophysiol. 18, S26–S31 ͑2007͒. izing the MTF and DQE to include x-ray scatter and focal spot unsharp- 69C. Pappone et al., “Robotic magnetic navigation for atrial fibrillation ness: Application to a new micro-angiographic system for clinical use,” ablation,” J. Am. Coll. Cardiol. 47, 1390–1400 ͑2006͒. Med. Phys. 32, 613–626 ͑2005͒. 70E. Florin, H. S. Rangwala, and S. Rudin, “Method to rotate an endovas- 49G. K. Yadava, I. S. Kyprianou, S. Rudin, D. R. Bednarek, and K. R. cular device around the axis of a vessel using an external magnetic field,” Hoffmann, “Generalized performance evaluation of x-ray image intensi- Med. Phys. 34, 328–333 ͑2007͒. fier compared with a microangiographic system,” Proc. SPIE 5745, 419– 71F. Settecase, M. S. Sussman, M. W. Wilson, S. Hetts, R. L. Arenson, V. 429 ͑2005͒. Malba, A. F. Bernhardt, W. Kucharczyk, and T. P. L. Roberts, 50Siemens iPilot, Axiom No. 2, March, 2006, pp. 10–17, pamphlet from “Magnetically-assisted remote control ͑MARC͒ steering of endovascular Siemens Medical Corp., http://www.medical.siemens.com/siemens/ catheters for interventional MRI: A model for deflection and design im- sv_SE/rg_marcom_FBAs/files/brochures/magazin_archive_ax/AXIOM_ plications,” Med. Phys. 34, 3135–3142 ͑2007͒. Innovation_in_Intervention_March_2006.pdf 72http://www.hansenmedical.com/products/sensei.aspx 51Philips Xpervision Newsletter, November, 2006, http:// 73A. D. Al-Ahmad, J. Grossman, and P. J. Wang, “Early experience with a www.medical.philips.com/us/products/cardiovascular/assets/docs/ computerized robotically controlled catheter system,” J. Interv. Card. XperVision_Newsletter_int.pdf Electrophysiol. 12, 199–202 ͑2005͒. 52R. Chityala, K. R. Hoffmann, D. R. Bednarek, and S. Rudin, “Region of 74L. Cercenelli, E. Marcelli, and G. Plicchi, ““Initial experience with a interest ͑ROI͒ computed tomography ͑CT͒: comparison with full field of telerobotic system to remotely navigate and automatically reposition stan-

Medical Physics, Vol. 35, No. 1, January 2008 309 Rudin, Bednarek, and Hoffmann: Endovascular image-guided interventions 309

dard steerable EP catheters,” ASAIO J. 53, 523–529 ͑2007͒. namic ͑CFD͒ calculations in the computed tomography ͑CT͒ derived lu- 75P. R. Buckley, G. H. McKinley, T. S. Wilson, W. Small IV, W. J. Benett, men,” Proc. SPIE 6143, G1–G8 ͑2006͒. J. P. Bearinger, M. W. McElfresh, and D. J. Maitland, ““Inductively 88J. R. Cebral, R. S. Pergolizzi, Jr., and C. M. Putnam, “Computational fluid heated shape memory polymer for the magnetic actuation of medical dynamics model of intracranial aneurysms: qualitative comparison with devices,” IEEE Trans. Biomed. Eng. 53, 2075–2083 ͑2006͒. cerebral angiography,” Acad. Radiol. 14, 804–813 ͑2007͒. 76G. M. Nesbit, G. Luh, R. Tien, and S. L. Barnwell, “New and future 89J. Cebral, A. Radaelli, A. Frangi, and C. Putman, “Hemodynamics before endovascular treatment strategies for acute ischemic stroke,” J. Vasc. In- and after bleb formation in cerebral aneurysms,” Proc. SPIE 6511, terv. Radiol. 15, S103–S110 ͑2004͒. 65112C1–65112C9 ͑2007͒. 77B. J. Wood, J. K. Locklin, A. Viswanathan, J. Kruecker, D. Haemmerich, 90S. Appanaboyina, F. Mut, R. Löhner, C. Putman, and J. Cebral, “Patient J. Cebral, A. Sofer, R. Cheng, E. McCreedy, K. Cleary, M. J. McAuliffe, specific modeling of intracranial aneurysmal stenting,” Proc. SPIE 6511, N. Glossop, and J. Yanof, “Technologies for guidance of radiofrequency 65112D1–65112D11 ͑2007͒. ablation in the multimodality interventional suite of the future,” J. Vasc. 91Z. Wang, C. N. Ionita, S. Rudin, K. R. Hoffmann, A. B. Paxton, and D. R. Interv. Radiol. 18, 9–24 ͑2007͒͑review͒. Bednarek, “Angiographic analysis of blood flow modification in cerebral 78J. Seong, C. Sadasivan, M. Onizuka, M. J. Gounis, F. Christian, L. Mis- aneurysm models with a new asymmetric stent,” Proc. SPIE 5369, 307– kolczi, A. K. Wakhloo, and B. B. Lieber, “Morphology of elastase- 318 ͑2004͒. induced cerebral aneurysm model in rabbit and rapid prototyping of elas- 92S. Rudin, Z. Wang, I. Kyprianou, K. R. Hoffmann, Y. Wu, H. Meng, L. R. tomeric transparent replicas,” Biorheology 42, 345–361 ͑2005͒. Guterman, B. Nemes, D. R. Bednarek, J. Dmochowski, and L. N. Hop- 79J. R. Sherman, H. S. Rangwala, C. N. Ionita, A. C. Dohatcu, D. R. kins, “Measurement of flow modification in phantom aneurysm model: Bednarek, K. R. Hoffmann, and S. Rudin, “Investigation of new flow comparison of coils and a longitudinally and axially asymmetric stent– modifying endovascular image-guided interventional ͑EIGI͒ techniques in initial findings,” Radiology 231, 272–276 ͑2004͒. patient specific aneurysm phantoms ͑PSAPs͒ using optical imaging,” 93B. B. Lieber, C. Sadasivan, L. Miskolczi, L. Cesar, J. Seong, and A. K. Proc. SPIE ͑in press͒. Wakhloo, “Flow divertors to treat cerebral aneurysms: preliminary results 80M. Kohl, Shape Memory Microactuators ͑Springer, New York, 2004͒. in the rabbit elastase-induced aneurysm model,” in Proceedings BIO2006, 81M. I. T. Research, Laboratory of Electronics ͑RLE͒, J. G. Fujimoto, PI, ASME 2006 Summer Bioengineering Conference, June 21–25, 2006, http://www.rle.mit.edu/rleonline/research/ Amelia Island Plantation, Amelia Island, Florida. LaserMedicineandMedicalImagingGroup.html 94T. Alderliesten, M. K. Konings, and W. J. Niessen, “Simulation of mini- 82X.-W. Tang, Y. Yang, W. Kim, Q. Wang, P. Qi, H. Dai, and L. Xing, mally invasive vascular interventions for training purposes,” Comput. “Measurement of ionizing radiation using carbon nanotube field effect Aided Surg. 9, 3–15 ͑2004͒. transistor,” Phys. Med. Biol. 50, N23–N31 ͑2005͒. 95T. Alderliesten, M. K. Konings, and W. J. Niessen, “Modeling friction, 83C. Karmonik, C. M. Strother, X. Chen, F. Deinzer, R. Klucznik, and M. intrinsic curvature, and rotation of guidewires for simulation of minimally E. Mawad, “Stent-assisted coiling of intracranial aneurysms aided by vir- invasive vascular interventions,” IEEE Trans. Biomed. Eng. 54, 29–39 tual parent artery reconstruction,” AJNR Am. J. Neuroradiol. 26, 2368– ͑2007͒. 2370 ͑2005͒. 96C. Duriez, S. Cotin, J. Lenoir, and P. Neumann, “New approaches to 84K. Baráth, F. Cassot, D. A. Rüfenacht, and J. H. D. Fasel, “Anatomically catheter navigation for interventional radiology simulation,” Comput. shaped internal carotid artery aneurysm in vitro model for flow analysis to Aided Surg. 11, 300–308 ͑2006͒. evaluate stent effect,” AJNR Am. J. Neuroradiol. 25, 1750–1759 ͑2004͒. 97D. L. Dawson, “Training in carotid artery stenting: Do carotid simulation 85S. Baek, K. R. Rajagopla, and J. D. Humphrey, “A theoretical model of systems really help?,” Vascular 14, 256–263 ͑2006͒͑review͒. enlarging intracranial fusiform aneurysms,” J. Biomech. Eng. 128, 142– 98D. A. Gould, D. O. Kessel, A. E. Healey, S. J. Johnson, and W. E. 149 ͑2006͒. Lewandowski, “Simulators in catheter-based interventional radiology: 86M. D. Ford, G. R. Stuhne, H. N. Nikolov, D. F. Habets, S. P. Lownie, D. training or computer games?,” Clin Radiol. 61, 556–561 ͑2006͒͑review͒, W. Holdsworth, and D. A. Steinman, “Virtual angiography for visualiza- D. A. Gould, D. O. Kessel, A. E. Healey, S. J. Johnson, and W. E. tion and validation of computational models of aneurysm hemodynam- Lewandowski, Clin. Radiol. 61,903͑2006͒͑erratum͒. ics,” IEEE Trans. Med. Imaging 24, 1586–1592 ͑2005͒. 99A. Sengupta, T. Kesavadas, K. R. Hoffmann, R. E. Baier, and S. Schafer, 87M. Kim, C. N. Ionita, R. V. Tranquebar, K. R. Hoffmann, D. B. Taulbee, “Evaluating tool-artery interaction force during endovascular neurosur- H. Meng, and S. Rudin, “Evaluation of an asymmetric stent patch design gery for developing haptic engine,” Stud. Health Technol. Inform. 125, for a patient specific intracranial aneurysm using computational fluid dy- 418–420 ͑2007͒.

Medical Physics, Vol. 35, No. 1, January 2008 An outlook on x-ray CT research and development ͒ ͒ Ge Wanga and Hengyong Yub Biomedical Imaging Division, VT-WFU School of Biomedical Engineering and Science, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 240601 ͒ Bruno De Manc CT and X-ray Laboratory, GE Global Research, Niskayuna, New York 12309 ͑Received 5 October 2007; revised 20 December 2007; accepted for publication 20 December 2007; published 25 February 2008͒ Over the past decade, computed tomography ͑CT͒ theory, techniques and applications have undergone a rapid development. Since CT is so practical and useful, undoubtedly CT technology will continue advancing biomedical and non-biomedical applications. In this outlook article, we share our opinions on the research and development in this ﬁeld, emphasizing 12 topics we expect to be critical in the next decade: analytic reconstruction, iterative reconstruction, local/interior reconstruction, ﬂat-panel based CT, dual-source CT, multi-source CT, novel scanning modes, energy-sensitive CT, nano-CT, artifact reduction, modality fusion, and phase-contrast CT. We also sketch several representative biomedical applications. © 2008 American Association of Physicists in Medicine. ͓DOI: 10.1118/1.2836950͔

Key words: analytic reconstruction, iterative reconstruction, local/interior reconstruction, ﬂat-panel based CT, dual-source CT, multi-source CT, scanning mode, energy-sensitive CT, nano-CT, artifact reduction, modality fusion, phase-contrast CT

I. INTRODUCTION source CT scanner and other similar systems. Early 1990s, single-slice helical/spiral CT became the standard scanning The evolution of civilization has been largely driven by the model,5 and helical/spiral cone-beam CT was proposed.6,7 need for extending human’s capabilities. Arguably, the most Elscint developed a two-slice CT scanner in the mid 90’s and important way for us to sense the world is by visual percep- GE came out with the first four-slice CT scanner a few years tion. However, the human vision is severely limited by the opaqueness of many natural and artificial objects. Hence, later, quickly followed by all other major CT manufacturers.8,9 In 2004, Toshiba first successfully devel- how to achieve “an inner vision” was often pondered in vari- 10 ous scenarios through history. Mainly credited to the pio- oped 256-slice CT systems. With the fast evolution of the neering works of Cormack1 and Hounsfield,2 in the last cen- technology, true volumetric cone-beam CT scanners in heli- ͑ ͒ cal and other scanning modes are emerging as the next gen- tury, x-ray computed tomography CT is the first imaging 11,12 modality that allows accurate non-destructive interior image eration biomedical CT. On the algorithm side, over the past several years, triggered by an exact and efficient solu- reconstruction of an object from a sufficient number of x-ray 13,14 projections. Hounsfield’s x-ray CT prototype immediately tion to the long-standing helical cone-beam CT problem, there has been a remarkable surge in studies on image recon- generated a tremendous excitement in the medical commu- 15 nity and inspired a rapid technical development with an ever struction algorithms. Now, there are already a number of strong momentum. Also, x-ray CT as the first trans-axial to- exact reconstruction schemes and algorithms that deal with mography model promoted the development of other tomog- general scanning trajectories and appropriately truncated raphic modalities for biomedical applications and beyond, data. such as magnetic resonance imaging, ultrasound tomography, Will the progress of this magnitude in the CT field con- nuclear tomography, optical tomography, molecular tomog- tinue in the next decade? Based on the impressive track raphy, and so on. record in this field, we firmly believe it will. Then, what are Since its introduction in 1973,2 x-ray CT has revolution- the most important research topics/directions for the x-ray ized radiographic imaging and become a cornerstone of ev- CT research and development? The answer to this big ques- ery modern radiology department. Closely correlated to the tion is difficult to formulate because any prediction of that development of x-ray CT, the research for higher perfor- nature must be limited by our partial knowledge and inad- mance system architectures and more advanced image recon- equate ability to look into the future. Having acknowledged struction algorithms has been intensively pursued for impor- that, in this article we would like to share our opinions tant biomedical applications. A famous CT scanner is the for the purpose of information and inspiration, which dynamic spatial reconstructor ͑DSR͒ built at the Mayo Clinic would hopefully guide our efforts and facilitate the future in 1979.3,4 With the ability to acquire 240 contiguous 1 mm advancement. slices in a time window of 0.01 s, the heart, lung, and blood This outlook article is organized as follows. In Sec. II, we flow can be vividly observed. This DSR system is considered will quantitatively overview the CT literature to give a sense as the precursor of the electron-beam CT scanner, the dual- of the dynamics of this field. In Sec. III as the main part of

1051 Med. Phys. 35 „3…, March 2008 0094-2405/2008/35„3…/1051/14/$23.00 © 2008 Am. Assoc. Phys. Med. 1051 1052 Wang, Yu, and De Man: CT outlook 1052 this article, we will present 12 topics to cover the main TABLE I. Representative search data on CT studies and application, where trends in the CT ﬁeld. In Sec. IV, we will discuss biomedical the percentage means the number of hits for the past ﬁve years over that for the past ten years ͑searched on 9/4/07͒. implications of the proposed research and development. Fi- nally, in Sec. V we will make concluding remarks. No.ofHits No.ofHits Rule for 97-07 for 02-07 %

65.7 1829 2785 ”ءII. QUANTITATIVE LITERATURE ANALYSIS “CT” and “algorithm Our methodology for literature analysis is to search the “CT” and “cancer” 11 468 7642 66.6 “CT” and “cardiac” 2252 1517 67.4 ISI Web of Knowledge ͑http://portal.isiknowledge.com͒: Sci- “CT” and “dose” 5595 3609 64.5 ence Citation Index Expanded ͑SCI-EXPANDED͒ from ͑ ͒ “CT” and “dynamic” 2572 1456 56.7 1975 until now search performed on September 4, 2007 . “CT” and “dual-energy” 235 142 60.4 65.4 1812 2771 ”ءEach topic search is conveniently performed with one or “CT” and “screen 60.3 7296 099 12 ”ءmore terms within article titles, keywords, and abstracts. Our “CT” and “therap 57.7 15604 025 27 ”ءanalysis was intended to give a quantitative impression but is “CT” and “diagno necessarily selective and by no means exhaustive. A reader “CT” and “fusion” 1586 1134 71.5 can easily verify our data, modify our searches and reach “CT” and “mouse” 787 416 52.9 his/her own conclusions. Does the CT research have an increasing momentum? The answer is definitely “yes,” despite the great develop- III. TWELVE TOPICS FOR THE NEXT DECADE ments in all competing modalities. With the search rule “x- ray” and “CT,” there are 5857 hits for 1975–2007, of which III.A. Analytic reconstruction we have only 1210 hits for 1987–1996 and 4553 hits for the Since Katsevich’s 2002 paper on exact and efficient heli- past ten years 1997–2007. With the search rule “Cone-beam” cal cone-beam CT reconstruction,14 intensified research ef- and “CT,” we have 896 hits for 1975–2007, of which we forts have been made in this area.15 Various sophisticated have only 117 hits for 1992–2001, and 777 hits for the past formulas have been proposed for exact reconstruction from five years 2002–2007. More detailed yearly numbers of the projection data that can be longitudinally truncated and even retrieved articles are shown in Fig. 1. Some further represen- transversely truncated, and for not only a standard helical tative search results over the period 1997–2007 are summa- trajectory but also a quite general class of scanning loci ͑Fig. rized in Table I. Evidently, the above data are quite informa- 2͒.16–24 However, in the general case such as saddle-like tive, indicating steady and increasing efforts for the past ten scanning paths24 and nonstandard helical trajectories, these years over a wide spectrum of CT research, development and algorithms are far less computationally efficient as compared applications. However, there should be some noise and arti- to the popular filtered backprojection ͑FBP͒ with spatially facts in the results since the keywords and their combinations invariant filtering. In the 9th International Meeting on Fully could be misleading in some cases. Therefore, these data 3D Image Reconstruction in Radiology and Nuclear Medi- should not be interpreted without caution. cine ͑Lindau, Germany, July 9–13, 2007͒, Katsevich pre- We then retrieved all 363 “x-ray” and “CT” papers for the sented an important progress towards exact yet efficient gen- year 2007, excluded irrelevant ones, and categorized them, eral cone-beam reconstruction algorithms for two classes of as shown in Table II. Clearly, the biomedical applications scanning loci.25 The first class curves are smooth and of posi- remain the mainstream for x-ray CT, and a major portion of tive curvature and torsion. The second class consists of efforts is being devoted to research and development of circle-plus curves, with the segment for the plus part starting methods and systems. Also, there are some non-biomedical below the circle-like trajectory and ending above it.26 How- applications, which are about one third of the medical appli- ever, there are other important classes of trajectories for cations. which exact and efficient algorithms are desired and highly nontrivial. Therefore, it remains an open challenge to formulate such exact and efficient algorithms for many other types of scanning curves. Theoretical unification of these new exact algorithms is also worthwhile.27–29

TABLE II. Categorization of 262 relevant papers selected from the 363 articles in English retrieved under the rule “x-ray” and “CT” for 2007 ͑searched on 9/4/07͒.

Category No. of Papers %

Methods & systems 72 27.5 FIG. 1. Numbers of retrieved papers during 1997–2007 with the searching rules ͑a͒ “x-ray” and “CT” and ͑b͒ “cone-beam” and “CT,” respectively. Medical applications 127 48.5 Exponential ﬁtting shows that there is a 5% increment yearly for the former, Pre-clinical applications 14 5.3 while a 39% increment for the latter. Note that the numbers for 2007 are Non-biomedical applications 49 18.7 incomplete.

Medical Physics, Vol. 35, No. 3, March 2008 1053 Wang, Yu, and De Man: CT outlook 1053

There are two reasons. First, in a good number of applications, the data completeness required for exact reconstruction cannot be satisﬁed due to physical constraints. Hence, the only choice is to perform an approximate reconstruction. Second, even if an exact reconstruction is practically feasible, oftentimes the approximate algorithms can deliver similar or even better performance as compared to the exact reconstruction counterparts, which are not necessarily opti-

FIG. 2. Representative general scanning trajectories. ͑a͒ A non-standard he- mal in terms of the noise characteristics. Figure 3 shows two 33 lix, ͑b͒ a saddle curve and ͑c͒ a circle-plus-line combination. approximate reconstructions of excellent quality. It is our opinion that the popularity of approximate cone- beam reconstruction algorithms will definitely sustain in the Furthermore, it has been well recognized that the way to near future. With the development of exact cone-beam recon- formulate exact and efficient reconstruction is not struction algorithms, the approximate cone-beam reconstruc- 17,27,30 unique. The key is to select an appropriate weight tion algorithms will be surely improved as well. In addition function. Different choices of the weights would have dis- to various approximations to be improved or made on an tinct impacts on the image noise distribution. Depending on individual basis, a promising research direction for approxi- each specific clinical application, the preferred image noise mate cone-beam reconstruction would be to adapt new exact distribution may be uniform or least noisy in a region of cone-beam reconstruction algorithms.34–36 By doing so, the interest ͑ROI͒ while being more tolerable outside the ROI. In merits of exact cone-beam reconstruction algorithms can be other words, an ideal exact cone-beam reconstruction for- largely inherited at a much lower computational cost and mula needs to be not only efficient but also produce the best modified to have certain practically desirable features. This possible image noise distribution, which is application de- approach should be particularly attractive in the cases of in- pendent. The governing theory guiding this procedure has complete and/or inconsistent data such as cardiac CT, con- been studied from different aspects but it has not been thor- trast studies, artifact reduction, and so on. oughly developed yet. In contrast to impressive progress in solving the so-called III.B. Iterative reconstruction long objection problem ͑reconstruction of a long object from longitudinally truncated cone-beam data͒, cardiac cone-beam While the very first CT scanners used algebraic iterative CT is what we call the quasi-short object problem ͑recon- reconstruction ͑ART͒,37,38 FBP39 soon became the gold stan- struction of a short portion of a long object from longitudi- dard for CT reconstruction. A few years later, statistical it- nally truncated cone-beam data involving the short object͒ erative reconstruction was successfully introduced for emis- and deserves more research efforts. To solve the quasi-short sion tomography,40 because FBP reconstruction from a low object problem, the circular cone-beam scan only permits SNR ͑signal-noise-ratio͒ emission data set would produce approximate reconstruction and the helical cone-beam scan quite poor image quality. A simultaneous update variation of has inefficient photon utilization. The saddle-like cone-beam ART, called simultaneous ART, was presented in 1984.38 In scan can combine exact reconstruction and good photon uti- the past decade, thanks to the increasing computational lization, representing a promising direction.24,31,32 Again, we power, statistical iterative reconstruction has become a hot will need exact, efficient and optimized algorithms in the research topic for CT,41–46 with a focus on noise suppression, context of solving the quasi-short object problem. artifact reduction and dual energy/energy-sensitive In the CT applications, approximate cone-beam recon- imaging.46,47,92 Recent advances in statistical iterative struction algorithms have been dominating despite the rapid reconstruction48 promise to achieve dramatic improvements development of exact cone-beam reconstruction algorithms.6 in image quality, as illustrated in Fig. 4. Figure 4 shows the

FIG. 3. Images reconstructed from clinical data using an approximate helical cone-beam FBP algorithm ͑see Ref. 33͒. ͑a͒ A reformatted abdominal image ͓display window width/length: 381/83͑HU͔͒ and ͑b͒ a reformatted cardiac image ͓display window setting: 800/ 216͑HU͔͒ duplicated from Ref. 33 with the permission of the Institute of Physics Publishing.

Medical Physics, Vol. 35, No. 3, March 2008 1054 Wang, Yu, and De Man: CT outlook 1054

FIG. 4. Images analytically and iteratively reconstructed from clinical data. ͑a͒ A FBP reconstruction from a 300 mAs dataset, ͑b͒ a FBP reconstruction from a 75 mAs dataset, and ͑c͒ an iterative reconstruction from the same 75 mAs dataset ͑Ref. 48͒͑Courtesy of J.-B. Thibault͒. impact of a 4x reduction in x-ray tube current ͑mA͒. With noisy. Even in the cases where analytic reconstruction per- FBP, the noise level increases dramatically ͑the standard deforms well, there is no fundamental reason why iterative re- viation of the noise increases by a factor of 2 theoretically͒. construction would perform any worse. Hence, we predict With iterative reconstruction, the noise level is not increased that the fast development in computing methods and hard- or even descreased relative to the full-dose FBP counterpart, ware will lead to a shift from analytic to statistical recon- suggesting a 4x dose reduction in this particular case. New struction or at least a fusion of analytic and iterative ap- iterative reconstruction schemes will surely emerge, as will proaches. This evolution will happen gradually, because of be further discussed for Topics J and K. We believe that it is the high computational cost as well as the time needed for only a matter of time for statistical iterative reconstruction to the radiologists to adopt this new technology. become available on commercial CT scanners. Several factors have prevented statistical iterative recon- III.C. Local/interior CT struction from being deployed on CT products so far. The first is the huge computational cost, about two to three orders There is a long track record for the exact reconstruction of of magnitude larger than that of FBP. Despite recent ad- an ROI from a minimum dataset, starting from the work on vances in high-performance image reconstruction based on half-scan fan-beam reconstruction.50 The benefits include field-programmable gate arrays, multi-core processors such shorter data acquisition time, less radiation dose and more as IBM’s Playstation 3 Cell Broadband Engine, and graphics imaging flexibility. The most remarkable recent finding is the processing units, we expect that first product realizations will work by Katsevich in 2002 that demonstrates the feasibility be slow ͑tens of seconds per slice͒. The second is the robust- of the exact regional reconstruction within a long object from ness of iterative algorithms across different protocols and longitudinally truncated data collected along a PI ͑␲͒-turn of applications. Currently, some significant parameter tuning a helical scanning trajectory.14 The subsequent backprojec- needs to be done for practical use of an iterative method in a tion filtration variant51 and generalization into the quite arbi- specific application. The best imaging performance is usually trary scanning case16,18 significantly enriched the local CT very sensitive to the particular choice of parameters. The theory. As illustrated in Fig. 5, the latest results along this third is the potentially new look of statistically reconstructed direction are the one-sided inverse Hilbert transform based images. Since images are reconstructed in a statistically op- local reconstruction algorithm52 and the truly truncated Hil- timal fashion, their noise and artifact characteristics can be bert transform based interior reconstruction algorithm rather different from those of FBP. Radiologists are used to coupled with some a priori knowledge in an ROI to be the FBP image appearance and associated various image reconstructed,53,54 which is somehow challenging the con- quality trade-offs. Consequently, statistical reconstruction ventional wisdom that an interior problem ͑reconstruction of may give an impression of somewhat reduced diagnostic an interior region from projection data along lines through value in certain cases. In fact, its spatial resolution charac- the region͒ does not have a unique solution.55 Clearly, exact teristics are indeed very different from the FBP counterpart solutions to the interior problem have tremendous implica- and depend on many factors. A careful quantitative analysis tions for numerous biomedical and other applications.56 of image noise and spatial resolution as a function of loca- It is highly desirable to establish a unified theory for exact tion, contrast, and measurement statistics shows indeed that local/interior reconstruction that covers the exact reconstruc- statistical iterative reconstruction has the potential to im- tion schemes and methods from a minimum dataset in the prove the information content of reconstructed images.49 two-dimensional ͑2D͒ and three-dimensional ͑3D͒ cases In perspective, iterative reconstruction offers distinct ad- from parallel- and divergent-beam geometries. It should be vantages relative to analytic reconstruction in important valuable to refine the reported stability analysis and reflect cases when data are incomplete, inconsistent and rather the sampling geometry and data noise in an optimal fashion.

Medical Physics, Vol. 35, No. 3, March 2008 1055 Wang, Yu, and De Man: CT outlook 1055

manufacturers ͑GE, Hologic, Philips, Siemens, and Toshiba͒ offer FPD-based x-ray systems. GE, Hologic, Canon and Shimadzu make FPDs independently. FPDs in use today employ pixel sizes ranging from 70ϫ70 ␮m2 to 200 ϫ200 ␮m2, in arrays of up to 14 million pixels, and active areas of up to 43ϫ43 cm2. Some FPDs are of the indirect conversion type, in which a scintillator converts the x rays to visible light, and a 2D array of photodiodes converts the light to electronic charges to be digitized. In an alternative direct conversion technology, x-rays are converted directly to electronic charges and then digitized. Even prior to the development of FPDs, 3D reconstruction of multi-angle digital projection images from an II- based C-arm cardiology system was demonstrated.60 Once FPDs were incorporated into such systems, the non-ideal characteristics of the II tube were circumvented, and CT reconstruction of data from C-arm systems became practical. Today most clinical FPD-based C-arm systems have the ability to acquire and reconstruct 3D CT images. Digital Breast Tomosynthesis61 is a new modality using key elements of FPD-based mammography systems. The x-ray source is FIG. 5. Theoretically exact solution to the interior problem. The exactly recoverable regions are not the same according to the different sufficient moved along an arc and a relatively small number of projec- conditions-based on the truncated Hilbert Transform: ͑a͒ The exact recon- tions are acquired, enabling reconstruction of approximately struction region by Defrise et al. ͑Ref. 52͒, ͑b͒ that by Ye et al. ͑Ref. 53͒ 1.0-mm-thick image planes. This technology is currently in ͑ ͒ where f x is the object image along a given PI line within a compact advanced development. Researchers have also incorporated support and g͑x͒ is the corresponding Hilbert Transform, ͑c͒ a slice of the thorax phantom with a T-shaped local ROI, and ͑d͒ the image reconstructed FPDs into a conventional CT gantry to achieve high spatial 62 from a purely local dataset plus prior knowledge on a sub-region in the ROI resolution in medium to large field-of-view scans. This ar- using the POCS method ͑Ref. 53͒. chitecture was primarily intended for small animal imaging.63,64 FPDs are also under investigation in a few other application-specific areas, such as breast CT Also, it is critical to design numerically stable, robust and scanners,65,66 infra-operative imaging systems,67 and com- efficient algorithms for this purpose. The state-of-the-art pact or mobile CT systems for head or dental imaging.68 framework for local/interior reconstruction is the Hilbert FPD-based CT is still in its infancy, and substantial develop- transform analysis. Perhaps other possibilities exist for us to ments are expected in the future. gain a thorough understanding of this amazing problem. As an alternative technology for local/interior reconstruction, theoretically exact fan-beam lambda tomography ͑LT͒ III.E. Dual-source CT was also available for a general scanning locus based on the Most commercial clinical scanners until today are based 2D Calderon operator.57,58 However, exact cone-beam LT is on the so-called third-generation architecture. A single x-ray generally impossible based on the 3D Calderon operator for tube and a single detector assembly are positioned face to practical scanning loci such as a helix.58 It is promising to face and rotated jointly around the patient. Berninger and develop exact LT reconstruction methods in terms of the 2D Redington69 presented the idea of replicating the source and Calderon operator in some planes for data collected along a detector, as illustrated in Fig. 6͑a͒. The dynamic spatial re- general scanning locus. As a related area, partial derivatives constructor may have been the first real multi-source of a dynamically changing image volume can be directly prototype.4 About 25 years later, Siemens developed the first reconstructed from original cone-beam data. Thus, velocity commercial two-tube-two-detector scanner, also known as tomography may be improved from these partial derivatives dual-source CT.70 The main advantage of this architecture is based on the general velocity field constraint equation.59 its improved temporal resolution. In today’s state-of-the-art CT scanners, the gantry rotation time is reduced to about III.D. Flat-panel based CT 0.35 s, but it is mechanically challenging to reduce that time While clinical x-ray systems are conventionally limited to even further, which justifies the renewed interest in multi- projection images, digital, solid-state flat-panel x-ray detec- source architectures. For the dual-source CT system, the tors ͑FPDs͒ have enabled 3D reconstruction in these modali- minimum rotation interval is 90° +␣, compared to 180° +␣ ties. In 1999, GE Healthcare first introduced FPD-based for a third-generation scanner. For a cardiac fan angle ␣ of x-ray systems, in which FPDs replaced film in radiography 25°, this gives about 44% reduction in acquisition time. and mammography. Then, GE introduced an FPD-based car- The dual-source CT has been claimed to have a dose ben- diology system, replacing the conventional image intensifier efit because the second detector is smaller and hence the dose ͑II͒ tube. Today, all of the major diagnostic imaging system is reduced at the edge of the field of view. However, the

Medical Physics, Vol. 35, No. 3, March 2008 1056 Wang, Yu, and De Man: CT outlook 1056

FIG. 6. CT architecture with three sources and three detectors. ͑a͒ Berninger and Redington ﬁrst proposed to replicate the x-ray tube and detector assembly ͑Ref. 69͒ and ͑b͒ the triple-source system in the helical cone- beam geometry allows a perfect data mosaic pattern for exact reconstruction. Figure 6͑a͒ is duplicated from Ref. 69 with the permission of GE Company.

exact same dose profile is achieved with a third-generation cardiac scanning. A miniature version of the e-beam CT architecture and a more aggressive bowtie. A more fair com- scanner was also conceptualized for micro-CT cardiac parison would compare patient dose at an identical noise studies.78 Most of the drawbacks of EBCT are eliminated by level throughout the field of view. In fact, the cross scatter going to a distributed source with discrete electron emitters from the second source into the first detector is reported to and appropriate source-detector topologies.79 As shown in result in a scatter-to-primary ratio as high as 100% for obese Fig. 7͑a͒, another class of x-ray sources has multiple spots patients,71 corresponding to a severe dose penalty. Therefore, distributed along the longitudinal axis ͑in the z direction͒.80 more research will be needed on both hardware ͑scatter re- It has been shown that the combined information from the jection͒ and software ͑scatter correction͒ methods for dual- multiple spots in the z direction effectively eliminates cone- source CT. beam artifacts.81 A next step in this area is to use three sources and three Another example of a distributed x-ray source with a de- detectors.72–74 For a cardiac fan angle ␣ of 25°, a triple- flected e beam is the transmission x-ray source developed by source system with symmetric spacing would result in 59% NovaRay ͑formerly known as Cardiac Mariners and Nexray, reduction in acquisition time. In terms of exact cone-beam Palo Alto, California, USA͒, with thousands of focal spots. reconstruction, unlike the dual-source cone-beam geometry This area source was first used to demonstrate the concept of the triple-source cone-beam scanner allows a perfect mosaic inverse-geometry CT.82 In addition to eliminating cone-beam pattern of truncated cone-beam data to satisfy the Orlov artifacts, this architecture also has the benefit of a small condition,75 as shown in Fig. 6͑b͒. In the near future, manu- photon-counting detector and very good detection efficiency. facturers may or may not adopt the multi-source-multi- A related architecture is based on discrete electron emitters,83 detector strategy, depending on their ability to conquer tem- resulting in a 2D array source with tens of focal spots ͓Fig. poral resolution with other means, such as faster rotation, 7͑b͔͒. This source architecture is more compact than the virtual rotation ͑see next sub-section͒, or motion compensa- above and perhaps more compatible with the concept of a tion techniques.76 Triple-source CT has unique theoretical virtual bowtie, where the operation of each spot is modulated merits relative to dual-source CT. However, the brute-force in real time to optimize image quality and minimize dose, hardware approach of dual-source and triple-source CT depending on the patient anatomy. In the past decades, ad- comes with important technical and cost trade-offs, and vances in detector technologies defined the so-called “slice might limit them to be niche cardiac scanners, just like wars.” We expect that in the next decade dramatic advances electron-beam CT ͑EBCT͒. in distributed x-ray sources may define a new revolution in CT and give birth to a wide class of new multi-source CT III.F. Multi-source CT architectures, including line sources, inverse-geometry CT, and ultimately a rebirth of stationary CT, which means that Almost all modern CT architectures are based on one or neither the source nor the detector is in motion during the more single-spot x-ray tubes ͑possibly with focal spot data acquisition process. wobble͒. The best known counter example is the EBCT scanner,77 which uses a huge x-ray source surrounding the III.G. Novel scanning modes patient with an electron beam that is deflected to produce x-rays along four half-circle target rings. The distributed na- A very important trend in the CT field is the evolution in ture of the x-ray source makes it possible to rotate the focal scanning modes for improved imaging performance at re- spot freely, thereby eliminating any mechanical bottlenecks. duced patient dose. The introduction of single-/multi- This architecture is fairly complex, limited in source inten- detector-row/cone-beam helical CT was only the first step sity, and not so compatible with true volumetric scanning, towards fully volumetric CT. In practice, a number of more but it is extremely fast and therefore it is very useful for flexible scanning schemes are needed. An earliest example of

Medical Physics, Vol. 35, No. 3, March 2008 1057 Wang, Yu, and De Man: CT outlook 1057

FIG. 7. Novel source conﬁgurations. ͑a͒ A distributed source with multiple spots along the z direction to eliminate cone-beam artifacts ͑Ref. 80͒,and͑b͒ an inverse-geometry architecture with tens of spots combining the beneﬁts of a line source in z, a small photon-counting detector, and a virtual bowtie ͑Ref. 83͒. Figure 7͑a͒ is duplicated from Ref. 80 with the permission of GE Company.

a dynamic helical pitch trajectory is bolus-chasing CT geometry architecture with an array source is the ultimate angiography.84,85 In this application the table speed is ad- flexibility to customize the flux profile with the so-called justed on the fly to synchronize the CT imaging aperture with virtual bowtie.83 the contrast bolus peak. Also, the so-called shuttle mode is a Key to all the above methods is knowledge about the scanning scheme where the patient table travels back and patient anatomy. This knowledge may be based on scout 89 forth, enabling better dynamic applications than with con- scans, patient data or atlases. One can take huge advantage ventional scanning, including liver perfusion and brain per- of this knowledge not only to perform simple tasks such as fusion. These applications are based on cone-beam reconstruction algorithms specifically designed for dynamic helical pitch source trajectories.86 Another example is a combined cardiac and thorax scan, where the table speed is reduced in the cardiac region for phase-coherent imaging, and increased as soon as the scan aperture is past the cardiac region. Finally, the latest efforts on saddle-like cone-beam scanning seem also promising for exact solution of a quasi- short object problem ͑reconstruction of a short portion of a long object from longitudinally truncated cone-beam data involving the short object͒.24,31 Especially, the composite- circling scanning mode ͑Fig. 8͒ has some advantages over the existing scanning modes from perspectives of both engineering implementation and clinical applications because of its symmetry in mechanical rotation and the compatibility with the physiological conditions.24,31 To minimize patient dose in CT, it is critical to detect every transmitted photon and to treat it in a statistically optimal fashion during reconstruction. It is equally important to optimize the flux profile through the patient based on the patient attenuation profile and the organ sensitivities. A first way to achieve this is to pre-attenuate the x-rays with a so- called bowtie filter. Bowtie filters are becoming more ad- FIG. 8. Compositing-circling scanning mode. In such a CT system, the scan- vanced in targeting regions of interest, sometimes even using ning trajectory is a composition of two circular motions: While an x-ray one or more moving parts.87 A second way is to modulate the focal spot is rotated on a plane facing an object to be reconstructed, the tube current ͑and possibly other scan parameters such as kVp x-ray source is also rotated around the object on the gantry plane. Once a ͒ projection dataset is acquired, exact or approximate reconstruction can be or filtration as a function of rotation angle, longitudinal po- done ͑Copyright by G. Wang and H. Y. Yu, US Provisional Patent Applica- 88 sition, and cardiac phase. A major advantage of an inverse- tion, 2007͒.

Medical Physics, Vol. 35, No. 3, March 2008 1058 Wang, Yu, and De Man: CT outlook 1058

has been shown that its time misregistration can be as good as one or a few views ͑ϳ1ms͒.96 Advances in compact monochromatic x-ray sources may result in improved energy selectivity, but this solution does not address the time misregistration. The ultimate architecture for energy-sensitive CT may use an advanced polychromatic source to cover a spectrum of interest and a photon-counting-based energy- discriminating detector to record all these polychromatic photons and sort them into respective spectral bins.97 While this solution would give perfect energy separation and registration, the technology is still immature and suffers from severe count rate limitations. Along with dedicated hardware development, algorithm development, especially statistical methods, will deﬁnitely facilitate this type of application. The fact that all manufacturers are pursuing different approaches makes the area of energy-sensitive CT an extremely

FIG. 9. Energy dependence of the linear attenuation coefﬁcient varies across interesting area. None can change the laws of physics but different elements and tissues. The plot shows the linear attenuation coefﬁ- enormous efforts in the coming years will show how dra- cients for bone ͑continuous curve͒ and iodine ͑curve with a discontinuity at matic advances in CT source, detector, and reconstruction ͒ theKedge. While for the shown iodine concentration the average attenu- technologies will help us all to approach the fundamental ation is very similar to that of bone; their energy dependence is very different. performance limits of energy-sensitive CT.

III.I. Nano-CT bowtie selection and patient centering but also ultimately to compute optimal pulse sequences, avoid sensitive organs, The world’s first and only sub-100 nm nano-CT scanner 98 and perform true ROI imaging. nanoXCT™ was recently developed by the Xradia company ͑Concord, CA͒. This system is a revolutionary microscope for non-invasive investigations involving semiconductor III.H. Energy-sensitive CT analysis, drug discovery, molecular imaging, stem-cell re- The idea of decomposing the linear attenuation coefficient search and materials development. It allows 50 nm reso- into two or more basis functions in order to eliminate beam lution using proprietary condenser and objective optics. For hardening artifacts for material discrimination was proposed most samples in nanotechnology, the x-ray attenuation length soon after the invention of CT.90 The physical foundation is for low Z materials is very long, resulting in poor image that the linear attenuation coefficients are a function of en- contrast. The Xradia system can significantly increase image ergy and that this energy dependence is different for different contrast in the Zernike phase contrast mode. tissues and elements. Figure 9 also illustrates that various Since this century, nanotechnology has gained tremendous elements have different attenuation properties as functions of momentum through both governmental and private invest- photon energy.91 Previously, two measurements were ac- ments. Clearly, nano-CT may be a strategic enabling compo- quired at different tube kVp settings, also called dual-energy nent for the immediate future research and education. In a CT. It was then realized that iterative reconstruction can broad range of nano-CT applications, interior tomography is eliminate the need for a second measurement by incorporat- not only valuable but also necessary. For example,inthe ing prior information.43,46,92 Technological advances are now case of in-situ imaging of cells or tissue specimens at the making it possible to acquire two or more measurements cellular/molecular level, we require little morphological simultaneously at different effective x-ray energies. These changes and minimum radiation exposure, have the water or methods can be primarily evaluated by signal-to-noise ratio air component as reference and a volume of interest ͑VOI͒ and measurement registration. The process of material de- much smaller than the specimen. Since the recent theoretical composition results in a noise amplification. Noise can be and numerical results53,54,56,99 demonstrated that the interior minimized if the effective energies of the measurements are problem can be solved in a theoretically exact and stable well separated, and better algorithms are designed. fashion assuming that a small subregion within the interior Dual-layer detectors are fairly mature93,94 and the corre- region is known, it becomes now feasible to meet the above- sponding measurements are perfectly registered but of all mentioned interior reconstruction need for nano-CT. solutions have the poorest energy separation. Dual-source In the next decade, we believe that the existing nano-CT CT is an existing technology,70 its energy separation is better scanners will be further advanced, unique reconstruction al- than dual-layer detectors but there is a significant time mis- gorithms will be developed with multi-scale and interior im- registration ͑about 100 ms͒ between corresponding measure- aging capabilities, and more nano-CT applications will be ments, not suitable for dynamic applications. Fast kVp identified in the fields including but not limited to life sci- switching is an existing technology,95 with better energy ence, preclinical and clinical imaging studies in vitro, phar- separation than the dual-layer detector, and very recently it maceutical research, and so on.

Medical Physics, Vol. 35, No. 3, March 2008 1059 Wang, Yu, and De Man: CT outlook 1059

FIG. 10. Representative CT image artifacts. ͑a͒ A shoulder phantom image with streaks caused by photon starvation, ͑b͒ a patient with spine implants generating metal artifacts, and ͑c͒ a moving head leading to motion artifacts ͑Duplicated from Ref. 100 with the permission of the Radiological Society of North America͒.

III.J. Artifact reduction III.K. Modality fusion Reduction of image artifacts has been a central topic in A distinguished trend in modern biomedical imaging is the CT field.100 The paradigm shift towards volumetric CT, the area of multi-modal imaging, in which two or more im- novel architectures and dynamic and quantitative imaging aging systems are synergistically integrated for much better demands a more effective reduction of various artifacts. The performance, improving or enabling biomedical applications. well-known scattering artifacts become more and more seri- A primary example is the positive emission tomography ous with the increasing cone angle and dual-source CT con- ͑PET͒/CT systems.110 Another example is the hybrid optical figurations. Beam hardening artifacts must be suppressed to tomography systems such as those proposed for magnetic extract energy-dependent information.101 Motion artifacts re- resonance imaging ͑MRI͒-based diffuse optical main a main challenge for cardiac CT and contrast-enhanced tomography,111 CT/MRI integration,112 and CT-based biolu- studies.102,103 More than a dozen types of artifacts are well minescence tomography.113 Recently, the Siemens micro-CT- known to the field ͑Fig. 10͒, most of which assume new PET-single photon photo emission computed tomography forms and present new problems associated with the devel- ͑SPECT͒ system Inveon ͑Fig. 11͒ became commercially opment of new CT technologies. Therefore, the fight against available as an integrated preclinical imaging platform. From these artifacts remains active and requires new tools. the perspective of x-ray CT research and development, an While many traditional artifact reduction algorithms are unprecedented potential would be unlocked by identifying ad hoc and approximate, the future efforts may rely on more new combinations of complementary imaging modes and im- solid physical models and more rigorous inherent data proving the existing multi-modal systems, such as hybrid integrity.101,104,105 In this context, data consistency conditions CT-angio and CT-cardiac cath systems. There are good pos- were proposed to suppress motion artifacts, minimize beam sibilities for one-stop imaging centers or suites to emerge hardening and so on. The invariance of the integral was sug- where all the imaging tasks can be streamlined in a task- gested as a possible mechanism for this purpose. Neverthe- specific fashion, which is in some sense an extension of the less, much more work is required to advance this frontier. To currently already available trail based multi-modal small ani- a large degree, artifact reduction is very similar to image mal imager. reconstruction. In both cases, the goal is to find an optimum In addition to the architectural issues, we emphasize that subject to a set of constraints. Given the complexities im- there are excellent opportunities for algorithm development posed by the artifact-related constraints, the iterative ap- in this area. Traditionally, each component modality of a proach will play a more important role. Several iterative fusion-based system can be independently considered for im- schemes have been well studied so far.106–108 New iterative age reconstruction. Then, all reconstructed images are retro- schemes deserve major attention and refinement, such as the spectively combined via post-processing for further analysis. alternating iteration scheme for metal artifact reduction.109 However, there is generally some or strong correlation Only with optimized reduction of various artifacts, the future among the datasets acquired by multiple imaging tools ap- CT technology will deliver its ultimate performance that plied to study the same individual object. Ideally, we should should be spatially, dynamically, spectrally and quantita- not solve the imaging problems for these modalities sepa- tively correct. rately but couple these imaging problems with implicit or

Medical Physics, Vol. 35, No. 3, March 2008 1060 Wang, Yu, and De Man: CT outlook 1060

FIG. 12. Ordinary-x-ray-tube-based phase-contrast imaging system with three 1D gratings G0,G1 and G2. The key idea is to utilize the so-called Talbot effect, which is a periodic self-imaging phenomenon, to extract phase shift information ͑Duplicated from Ref. 121 with the permission of Nature Publishing Group͒.

X-ray phase-contrast imaging has been a hot topic over the past decade.117–120 It is traditionally implemented via interferometry, diffractometry and in-line holography, respectively. Interferometry and diffractometry are restricted by the availability of a synchrotron radiation facility. The in-line FIG. 11. Imaging platform Inveon for fusion of CT, PET and SPECT in preclinical applications ͑Courtesy of Siemens Company͒. holography approach was originally proposed by Gabor in 1948, for which he was awarded the Nobel Prize. Wilkins et al. developed in-line holography techniques with a micro- 120 explicit relationships describing dependence among the in- focus polychromatic x-ray source. However, a micro- ͑Ͻ ␮ ͒ volved datasets. Such an integrated inverse problem may re- focus 100 m x-ray tube offers limited x-ray flux. In quire an iterative solution containing several loops each of 2006, Pfeiffer et al. made a major improvement so that such a phase-contrast imaging system can be built on a hospital- which assumes other image reconstructions known and re- 121,122 fines an intermediate image, or have more sophisticated grade x-ray tube. As shown in Fig. 12, the key idea is forms like a truly simultaneous iterative solution.114 Theoret- to utilize the Talbot effect generated by x-ray gratings for ical studies are needed to establish the solution existence, sensing waveform deformation. It is anticipated that more uniqueness and stability with new iterative reconstruction research efforts will be devoted to x-ray phase-contrast imaging including x-ray phase-contrast tomography using the schemes, as already mentioned for Topics B and J. In the 123 cases of no unique solutions, regularization issues must be micro-focus or the grating-based framework. The forward addressed with the aid of a priori knowledge in the form of model will be a theoretically and computationally challeng- constraints, penalty terms and so on. ing problem, particularly for relatively large specimen. Ac- cordingly, the development of phase-contrast reconstruction algorithms will become an area of intense research. III.L. Phase-contrast CT In all mainstream x-ray CT imaging modalities, the con- IV. BIOMEDICAL APPLICATIONS trast mechanism has been attenuation based for over a cen- Image quality can essentially be summarized by four main tury. As a result, weak-absorbing tissues are not imaged well, performance characteristics. First, high-contrast image reso- and radiation dose has been a general concern. On the other lution ͑spatial resolution͒ is the ability to distinguish adjacent hand, x-ray phase-contrast imaging relies on the diffraction high-contrast features. Second, low-contrast image resolution properties of structures, promising to have much better con- ͑contrast resolution͒ measures the ability to differentiate a trast at much lower dose. Specifically, for x-rays the refrac- low-contrast feature from its background. Image noise im- tion index of biological soft tissues is approximately 1.0, poses a grainy appearance due to random fluctuations of the namely, n=1−␦+i␤, where ␤ and ␦ represent attenuation x-ray photon flux, and is a key factor in limiting low-contrast and diffraction, respectively. In the range of 15–150 KeV, ␦ resolution. Third, temporal resolution determines the ability is about three orders of magnitude greater than ␤, making to capture structures in motion. Fourth, quantitative accuracy phase-contrast imaging about three orders of magnitude is desired to relate the image pixel values to physically more sensitive than attenuation-based methods.115 Typical meaningful quantities in the absolute sense, which is particu- values of refraction indexes of breast tissue are plotted in larly important in dual/multi-energy CT. Image artifacts are Ref. 116. structured interferences of any type and clearly need to be

Medical Physics, Vol. 35, No. 3, March 2008 1061 Wang, Yu, and De Man: CT outlook 1061 minimized at all times, but are generally hard to quantify. cone-beam technologies has increased and continues increas- The aforementioned 12 topics of x-ray CT research and de- ing the usage of CT. There is a substantial room for dose velopment are all aimed at major improvements in image reduction using algorithmic means for attenuation-based CT. quality and are well motivated by the imaging needs of im- Other possible directions include more dose-efficient scan- portant biomedical applications. ning protocols, better a priori knowledge, more effective re- Just like for clinical CT, there is a strong need for im- construction methods and smarter post-processing strategies. proved technologies for micro-CT of small animals, espe- Phase-contrast based CT, if successfully developed and clini- cially genetically engineered mice.124–126 Most CT research cally utilized, will revolutionize its x-ray imaging applica- results can be similarly applied in either clinical or preclini- tions by virtually eliminating the dose problems and greatly cal scenarios. CT of large animals will remain important for boosting contrast resolution, which may open doors to novel veterinary medicine and research. functional and molecular imaging studies, and overtake or In terms of spatial resolution, CT has come a long way. complement some MRI applications. X-ray phase-contrast Only a few years ago routine studies were done at 5–7 mm CT/micro-CT is a technically very challenging and relatively slice thickness, while today’s scanners offer half-mm isotro- immature area, but it has the potential to have huge impact in pic spatial resolution. Still, there is an opportunity to dra- certain pre-clinical and clinical applications. matically improve upon the state-of-the-art CT resolution As far as temporal resolution is concerned, cardiac CT is clinically available. As an example, we are working to estab- by far the most prominent application.131 Most common CT lish the feasibility of a clinical micro-CT ͑CMCT͒ prototype targets are relatively motionless, such as bony structures, targeting 60–100 ␮m resolution for temporal bone imaging. head, neck, and abdomen. However, the closer we get to the There has been an explosive growth in the development of heart, the poorer the image quality becomes, because of the micro-CT scanners with an emphasis on high spatial cardiac motion. The ͑coronary͒ arteries are too elusive to be resolution126 but none of them allow patient studies due to clearly captured in challenging cases such as when the car- the narrow imaging aperture, long acquisition time, and dose diac rate is too high or irregular, since the relative rest phase limitations. Our proposed CMCT system consists of a special of the coronary arteries is only about 60 ms. Most demand- micro-CT scanner, a clinical CT scanner, and a crossing cardiac imaging used to be done by EBCT, which is modality registration mechanism involving both hardware expensive and rarely available. In addition to its remarkable and software.127 This system will integrate the strengths of applications for dynamic anatomical imaging of cardiac micro-CT and clinical CT techniques to achieve the spatial structures, EBCT is also a powerful tool for physiological resolution that is several times or even an order of magnitude imaging. Following the introduction of the Siemens dual- finer than any commercially available scanner for clinical source scanner, it seems that more efforts are warranted to temporal bone imaging. Our preliminary system design and design better multi-source or distributed source systems and simulation results indicate that such a system is possible at a methods for cardiac CT. The ideas and schemes already exist clinically acceptable dose, provided motion artifacts can be on triple-source and multi-source CT systems, and hopefully effectively eliminated. An enabling technology for CMCT at will be refined and realized in the not too distant future. a minimum patient dose is to perform local CT reconstruc- Finally, CT images with a high quantitative accuracy will tion and/or local tomosynthesis of a volume of interest be more informative in general and extremely useful with ͑VOI͒, by physically monitoring the patient motion and com- energy-sensitive CT in particular. It is anticipated that more pensating for it during the reconstruction, subject to various advanced x-ray sources such as portable synchrotron radia- constraints. This technique is particularly useful for imaging tion devices will be much more accessible one or two de- of the inner ear, because of its small dimensions, high- cades from now. In the meantime, innovative sources and contrast structures, fine features, and stationary nature, and detectors will be developed to generate spectrally resolved may be extended for other applications such as bone cancer projection data directly or indirectly. Statistical reconstruc- studies. Another potentially useful solution would be to ap- tion can be applied to design and refine iterative algorithms ply exact local reconstruction,53,99 as discussed earlier, which that fully utilize all detected photons, and add a spectral di- can be immediately applied to dental CT as well. In such a mension to CT images. Presumably, this type of energy- configuration, x-rays would only go through a tooth of inter- sensitive CT will dramatically improve the characterization est and its neighborhood. Based on the known CT numbers of heart and lung diseases as well as various cancers. Along in the neighborhood ͑air͒, the tooth can be reconstructed ac- this direction, scattering-based CT, x-ray induced fluores- curately, allowing characterization of bony loss and so on. cence CT, and CT in other hybrid modes may also become Improvements in low-contrast resolution will lead to re- useful. duced radiation dose and superior diagnostic performance. Worldwide there are active discussions and public concerns on radiation induced genetic, cancerous and other V. CONCLUDING REMARKS diseases.128,129 CT is considered a radiation-intensive proce- When the first author of this paper graduated with a CT dure, yet becoming more and more widespread. In the mid- dissertation in 1992, he considered to switch to a different 1990s, CT scans only accounted for 4% of the total x-ray imaging field. His former mentor, Dr. Vannier, who is an procedures but they contributed to 40% of the collective authority in x-ray imaging and a certified radiologist, advised dose.130 The recent introduction of helical, multi-slice and him not to do so because CT was “just too practical and

Medical Physics, Vol. 35, No. 3, March 2008 1062 Wang, Yu, and De Man: CT outlook 1062 useful.” After over a decade, Dr. Vannier’s advice seems still cone-beam spiral/helical CT,” IEEE Trans. Med. Imaging 19͑9͒,817–821 ͑ ͒ valid. Even if just a few of the aforementioned possibilities 2000 . 12L. A. Feldkamp, L. C. Davis, and J. W. Kress, “Practical cone-beam are realized, CT will become much more powerful than it is algorithm,” J. Opt. Soc. Am. A 1͑A͒, 612–619 ͑1984͒. now. The ideal CT system should waste no information re- 13A. Katsevich, “An improved exact filtered backprojection algorithm for lated to absorption, scattering, diffraction, energy, time of spiral computed tomography,” Adv. Appl. Math. 32͑4͒, 681–697 ͑2004͒. 14 flight, prior information, and so on. Correspondingly, the im- A. Katsevich, “Theoretically exact filtered backprojection-type inversion algorithm for spiral CT,” SIAM J. Appl. Math. 62͑6͒, 2012–2026 ͑2002͒. aging model will become more complicated: going from a 15G. Wang, Y. B. Ye, and H. Y. Yu, “Appropriate and exact cone-beam simple line integral model and the radiation transport equa- reconstruction with standard and nonstandard spiral scanning,” Phys. tions for describing attenuation and scattering to Maxwell’s Med. Biol. 52͑6͒, R1–R13 ͑2007͒. 16 equations for accurately modeling the wave nature of phase- Y. B. Ye, S. Y. Zhao, H. Y. Yu, and G. Wang, “Exact reconstruction for cone-beam scanning along nonstandard spirals and other curves,” Pro- contrast imaging. Although the computational obstacles ap- ceedings of SPIE, Vol. 5535, pp. 293–300, Denver, CO ͑2004͒. pear overwhelming at this time, we remain optimistic about 17Y. B. Ye and G. Wang, “Filtered backprojection formula for exact image our collective creativity and capabilities. The dream of whole reconstruction from cone-beam data along a general scanning curve,” ͑ ͒ ͑ ͒ body CT imaging could come through in the future to pro- Med. Phys. 32 1 , 42–48 2005 . 18Y. B. Ye, S. Y. Zhao, H. Y. Yu, and G. Wang, “A general exact recon- vide thorough, detailed and individualized image data when- struction for cone-beam CT via backprojection-filtration,” IEEE Trans. ever needed for healthcare. Med. Imaging 24͑9͒, 1190–1198 ͑2005͒. As indicated earlier, this outlook paper is meant to be 19J. Pack and F. Noo, “Cone-beam reconstruction using 1D filtering along ͑ ͒ ͑ ͒ suggestive and not exhaustive. As a result, the citations are the projection of M-lines,” Inverse Probl. 21 4 , 1105–1120 2005 . 20J. D Pack, F. Noo, and R. Clackdoyle, “Cone-beam reconstruction using not comprehensive relative to the huge related literature the backprojection of locally filtered projections,” IEEE Trans. Med. Im- base. Nevertheless, to the best of our knowledge it reflects aging 24͑1͒, 70–85 ͑2005͒. the current trends in CT and, while our insights are unavoid- 21T. L. Zhuang, S. Leng, B. E. Nett, and G. H. Chen, “Fan-beam and ably biased, the reality should not be too far from the targets cone-beam image reconstruction via filtering the backprojection image of differentiated projection data,” Phys. Med. Biol. 49͑24͒, 5489–5503 we hope for and believe in. It is our intension to keep refin- ͑2004͒. ing our predictions in this framework as time goes by and to 22Y. Zou, X. Pan, and E. Y. Sidky, “Theory and algorithms for image update this outlook in a few years. Thus, we highly welcome reconstruction on chords and within regions of interest,” J. Opt. Soc. Am. A 22͑11͒, 2372–2384 ͑2005͒. comments and critiques from colleagues and peers. 23G. Wang and Y. B. Ye, “Nonstandard spiral cone-beam scanning methods, apparatus, and applications,” US Provisional Patent Application 60/ 588,682, Filing date: July 16, 2004 ͑2004͒. ACKNOWLEDGMENTS 24G. Wang and H. Y. Yu, “Scanning method and system for cardiac imag- This work is partially supported by the NIH Grant Nos. ing,” Patent disclosure submitted to Virginia Tech. Intellectual Properties on July 17 ͑2007͒. EB002667, EB004287, EB007288, and EB006837. The au- 25A. Katsevich and M. Kapralov, “Theoretically exact FBP reconstruction thors also express their gratitude to Dr. Michael Cable, Dr. algorithms for two general classes of curves,” 9th International Meeting Paul Fitzgerald, Dr. Ming Jiang, Dr. Xuanqin Mou, Dr. Bob on Fully Three-Dimensional Image Reconstruction in Radiology and Senzig, Dr. Xiangyang Tang, Dr. Xizeng Wu, Dr. Wenbing Nuclear Medicine, pp. 80–83, Lindau, Germany ͑2007͒. 26A. Katsevich, “Image reconstruction for a general circle-plus trajectory,” Yun, and Dr. Jun Zhao for their valuable comments and sug- Inverse Probl. 23͑5͒, 2223–2230 ͑2007͒. gestions. 27A. Katsevich, “A general scheme for constructing inversion algorithms for cone-beam CT,” Int. J. Math. Math. Sci. 21, 1305–1321 ͑2003͒. ͒ a Electronic mail: [email protected] 28Y. C. Wei, H. Y. Yu, J. Hsieh, W. X. Cong, and G. Wang, “Scheme of ͒ b Electronic mail: [email protected] computed tomography,” J. X-Ray Sci. Technol. 15͑4͒, 235–270 ͑2007͒. ͒ c Electronic mail: [email protected] 29S. Y. Zhao, H. Y. Yu, and G. Wang, “A unified framework for exact 1A. M. Cormack, “Representation of a function by its line integrals, with cone-beam reconstruction formulas,” Med. Phys. 32͑6͒, 1712–1721 some radiological applications,” J. Appl. Phys. 34͑9͒, 2722–2727 ͑1963͒. ͑2005͒. 2G. N. Hounsfield, “Computerized transverse axial scanning ͑tomogra- 30G. H. Chen, “An alternative derivation of Katsevich’s cone-beam recon- phy͒: Part I. Description of system,” Br. J. Radiol. 46, 1016–1022 ͑1973͒. struction formula,” Med. Phys. 30͑12͒, 3217–3226 ͑2003͒. 3R. A. Robb et al., “High-sped three-dimensional x-ray computed tomog- 31H. Y. Yu and G. Wang, “Cone-beam composite-circling scan and exact raphy: The dynamic spatial reconstructor,” Proceedings of the IEEE, image reconstruction for a quasi-short object,” Int. J. Biomed. Imaging 71͑3͒, 308–319 ͑1983͒. 2007, Article ID 87319, 10 pages ͑2007͒. 4E. L. Ritman, R. A. Robb, and L. D. Harris, Imaging Physiological Func- 32J. D. Pack, F. Noo, and H. Kudo, “Investigation of saddle trajectories for tions: Experience with the DSR, Praeger, Philadelphia, ͑1985͒. cardiac CT imaging in cone-beam geometry,” Phys. Med. Biol. 49͑11͒, 5W. A. Kalender, “Thin-section three-dimensional spiral CT: Is isotropic 2317–2336 ͑2004͒. imaging possible?,” Radiology 197͑3͒, 578–580 ͑1995͒. 33X. Y. Tang, J. Hsieh, R. A. Nilsen, S. Dutta, D. Samsonov, and A. Hagi- 6G. Wang, T. H. Lin, P. C. Cheng, and D. M. Shinozaki, “A general cone wara, “A three-dimensional-weighted cone beam filtered backprojection beam reconstruction algorithm,” IEEE Trans. Med. Imaging 12͑3͒, 486– ͑CB-FBP͒ algorithm for image reconstruction in volumetric CT - helical 496 ͑1993͒. scanning,” Phys. Med. Biol. 51͑4͒, 855–874 ͑2006͒. 7G. Wang et al., “Scanning cone-beam reconstruction algorithms for x-ray 34X. Y. Tang and J. Hsieh, “A filtered backprojection algorithm for cone microtomography,” Proceedings of SPIE, Vol. 1556, pp. 99–112 ͑1991͒. beam reconstruction using rotational filtering under helical source trajec- 8K. Taguchi and H. Aradate, “Algorithm for image reconstruction in multi- tory,” Med. Phys. 31͑11͒, 2949–2960 ͑2004͒. slice helical CT,” Med. Phys. 25͑4͒, 550–561 ͑1998͒. 35X. Y. Tang and J. Hsieh, “Handling data redundancy in helical cone beam 9M. Kachelriess, S. Schaller, and W. A. Kalender, “Advanced single-slice reconstruction with a cone-angle-based window function and its rebinning in cone-beam spiral CT,” Med. Phys. 27͑4͒, 754–772 ͑2000͒. asymptotic approximation,” Med. Phys. 34͑6͒, 1989–1998 ͑2007͒. 10S. Mori et al., “Physical performance evaluation of a 256-slice CT- 36X. Y. Tang, J. Hsieh, R. A. Nilsen, and S. M. McOlash, “Extending scanner for four-dimensional imaging,” Med. Phys. 31͑6͒, 1348–1356 three-dimensional weighted cone beam filtered backprojection ͑CB-FBP͒ ͑2004͒. algorithm for image reconstruction in volumetric CT at low helical 11G. Wang, C. R. Crawford, and W. A. Kalender, “Multirow detector and pitches,” Int. J. Biomed. Imaging 2006, Article ID 45942, 8 pages ͑2006͒.

Medical Physics, Vol. 35, No. 3, March 2008 1063 Wang, Yu, and De Man: CT outlook 1063

37R. Gordon, R. Bender, and G. T. Herman, “Algebraic reconstruction tech- 62W. Ross, D. D. Cody, and J. D. Hazle, “Design and performance charac- niques ͑ART͒ for three-dimensional electron microscopy and x-ray pho- teristics of a digital flat-panel computed tomography system,” Med. Phys. tography,” J. Theor. Biol. 29, 471–482 ͑1970͒. 33͑6͒, 1888–1901 ͑2006͒. 38A. H. Andersen and A. C. Kak, “Simultaneous algebraic reconstruction 63S. Greschus et al., “Potential applications off lat-panel volumetric CT in technique ͑SART͒: a superior implementation of the ART algorithm,” morphologic and functional small animal imaging,” Neoplasia 7͑8͒, 730– Ultrason. Imaging 6, 81–94 ͑1984͒. 740 ͑2005͒. 39L. A. Shepp and B. F. Logan, “The Fourier reconstruction of a head 64F. Kiessling et al., “Volumetric computed tomography ͑VCT͒:Anew section,” IEEE Trans. Nucl. Sci. NS21͑3͒, 21–34 ͑1974͒. technology for noninvasive high-resolution monitoring of tumor angio- 40A. J. Rockmore and A. Macovski, “A maximum likelihood approach to genesis,” Nat. Med. 10͑10͒, 1133–1138 ͑2004͒. emission image reconstruction from projections,” IEEE Trans. Nucl. Sci. 65J. M. Boone et al., “Computed tomography for imaging the breast,” J. 23͑4͒, 1428–1432 ͑1976͒. Mammary Gland Biol. Neoplasia 11͑2͒, 103–111 ͑2006͒. 41J. Nuyts et al., “Iterative reconstruction for helical CT: A simulation 66B. Chen and R. Ning, “Cone-beam volume CT breast imaging: Feasibility study,” Phys. Med. Biol. 43͑4͒, 729–737 ͑1998͒. study,” Med. Phys. 29͑5͒, 755–770 ͑2002͒. 42B. De Man et al., “Reduction of metal streak artifacts in x-ray computed 67L. T. Holly and K. T. Foley, “Image guidance in spine surgery,” Orthop. tomography using a transmission maximum a posteriori algorithm,” Clin. North Am. 38͑3͒, 451–461 ͑2007͒. IEEE Trans. Nucl. Sci. 47͑3͒, 977–981 ͑2000͒. 68N. Clinthorne, “Intra-operative imaging,” J. Laparoendosc Adv. Surg. 43I. A. Elbakri and J. A. Fessler, “Statistical image reconstruction for poly- Tech. A 15͑5͒, 549–555 ͑2005͒. energetic x-ray computed tomography,” IEEE Trans. Med. Imaging 21͑2͒, 69W. Berninger and R. Redington, “Multiple purpose high speed tomogra- 89–99 ͑2002͒. phic x-ray scanner,” US Patent No. 4,196,352A ͑1980͒. 44J. A. Fessler, “Statistical image reconstruction methods for transmission 70T. G. Flohr et al., “First performance evaluation of a dual-source CT tomography,” in Medical Image Processing and Analysis, edited by M. ͑DSCT͒ system,” Eur. Radiol. 16͑2͒, 256–268 ͑2006͒. Sonka and J. M. Fitzpatric ͑SPIE Press, Bellingham, Washington, 2000͒, 71Y. Kyriakou and W. A. Kalender, “Intensity distribution and impact of Vol. 3, pp. 1–70. scatter for dual-source CT,” Phys. Med. Biol. 52͑23͒, 6969–6989 ͑2007͒. 45J. A. Fessler and A. O. Hero, “Space-alternating generalized expectation- 72J. Zhao, M. Jiang, T. Zhuang, and G. Wang, “An exact reconstruction maximization algorithm,” IEEE Trans. Signal Process. 42͑10͒, 2664– algorithm for triple-source helical cone-beam CT,” J. X-Ray Sci. Technol. 2677 ͑1994͒. 14͑3͒, 191–206 ͑2006͒. 46I. A. Elbakri and J. A. Fessler, “Segmentation-free statistical image re- 73J. Zhao, M. Jiang, T. G. Zhuang, and G. Wang, “Minimum detection construction for polyenergetic x-ray computed tomography with experi- window and inter-helix PI-line with triple-source helical cone-beam scan- mental validation,” Phys. Med. Biol. 48͑15͒, 2453–2477 ͑2003͒. ning,” J. X-Ray Sci. Technol. 14͑2͒, 95–107 ͑2006͒. 47P. E. Kinahan, A. M. Alessio, and J. A. Fessler, “Dual energy CT attenu- 74J. Zhao, Y. N. Jin, Y. Lu, and G. Wang, “A reconstruction algorithm for ation correction methods for quantitative assessment of response to can- triple-source helical cone-beam CT via filtered backprojection,” 9th Inter- cer therapy with PET/CT imaging,” Technol. Cancer Res. Treat. 5͑4͒, national Meeting on Fully Three-Dimensional Image Reconstruction in 319–327 ͑2006͒. Radiology and Nuclear Medicine, pp. 205–208, Lindau, Germany ͑2007͒. 48J. B. Thibault, A. K. Sauer, A. C. Bouman, and J. Hsieh, “Three- 75S. S. Orlov, “Theory of three dimensional reconstruction I: Conditions for dimensional statistical modeling for image quality improvements in a complete set of projections,” Sov. Phys. Crystallogr. 20, 312–314 multi-slice helical CT,” 8th Meeting on Fully Three–Dimensional Image ͑1975͒. Reconstruction in Radiology and Nuclear Medicine, pp. 271–274, Salt 76B. De Man, P. Edic, and S. Basu, “An iterative algorithm for time- Lake City, UT ͑2005͒. resolved reconstruction of a CT scan of a beating heart,” 8th Meeting on 49M. Iatrou, B. De Man, and S. Basu, “A comparison between filtered Fully Three–Dimensional Image Reconstruction in Radiation and backprojection, post-smoothed weighted least squares, and penalized Nuclear Medicine, Salt Lake City, UT, 356–359 ͑2005͒. weighted least squares for CT reconstruction,” IEEE Nuclear Science 77D. Boyd et al., “High-speed, multi-slice, x-ray computed tomography,” Symposium Conference Record, 2006, pp. 2845–2850, San Diego, CA Proceedings of SPIE, Vol. 372, pp. 139–150, Pacific Grove, CA ͑1982͒. ͑2006͒. 78G. Wang et al., “Top-level design and preliminary physical analysis for 50D. L. Parker, “Optimal short scan convolution reconstruction for fanbeam the first electron-beam micro-CT scanner,” J. X-Ray Sci. Technol. 12͑4͒, CT,” Med. Phys. 9͑2͒, 254–257 ͑1982͒. 251–260 ͑2004͒. 51Y. Zou and X. C. Pan, “Exact image reconstruction on PI-lines from 79B. De Man et al., “Stationary computed tomography system and method,” minimum data in helical cone-beam CT,” Phys. Med. Biol. 49͑6͒, 941– US Patent No. 7,280,631 B2͑2005͒. 959 ͑2004͒. 80J. S. Price, W. Block, and M. Vermilyea, “Extended multi-spot computed 52M. Defrise, F. Noo, R. Clackdoyle, and H. Kudo, “Truncated Hilbert tomography x-ray source,” US Patent No. 6,983,035 B2͑2006͒. transform and image reconstruction from limited tomographic data,” In- 81Z. Yin, B. De Man, and J. Pack, “Analytical cone-beam reconstruction verse Probl. 22͑3͒, 1037–1053 ͑2006͒. using a multi-source inverse geometry CT system,” Proceedings of SPIE, 53Y. B. Ye, H. Y. Yu, Y. C. Wei, and G. Wang, “A general local reconstruc- Vol. 6510, San Diego, CA ͑2007͒. tion approach based on a truncated Hilbert transform,” Int. J. Biomed. 82T. G. Schmidt, R. Fahrig, N. J. Pelc, and E. G. Solomon, “An inverse- Imaging 2007, Article ID 63634, 8 pages ͑2007͒. geometry volumetric CT system with a large-area scanned source: A fea- 54Y. B. Ye, H. Y. Yu, and G. Wang, “Exact interior reconstruction with sibility study,” Med. Phys. 31͑9͒, 2623–2627 ͑2004͒. cone-beam CT,” Int. J. Biomed. Imaging 2007, Article ID 10693, 5 pages 83B. De Man et al., “Multi-source inverse geometry CT: A new system ͑2007͒. concept for X-ray computed tomography,” Proceedings of SPIE,Vol. 55F. Natterer, The Mathematics of Computerized Tomography ͑Society for 6510, San Diego, CA ͑2007͒. Industrial and Applied Mathematics, Philadelphia, 2001͒. 84G. Wang and M. W. Vannier, “Bolus-chasing angiography with adaptive 56G. Wang, Y. B. Ye, and H. Y. Yu, “General VOI/ROI reconstruction real-time computed tomography,” U.S. Patent No. 6,535,821, allowed on methods and systems using a truncated Hilbert transform,” Patent disclo- 11/26/2002, issued on 3/18/2003 ͑2003͒. sure submitted to Virginia Tech. Intellectual Properties on May 15 ͑2007͒. 85E. W. Bai et al., “Study of an adaptive bolus chasing CT angiography,” J. 57H. Y. Yu and G. Wang, “A general formula for fan-beam lambda tomog- X-Ray Sci. Technol. 14͑1͒, 27–38 ͑2006͒. raphy,” Int. J. Biomed. Imaging 2006, Article ID 10427, 9 pages ͑2006͒. 86A. Katsevich, S. Basu, and J. Hsieh, “Exact filtered backprojection recon- 58H. Y. Yu, Y. C. Wei, Y. B. Ye, and G. Wang, “Lambda tomography with struction for dynamic pitch helical cone beam computed tomography,” discontinuous scanning trajectories,” Phys. Med. Biol. 52͑14͒, 4331–4344 Phys. Med. Biol. 49͑14͒, 3089–3103 ͑2004͒. ͑2007͒. 87E. Tkaczyk et al., “Simulation of CT dose and contrast-to-noise as func- 59H. Y. Yu and G. Wang, “A general scheme for velocity tomography,” tion of bowtie shape,” Proceedings of SPIE,Vol.5368, pp. 403–410, San Signal Process. 88͑5͒, 1165–1175 ͑2008͒. Diego, CA ͑2004͒. 60D. Saintfelix et al.,“In-vivo evaluation of a new system for 3D comput- 88M. Kalra, N. Naz, S. Rizzo, and M. Blake, “Computed tomography ra- erized angiography,” Phys. Med. Biol. 39͑3͒, 583–595 ͑1994͒. diation dose optimization: Scanning protocols and clinical applications of 61L. T. Niklason et al., “Digital tomosynthesis in breast imaging,” Radiol- automatic exposure control,” Curr. Probl Diagn. Radiol. 34͑5͒, 171–181 ogy 205͑2͒, 399–406 ͑1997͒. ͑2005͒.

Medical Physics, Vol. 35, No. 3, March 2008 1064 Wang, Yu, and De Man: CT outlook 1064

89B. De Man and B. Senzig, “Method and system for radiographic imaging ͑2007͒. with organ-based radiation profile prescription,” US Patent No. 110T. Beyer et al., “A combined PET/CT scanner for clinical oncology,” J. 20070147579 A1͑2007͒. Nucl. Med. 41͑8͒, 1369–1379 ͑2000͒. 90R. E. Alvarez and A. Macovski, “Energy-selective reconstructions in 111D. A. Boas and A. M. Dale, “Simulation study of magnetic resonance x-ray computerized tomography,” Phys. Med. Biol. 21͑5͒, 733–744 imaging-guided cortically constrained diffuse optical tomography of hu- ͑1976͒. man brain function,” Appl. Opt. 44͑10͒, 1957–1968 ͑2005͒. 91 J. H. Hubbell and S. M. Seltzer, Tables of X-ray mass attenuation coef- 112K. Kagawa et al., “Initial clinical assessment of CT-MRI image fusion ficients 1 keV to 20 MeV, for elements Z͑1/4͒ 1 to 92 and 48 additional software in localization of the prostate for 3D conformal radiation substances of dosimetric interest. ͑National Institute of Standards and therapy,” Int. J. Radiat. Oncol., Biol., Phys. 38͑2͒, 319–325 ͑1997͒. Technology, Gaithersburg, MD, 1995͒. 113G. Wang, Y. Li, and M. Jiang, “Uniqueness theorems in bioluminescence 92 B. De Man et al., “An iterative maximum-likelihood polychromatic algo- tomography,” Med. Phys. 31͑8͒, 2289–2299 ͑2004͒. rithm for CT,” IEEE Trans. Med. Imaging 20͑10͒, 999–1008 ͑2001͒. 114J. Nuyts et al., “Simultaneous maximum a posteriori reconstruction of 93 R. Carmi, G. Naveh, and A. Altman, “Material separation with dual-layer attenuation and activity distributions from emission sinograms,” IEEE CT,” IEEE Nuclear Science Symposium Conference Record, pp. 1876– Trans. Med. Imaging 18͑5͒, 393–403 ͑1999͒. 1878, Wyndham El Conquistador Resort, Puerto Rico ͑2005͒. 115 94 A. Momose and J. Fukuda, “Phase-contrast radiographs of nonstained rat J. E. Tkaczyk et al., “Atomic number resolution for three spectral CT cerebellar specimen,” Med. Phys. 22͑4͒, 375–379 ͑1995͒. imaging systems,” Proceedings of SPIE, 6510, paper No. 651009, San 116R. A. Lewis, “Medical phase contrast X-ray imaging: Current status and Diego, CA ͑2007͒. ͑ ͒ ͑ ͒ 95 future prospects,” Phys. Med. Biol. 49 16 , 3573–3583 2004 . S. Kuribayashi, “Dual energy CT of peripheral arterial disease with 117A. Momose, “Recent advances in x-ray phase imaging,” Jpn. J. Appl. single-sorurce 64–slice MDCT,” presented at 9th Annual International Phys., Part 1 44͑9A͒, 6355–6367 ͑2005͒. Symposium on Multidetector-Row CT ͑ ͒ 118 , San Francisco, CA 2007 . X. Z. Wu and H. Liu, “Clarification of aspects in in-line phase-sensitive 96X. Wu et al., “Dual kVp computed tomography via view-to-view kV X-ray imaging,” Med. Phys. 34͑2͒, 737–743 ͑2007͒. switching: Temporal resolution and energy separation ͑submitted͒. 119X. Z. Wu, H. Liu, and A. M. Yan, “x-ray phase-attenuation duality and 97P. M. Shikhaliev, “Tilted angle CZT detector for photon counting/energy phase retrieval,” Opt. Lett. 30͑4͒, 379–381 ͑2005͒. weighting x-ray and CT imaging,” Phys. Med. Biol. 51͑17͒, 4267–4287 120S. W. Wilkins et al., “Phase-contrast imaging using polychromatic hard ͑2006͒. X-rays,” Nature ͑London͒ 384, 335–338 ͑1996͒. 98nanoXCT, available from: http://www.xradia.com/Products/nanoxct.html. 121F. Pfeiffer, T. Weitkamp, O. Bunk, and C. David, “Phase retrieval and 99H. Y. Yu, Y. B. Ye, and G. Wang, “Local reconstruction using the trun- differential phase-contrast imaging with low-brilliance x-ray sources,” cated Hilbert transform via singular value decomposition,” Phys. Med. ͑ ͒ Nat. Phys. 2͑4͒, 258–261 ͑2006͒. Biol. under review . 122 100J. F. Barrett and N. Keat, “Artifacts in CT: Recognition and avoidance,” C. Kottler, C. David, F. Pfeiffer, and O. Bunk, “A two-directional ap- Radiographics 24͑6͒, 1679–1691 ͑2004͒. proach for grating based differential phase contrast imaging using hard x 101 rays,” Opt. Express 15͑3͒, 1175–1181 ͑2007͒. X. Q. Mou, S. J. Tang, and H. Y. Yu, “A beam hardening correction 123 method based on HL consistency,” Proc. of SPIE, Vol. 6318, San Diego, M. Jiang, C. L. Wyatt, and G. Wang, “X-ray phase-contrast imaging with CA ͑2006͒. three 2D gratings,” Int. J. Biomed. Imaging 2007, Article ID 27152 102 ͑2007͒. R. P. Zeng, J. A. Fessler, and J. M. Balter, “Estimating 3-D respiratory 124 motion from orbiting views by tomographic image registration,” IEEE D. W. Holdsworth, “Micro-CT in small animal and specimen imaging,” ͑ ͒ ͑ ͒ Trans. Med. Imaging 26͑2͒, 153–163 ͑2007͒. Trends Biotechnol. 20 8 , S34–S39 2002 . 125 103R. P. Zeng, J. A. Fessler, and J. M. Balter, “Respiratory motion estimation M. J. Paulus, “A review of high-resolution x-ray computed tomography from slowly rotating X-ray projections: Theory and simulation,” Med. and other imaging modalities for small animal research,” Lab Anim. 30, Phys. 32͑4͒, 984–991 ͑2005͒. 36–45 ͑2001͒. 126 104Y. C. Wei, H. Y. Yu, and G. Wang, “Integral invariants in fan-beam and G. Wang, “Micro-CT scanners for biomedical applications: An over- cone-beam computed tomography,” IEEE Signal Process. Lett. 13͑9͒, view,” Adv. Imaging 16, 18–27 ͑2001͒. 127 549–552 ͑2006͒. G. Wang et al., “Design, analysis and simulation for development of the 105H. Y. Yu and G. Wang, “Data consistency based general motion artifact first clinical micro-CT scanner,” Acad. Radiol. 12͑4͒, 511–525 ͑2005͒. 128 reduction in fan-beam CT,” IEEE Trans. Med. Imaging 26͑2͒, 249–260 D. J. Brenner, C. D. Elliston, E. J. Hall, and W. E. Berdon, “Estimated ͑2007͒. risks of radiation-induced fatal cancer from pediatric CT,” AJR, Am. J. 106G. Wang, M. W. Vannier, and P. C. Cheng, “Iterative X-ray cone-beam Roentgenol. 176͑2͒, 289–296 ͑2001͒. tomography for metal artifact reduction and local region reconstruction,” 129A. Berrington de Gonzalez and S. Darby, “Risk of cancer from diagnostic Microsc. Microanal. 5, 58–65 ͑1999͒. x rays: Estimates for the UK and 14 other countries,” Lancet 363, 345– 107J. A. Fessler, “Penalized weighted least-squares image-reconstruction for 351 ͑2004͒. positron emission tomography,” IEEE Trans. Med. Imaging 13͑2͒, 290– 130O. W. Linto and F. A. Mattler, Jr. , “National conference on dose reduc- 300 ͑1994͒. tion in computed tomography, emphasis on pediatrics,” AJR, Am. J. 108Bruno De Man, “Iterative reconstruction for reduction of metal artifacts Roentgenol. 181, 321–329 ͑2003͒. in CT,” Ph.D. Dissertation, University of Leuven, Belgium ͑2001͒. 131G. Wang, S. Y. Zhao, and D. Heuscher, “A knowledge-based cone-beam 109J. A. O’Sullivan and J. Benac, “Alternating minimization algorithms for x-ray CT algorithm for dynamic volumetric cardiac imaging,” Med. Phys. transmission tomography,” IEEE Trans. Med. Imaging 26͑3͒, 283–297 29͑8͒, 1807–1822 ͑2002͒.

Medical Physics, Vol. 35, No. 3, March 2008 Assessing the future of diffuse optical imaging technologies for breast cancer management Bruce J. Tromberg Beckman Laser Institute and Medical Clinic, University of California Irvine, Irvine, California 92612 and NCI Network for Translational Research in Optical Imaging, Beckman Laser Institute, Irvine, California 92612 ͒ Brian W. Poguea and Keith D. Paulsen Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire 03755 and NCI Network for Translational Research in Optical Imaging, Beckman Laser Institute, Irvine, California 92612 Arjun G. Yodh Department of Physics & Astronomy, University of Pennsylvania, Philadelphia, Pennsylvania 19104–6396 and NCI Network for Translational Research in Optical Imaging, Beckman Laser Institute, Irvine, California 92612 David A. Boas NMR Center, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129 and NCI Network for Translational Research in Optical Imaging, Beckman Laser Institute, Irvine, California 92612 Albert E. Cerussi Beckman Laser Institute and Medical Clinic, University of California Irvine, Irvine, California 92612 and NCI Network for Translational Research in Optical Imaging, Beckman Laser Institute, Irvine, California 92612 ͑Received 25 January 2008; revised 2 April 2008; accepted for publication 3 April 2008; published 22 May 2008͒ Diffuse optical imaging ͑DOI͒ is a noninvasive optical technique that employs near-infrared ͑NIR͒ light to quantitatively characterize the optical properties of thick tissues. Although NIR methods were first applied to breast transillumination ͑also called diaphanography͒ nearly 80 years ago, quantitative DOI methods employing time- or frequency-domain photon migration technologies have only recently been used for breast imaging ͑i.e., since the mid-1990s͒. In this review, the state of the art in DOI for breast cancer is outlined and a multi-institutional Network for Translational Research in Optical Imaging ͑NTROI͒ is described, which has been formed by the National Cancer Institute to advance diffuse optical spectroscopy and imaging ͑DOSI͒ for the purpose of improving breast cancer detection and clinical management. DOSI employs broadband technology both in near-infrared spectral and temporal signal domains in order to separate absorption from scattering and quantify uptake of multiple molecular probes based on absorption or fluorescence contrast. Additional dimensionality in the data is provided by integrating and co-registering the functional information of DOSI with x-ray mammography and magnetic resonance imaging ͑MRI͒, which provide structural information or vascular flow information, respectively. Factors affecting DOSI performance, such as intrinsic and extrinsic contrast mechanisms, quantitation of biochemical components, image formation/visualization, and multimodality co-registration are under investigation in the ongoing research NTROI sites. One of the goals is to develop standardized DOSI platforms that can be used as stand-alone devices or in conjunction with MRI, mammography, or ultrasound. This broad-based, multidisciplinary effort is expected to provide new insight regarding the origins of breast disease and practical approaches for addressing several key challenges in breast cancer, including: Detecting disease in mammographically dense tissue, distinguishing between malignant and benign lesions, and understanding the impact of neoadjuvant chemotherapies. © 2008 Ameri- can Association of Physicists in Medicine. ͓DOI: 10.1118/1.2919078͔

I. INTRODUCTION for each specific clinical need. For example, even within the The field of optical imaging in medicine has seen continuous categories of light sources, detectors, and light delivery, there growth for decades, and there is a wide array of technologies are many dozens of options to choose from, and the choices and applications in development and clinical use. The range made can drastically alter the data that is possible to be ob- of different optical hardware choices available leads to a tained. Two central benefits from optical imaging are the complicated process of convergence upon the optimal system ability to gain molecular-level information and submicro-

Role in Breast Imaging Population Size of Target cost in the range of 100’s of dollars per exam. In contrast, if an benefiting Clinical trial per scan optical technology is used as part of a magnetic resonance imaging ͑MRI͒ scanner, then the population imaged would All be considerably smaller, but the efficacy could be demon- •Screening society 10,000’s $100 strated with only hundreds of patients, and ultimately the •Screening Select cost per scan could be similar to MRI, which is in the range high risk groups groups 1000’s of a few thousand dollars per exam. While Fig. 1 is just a rough illustration, it is a useful guide to think about how the •Diagnosis following 500+ area of application helps determine the clinical trial needed abnormal mammogram Those previously $1000 to prove utility, and ultimately the cost effectiveness targets screened for the commercial scale system. •Integration into clinical imaging systems In the following sections the key opportunities for having 100’s an impact upon breast cancer management are outlined. The Cancer structure of the following sections is that each of the most •Monitoring patients $2,000+ Therapy compelling applications are outlined, together with a discussion of the most useful technologies using Spectroscopy, Im- aging and Tomography. In some cases, single institutional FIG. 1. A schematic illustration of the issues involved in determining a new technologies role in breast imaging is shown, with the main factors being the trials are sufficient to study the problem and advance the type of application ͑left column͒ and which population this then impacts, technology, and in some cases multicenter trials are required which will then determine the size of the clinical trial required to prove the to achieve a meaningful impact. This is in the context of both technology is effective. Then ultimately there is a target cost per scan which will need to be considered for the technology to be economically feasibly in the trials ongoing presently, and those which will likely be the current healthcare market. carried out in the next decade. One goal of this work is also to help define areas where government and industry collaboration might be partnered, to advance the field of optical scopic structural information, about the tissue function. Fun- imaging in order to have useful impact in breast cancer. damental studies indicate that the molecular and cellular specificity are possible, in both endogenous tissue markers and with exogenous contrast agents. However, rapid medical II. MONITORING OF NEOADJUVANT translation can be slowed by the lack of convergence to a CHEMOTHERAPY RESPONSE single technology, and yet strategic industry and academic One of the most compelling applications to be studied in collaborations can be used to help advance translation. The the past few years has been the ability to track neoadjuvant National Cancer Institute ͑NCI͒ has funded specific Net- chemotherapy response in breast cancer tumors. The ability works for Translational Research in Optical Imaging to take measurements of light transmission through bulk tis- ͑NTROI͒ through a competitive review process, whose mis- sue and recover absorption and scattering values, at multiple sion has been to define technologies which have the highest wavelengths, has provided the critical ability to quantify tis- potential promise for impact in cancer, and find ways to test sue chromophore concentrations in vivo. Convergence on and validate them in multicenter trials. The Network prepar- one technology in this area is critical, since the numbers of ing this report was funded to advance optical imaging tech- subjects who would be imaged is relatively small and so nologies that have high potential to translate into successful unifying the technical implementation is critical to achieve multicenter trials in a setting related to breast cancer man- meaningful summary data which can demonstrate efficacy. agement. The focus of this paper is to outline these promis- The cost of the instrument, the system accuracy, and impact ing technological innovations and look towards what devel- upon patient management are all key factors, and choosing opment time scales they should be expected on. an application where no good tools exist today is also criti- In any imaging technology development, there is a key set cal. As can be seen in Fig. 1, the population benefiting from of trade-offs which are dictated largely by the application this system would be those with locally advanced breast can- needs. In Fig. 1, an illustration of the key needs in breast cer, and because the need is acute, the ability to complete a cancer detection, diagnosis, and management are listed on clinical trial demonstrating efficacy is a little easier than in the left, along with estimates of the subject population who screening applications. Interestingly also, since the applica- would benefit from the system, and an order of magnitude tion is not widespread but targeted to those who need the estimate of the scope of a clinical trial which would be system to assess their treatment efficacy, the cost per scan needed to demonstrate the system utility. Additionally, the ultimately could be substantially higher, as treatments can application area of the system will ultimately have a cost typically be in the thousands to tens of thousands if they are which makes the system financially viable for the applica- truly effective. The NCI sponsored NTROI has been advanc- tion. For example, population wide screening programs ing the development of Diffuse Optical Spectroscopy to be would have widespread societal impact, yet would require used to track response to neoadjuvant chemotherapy in lo- clinical trials with potentially tens of thousands of people to cally advanced breast cancer cases. prove the system efficacy, and ultimately could only be cost Neoadjuvant chemotherapy treatment is in widespread effective if the cost per person was as low as mammography, use, and is growing in its use in treatment of other types of

Medical Physics, Vol. 35, No. 6, June 2008 2445 Tromberg et al.: Diffuse optical imaging technologies for breast cancer management 2445

FIG. 2. The Laser Breast Scanner ͑LBS͒ system developed at the University of California Irvine, Beckman Laser Institute, which has been produced for multicenter trials of monitoring neoadjuvant chemotherapy response in breast cancer. The system electronics and console are shown in ͑A͒, and the tissue probe with light source fibers and light detectors in ͑B͒, and the procedure to take measurements across the tumor region ͑right breast͒ and the controlateral breast ͑left breast͒ are shown, with the probe being moved in 1 cm increments, to allow measurement of the on-tumor and off-tumor values of the tissue optical index ͑TOI͒. cancer beyond breast. One rationale for this therapy is to screen treated patients and determine those who were not allow tumor reduction prior to lumpectomy surgery of the responding, such that they could be shifted to another more tumor mass, thereby allowing smaller surgeries with better promising therapeutic approach. normal tissue sparing. The other major rationale is to reduce A multicenter trial is under way with the system con- the probability of distant metastases prior to mastectomy or structed at the University of California Irvine’s Beckman La- lumpectomy. However, about 30% of women with locally ser Institute, called the Laser Breast Scanner ͑LBS͒͑Fig. advanced breast cancer will not respond at all to neoadjuvant 2͒.8,9 The LBS is a bedside-capable system that combines 1,2 therapy, so it is critical to determine which subjects are frequency-domain measurements with steady-state broad- responding and which are not. While most of the decisions in band tissue spectroscopy to measure complete broadband this treatment scheme are done at the end of the chemo- quantitative near-infrared ͑NIR͒ absorption and reduced scat- therapy that was prescribed, it is possible that earlier detec- tering spectra of breast tissue in vivo. This technology solution of nonresponse would be beneficial so that alternative tion is ideal for the task of scanning women for determining therapies could be attempted earlier in the disease manage- response to neoadjuvant chemotherapy for several reasons. ment process. The concept of neoadjuvant chemotherapy and The key factors involved in this decision are: monitoring the response has also been proposed as the optimal way to “test” if the patient will respond to chemo- • Low patient numbers per medical center, requiring mul- therapy, and this testing is ideally done prior to surgery. The ticenter trial collaboration optical imaging system being proposed for multicenter stud- • Requirement of low cost for initial multicenter clinical ies should provide both molecular absorber information and trials. ultrastructural information from scattering. Early pilot stud- • Requirement of established system hardware and stan- ies have indicated that changes in tumor absorption can be dard operating procedures for multicenter trials. observed within the first days after treatment,3–7 and that the • Most tumors undergoing neoadjuvant therapy are large, specificity of these changes can be as high as 95%–100%. and often near the breast surface, making the surface The clinical goal in using the system would be to accurately scanning approach a good option.

Medical Physics, Vol. 35, No. 6, June 2008 2446 Tromberg et al.: Diffuse optical imaging technologies for breast cancer management 2446

• Mulitiple track measurements over the tumor will avoid • Complex breast tissue due to previous surgery. the confusion associated with interpreting imaging data • Younger women who are within the age range where in multicenter setting. annual screening is recommended. The LBS instrumentation and theory have been described in In each of these groups, there are research studies ongoing to several previous publications.10 The approach is highly sta- determine the best way to manage or indicate regular screen- bilized and rich in information because of using multiple ing for cancer, yet the ideal situation of nonionizing radiation fiber-coupled laser diodes that are intensity modulated, with or more sensitive tools is attractive for these applications. solid state detection. The diffusely transmitted spectra mea- The problems with screening in these groups largely fall into sured from the tissue are fit to a model of diffuse light trans- the logistics of: port, and are used to recover average tissue concentrations of ͑ ͒ • Contrast to noise problems with detecting abnormalities oxygenated hemoglobin ctO2Hb , deoxygenated hemoglobin ͑ctHHb͒, total hemoglobin concentration ͑ctTHb through dense or complex tissues ͒ • Difficulty in imaging or scanning the entire breast vol- =ctO2Hb+ctHHb tissue hemoglobin oxygenation saturation ͑ / ϫ ͒ ͑ ͒ ume stO2 =ctO2Hb ctTHb 100% water ctH2O , and lipid concentration. A contrast function is used to combine DOS • Difficulty in justifying the cost of screening programs, measurements to locate the location of maximum lesion op- prior to knowing the sensitivity and specificity of the ϫ ͑ system proposed. tical contrast: Tissue Optical Index, TOI=ctHHb ctH2O/ % lipid͒. The parameters of this contrast function were deter- This latter issue is really a key factor, since in many cases the mined from an evaluation of diffuse optical spectroscopy first two problems may be fixed for given systems. The ma- ͑DOS͒ measurements in a larger population of 58 malignant jor factor is that once a system is chosen, there needs to be a breast lesions. Tissue scattering is reported by the results of a large clinical trial done to assess the sensitivity and specific- ͑ power law fit of the form transport scattering coefficient ity of detection of tumors in each subpopulation as indicated ͒ ϭ A␭−SP, where ␭ is the optical wavelength. The probe is in Fig. 1 , and these values can then help determine if the moved along a linear position on the surface of the tissue system is going to have clinical utility. There are major bio- ͓Fig. 2͑C͔͒, and future versions of the system use will focus logical and clinical factors that influence the imaging, and so on 2D scanning in both x and y directions along the breast pilot trials have already been completed to assess the factors surface to map the tumor from above. The measurements associated with age, body mass index, breast density, menstrual cycle effects, menopausal status, and hormone replace- must be made by placing the probe on the breast with light 9,11–13 pressure to ensure contact. For comparison, a surface 2D ment therapy status. Now that these are reasonably well scan is also performed at an identical location on the contra- understood, it is possible to design screening studies which lateral breast. will have matched controls to assess the system performance The goals for the multicenter studies ongoing with this in the relevant subpopulation. As indicated in Fig. 1, screen- system are: ing has maximal benefit, but because the application is applied widespread the cost to society is enormous, and drives • To assess therapeutic efficacy early in treatment with down the target cost per scan to very low values. The optimal the LBS to allow future studies of tailoring treatment societal benefit in screening is likely in those not well served regimens for maximizing response, minimizing toxicity, by existing mammography programs, such as young women and increasing overall survival; and radio-dense women. As the numbers of subjects in these • To provide quantitative, noninvasive monitoring of tu- groups is still very large, the medical impact of a successful mor physiology and treatment response, correlated with technology would be enormous, albeit potentially costly. histopathology and MRI, will provide new insights re- For the problem of screening these specific subpopula- garding mechanisms of chemotherapy; tions of women, there are two technological approaches • To examine how dissemination of the LBS technology which will work. The LBS mentioned in the previous section into general practice works, and increase the availability is a logical choice to screen women with a lower cost solu- of potentially valuable technologies to a broader tion. This system would require scanning the entire breast population. surface and is maximally sensitive to the outer few centimeters of tissue under the probe. Alternatively, a breast spectral III. SCREENING FOR SUBPOPULATIONS OF tomography system could be used for transmission tomogra- WOMEN phy imaging of the breast. A couple of such systems have been developed to an advanced clinical trial stage ͓Fig. 3͑A͔͒ Screening women for cancer has become one of the larg- with approval for sale in several countries, and several labo- est success stories in preventative medicine, with annual ratory research systems have been developed and used in mammography being the “standard of care” for women over large clinical trials ͓Figs. 3͑B͒ and 3͑C͔͒. The advantage of the age of 50 in most of the developed world. But still there these systems is that the tumor characteristics can be imaged are populations where this screening program does not work while the patient is lying in a prone position, and there is well, and this is in women with: reasonably good coverage of most of the breast. There are • Highly radio-dense breast tissue. still problems with imaging very small or very large breasts, • Known higher risk due to genetic factors. as there are in mammography, yet for a majority of women,

Medical Physics, Vol. 35, No. 6, June 2008 2447 Tromberg et al.: Diffuse optical imaging technologies for breast cancer management 2447

FIG. 3. Tomographic imaging systems developed for breast tumor characterization and imaging during therapy have been developed and large clinical trial results have been published. The commercial system from ART Inc. ͑see Ref. 15͒ is shown in a photograph ͑A͒, and research at Dartmouth resulted in the system shown in ͑B͒͑Refs. 14, 28,and29͒, and a schematic of the system at the University of Pennsylvania is shown in ͑C͒͑Refs. 6 and 30͒. Each system uses multiple sets of measurements at multiple wavelengths of NIR light, transmitted through the breast to reconstruct images of hemoglobin, oxygen saturation, water, and scattering values. this imaging can be done readily with a visit taking less than and either help determine whether biopsy is needed, or ulti- 30 min. The utility of these systems in a truly widespread mately track suspected abnormalities over time to detect ma- screening application is still unproven, but clinical trials are lignant types of changes. There have been several commer- ongoing to assess sensitivity and speciﬁcity in subgroups. cial ventures aimed at this particular technology space in the health care market, and two devices have gained approvals in IV. OPTICAL AS AN ADJUNCT IMAGING some countries and in an evaluation phase in the U.S., in- TOOL cluding ComfortScan ͑ART Inc., Montreal Canada͒ and Optical imaging as an adjunct device to mammography or Computed Tomography Laser Mammography system ultrasound imaging is a natural choice, because the informa- ͑CTLM͒͑Imaging Diagnostic Systems, Inc., Plantation FL͒. tion gained with the optical signal is distinctly different from Research in this area has also been carried out by a European that of the clinical imaging information. Near-infrared scan- consortium and by Philips Medical Systems. The key to suc- ning of suspected abnormalities could provide the added in- cess in this area has been to ﬁnd an optimal way to maximize formation required to better determine the malignancy status, the clinical use of information of the optical image alongside

Medical Physics, Vol. 35, No. 6, June 2008 2448 Tromberg et al.: Diffuse optical imaging technologies for breast cancer management 2448

(A)

(B) (C)

FIG. 4. Hybrid Modality systems have been developed and used in pilot clinical trials to characterize tumors and test the synergy in having mutual information and the ability to combine information data sets to create a new class of hybrid images. The University of Pennsylvania system was the ﬁrst such device ͑A͒ ͑Refs. 26 and 27͒, and similar systems were built into a 3Tesla MRI at Dartmouth ͑B͒͑Refs. 18 and 20͒, and into an x-ray tomosynthesis system at the Massachusetts General Hospital ͑C͒͑Ref. 31͒.

standard mammography. This is more of a clinical workflow can be in the range which should be highly useful question and significant focus has been on making a work- clinically.15 The clinical trials to assess these systems in station model which could be truly integrated into a radiol- larger cohorts are still ongoing, and useful conclusions ogy department. So interestingly in this application, the ac- should be reached within a few years about the feasibility of tual success may depend more upon the business model, and using NIR as an adjunct to mammography. the ability to integrate the information into a standard Radi- ology workflow, rather than the system, yet system performance must also be at a high level. V. OPTICAL SPECTROSCOPY INTEGRATED INTO Academic research studies have examined the combina- CLINICAL IMAGING TOOLS tion of optical tomography as an adjunct to mammography, One key way for optical imaging to readily be integrated and publications by Poplack et al., report on the first blinded, into medicine is as an “add-on” to larger and currently ac- age-matched control trial using NIR spectral tomography as cepted clinical imaging systems, such as mammography, ul- additional information to mammography, and the data indi- trasound ͑US͒, x-ray computed tomography or tomosynthe- cate that for tumors with sufficiently high hemoglobin signa- sis, and Magnetic Resonance Imaging ͑MRI͒. Research in tures, that there is definitely added information from the NIR system integration has taken place in all of these areas, with images.14 The analysis of data from the ART system indi- a primary focus on breast imaging, to follow up on some cates that when the mammography and NIR images are used earlier screening. Illustrative systems are shown in Fig. 4, side by side with co-localized analysis, that the ROC values with the first MR coupled system shown ͑A͒, and a Philips/

Medical Physics, Vol. 35, No. 6, June 2008 2449 Tromberg et al.: Diffuse optical imaging technologies for breast cancer management 2449

NIH sponsored 3T MR-coupled system being tested cur- MR, there is increased ability to constrain the optical prop- rently ͑B͒, and the NIR system built into an x-ray breast erty recovery both spatially as well as in chromophore con- tomosynthesis system ͑C͒. While the primary screening mo- centrations, as the MR can yield water and fat maps which dality for the breast is x-ray mammography, there has been can be used to constrain the spectral recovery of hemoglobin, comparatively little study of how to introduce optics into this oxygen saturation, scatter, and exogenous agents. modality, indicating that integration with the other modalities The integration of NIR into clinical imaging is a natural would lead to applications which are not in the screening step in the progression of integration of clinical information area. Thus the potential for adding optics into a secondary into a streamlined series of information sources. One illus- imaging modality then lies in the area of providing informa- tration of this with widespread acceptance is the newly used tion which can differentiate the diagnosis of the lesion, or hybrid PET/CT scanners, where the PET information has perhaps track therapy response. gained much wider appreciation through the ability to super- If the key role for optics integrated into clinical systems is impose the scan on the high resolution CT image, and further to provide functional information for a targeted region within to allow enhancement of the image quality through postpro- the breast, then the system integration needs to be carried out cessing based upon the CT. Similar to this, overlay of NIR to maximally utilize the information from the two systems in spectral data on the MR scans and enhancement of the NIR a complementary or ideally synergistic manner. A key spectral data quantitatively should allow easier clinical ac- method of integration is then to maximize the spectral con- ceptance of this new information stream. tent of the optical hardware and utilize the spatial prior relations from the clinical imaging system.16–20 This approach to integrating spectral constraints and spatial prior information VI. CONCLUSIONS as a constraint has been demonstrated in tumor imaging,20 The four applications listed here are key areas where the and can now be implemented with optimized software algo- healthcare need overlaps very well with the emerging tech- rithms becoming available through the network. As illus- nology which is available in the next decade. Each area re- trated in Fig. 1, DOS imaging within other imaging devices quires refinement of the NIR technology or completion of would have a cost that was likely matched to the system it multicenter clinical trials to verify that the technology will was coupled to, such that DOS coupled to ultrasound would truly be a useful solution to the problem. NIR spectral to- likely have to be quite inexpensive to make an impact, mography of tissue has had a rich history of development in whereas DOS coupled MR could be considerably more ex- NIH funded work, and some of the designs discussed in this pensive since the latter cost is limited by the MR mainly. The overview are a result of decades of development. Advanced economic feasibility of these hybrid systems is a little uncer- stage clinical designs that will be advanced towards multi- tain at present, however performance will likely have a major center trials are desperately needed to carry out these valida- influence on the cost which is appropriate. tion trials. Coordination of these trials with the established Optical tomography has been integrated into a breast medical clinical trials bodies such as the National Cancer x-ray tomosynthesis system ͓Fig. 4͑C͔͒ at the Massachusetts Institutes Imaging Clinical Trials program or through the General Hospital, and is undergoing clinical trials.21,22 Be- American College of Radiology Imaging Network ͑ACRIN͒ cause of the widespread use of x-ray imaging of the breast, would be the ideal way to ensure that these technologies are this combination makes fundamental sense, and may provide advanced appropriately with maximal overlap with other in- additional information where mammography has limited ef- formation sources. ficacy, such as in the dense breast or for distributed or com- In some cases the business model involved in the system plex lesions. development can lead to success or failure of the technology, Additionally, soft tissue imaging with US is the natural however designs which have been vetted through both peer- follow on procedure for certain diagnoses, and integration of reviewed development as well as business plan evaluation optical spectroscopy into this has been productive and led the would be ideal to ensure that the right technology is ad- way towards region-based estimation of tissue vanced with the greatest promise for success. Ensuring that properties.23–25 This approach makes sense for US, as the academic-industry partnerships have a pathway for this co- region to be characterized is usually known when US is be- operation is critical, in a manner which is not too encum- ing used, and the goal is then to provide as much information bered by limited funding issues, but also provides room for about the tumor as is feasible. The ability to image hemoglo- competition and intellectual property preservation. This is a bin, oxygen saturation, and scatter has all been shown, with complex landscape in which to develop advanced technolo- strong potential for added diagnostic information. gies, but the National Cancer Institute has made the first The integration of diffuse tomography into MRI was a solid step in this process through sponsorship of the Network key development which was initially pioneered at the Uni- for Translational Research in Optical Imaging. Development versity of Pennsylvania26,27 and this work is being carried on of optical contrast agents which will provide true molecular to explore ways to synergize the mutual information through or compartmental specificity for cancer still remain to be the use of MR-derived spatial constraints in the diffuse opti- developed to the point of FDA approval and commercial cal imaging ͑DOI͒ spectroscopy,18,20 and the exponential distribution, however large amounts of research are still un- growth of breast MRI in recent years makes these develop- der way in this area. It is likely that these exogenous contrast ments of heightened importance ͓Figs. 4͑A͒ and 4͑B͔͒. With agents will be used in breast cancer imaging or therapy, but

Medical Physics, Vol. 35, No. 6, June 2008 2450 Tromberg et al.: Diffuse optical imaging technologies for breast cancer management 2450 the timeline for FDA approval for human use is still quite Valentini, “Effects of the menstrual cycle on the red and near-infrared ͑ ͒ uncertain at this time. The technologies outlined here for optical properties of the human breast,” Photochem. Photobiol. 72 3 , 383–391 ͑2000͒. intrinsic contrast imaging are capable and ready to be used in 12B. W. Pogue, S. Jiang, H. Dehghani, C. Kogel, S. Soho, S. Srinivasan, X. molecular contrast imaging as well, so it is likely that after Song, T. D. Tosteson, S. P. Poplack, and K. D. Paulsen, “Characterization the first round of multicenter trials begin in endogenous im- of hemoglobin, water, and NIR scattering in breast tissue: Analysis of aging, that this may facilitate the means for studying contrast intersubject variability and menstrual cycle changes,” J. Biomed. Opt. 9͑3͒, 541–552 ͑2004͒. agents in a multicenter setting as well. 13A. Cerussi, N. Shah, D. Hsiang, A. Durkin, J. Butler, and B. J. Tromberg, This paper is a summary report from one of these spon- “In vivo absorption, scattering, and physiologic properties of 58 malig- sored networks for translational research in optical imaging, nant breast tumors determined by broadband diffuse optical spectros- ͑ ͒ ͑ ͒ where the outcome of the network has been exactly focused copy,” J. Biomed. Opt. 11 4 , 044005 2006 . 14S. P. Poplack, K. D. Paulsen, A. Hartov, P. M. Meaney, B. W. Pogue, T. on providing a convergence in the space of advanced NIR D. Tosteson, S. K. Soho, and W. A. Wells, “Electromagnetic breast im- technology, breast cancer health care need, and business de- aging - Pilot results in women with abnormal mammography,” Radiology velopment capacity. The clinical trials proposed here will be 243͑2͒, 350–359 ͑2007͒. 15 carried out over the next decade or so, and will likely have a X. Intes, “Time-domain optical mammography SoftScan: Initial results,” Acad. Radiol. 12͑8͒, 934–947 ͑2005͒; see erratum also in Acad. Radiol. direct impact on both the technologies, businesses, and 12͑10͒, 1355 ͑2005͒. medical practice involved in breast cancer detection and 16A. Li, G. Boverman, Y. Zhang, D. Brooks, E. L. Miller, M. E. Kilmer, Q. management. Zhang, E. M. C. Hillman, and D. A. Boas, “Optimal linear inverse solution with multiple priors in diffuse optical tomography,” Appl. Opt. 44͑10͒, 1948–1956 ͑2005͒. 17B. Brooksby, S. Jiang, H. Dehghani, B. W. Pogue, K. D. Paulsen, J. B. ACKNOWLEDGMENT Weaver, C. Kogel, and S. P. Poplack, “Combining near infrared tomog- This work has been funded by the Network for Transla- raphy and magnetic resonance imaging to study in vivo breast tissue: Implementation of a Laplacian-type regularization to incorporate MR tional Research in Optical Imaging, within the National Can- structure,” J. Biomed. Opt. 10͑5͒, 050504-1–10 ͑2005͒. cer Institute ͑U54CA105480͒. 18B. Brooksby, B. W. Pogue, S. Jiang, H. Dehghani, S. Srinivasan, C. Kogel, T. Tosteson, J. B. Weaver, S. P. Poplack, and K. D. Paulsen, ͒ a Author to whom correspondence should be addressed. Electronic mail: “Imaging breast adipose and fibroglandular tissue molecular signatures [email protected] using hybrid MRI-guided near-infrared spectral tomography,” Proc. Natl. 1H. M. Kuerer, K. K. Hunt, L. A. Newman, M. I. Ross, F. C. Ames, and S. Acad. Sci. U.S.A. 103͑23͒, 8828–8833 ͑2006͒. E. Singletary, “Neoadjuvant chemotherapy in women with invasive breast 19P. K. Yalavarthy, B. W. Pogue, H. Dehghani, and K. D. Paulsen, “Weight- carcinoma: Conceptual basis and fundamental surgical issues,” J. Am. matrix structured regularization provides optimal generalized least- Coll. Surg. 190͑3͒, 350–363 ͑2000͒. squares estimate in diffuse optical tomography,” Med. Phys., 34͑6͒, 2L. Esserman, “Neoadjuvant chemotherapy for primary breast cancer: Les- 2085–2098 ͑2007͒. sons learned and opportunities to optimize therapy,” Ann. Surg. Oncol. 20C. M. Carpenter, B. W. Pogue, S. Jiang, H. Dehghani, X. Wang, K. D. 11͑1 Suppl.͒,3S–8S͑2004͒. Paulsen, W. A. Wells, J. Forero, C. Kogel, J. B. Weaver, S. P. Poplack, 3A. Cerussi, D. Hsiang, N. Shah, R. Mehta, A. Durkin, J. Butler, and B. J. and P. A. Kaufman, “Image-guided optical spectroscopy provides Tromberg, “Predicting response to breast cancer neoadjuvant chemo- molecular-specific information in vivo: MRI-guided spectroscopy of therapy using diffuse optical spectroscopy,” Proc. Natl. Acad. Sci. U.S.A. breast cancer hemoglobin, water, and scatterer size,” Opt. Lett. 32͑8͒, 104͑10͒, 4014–4019 ͑2007͒. 933–935 ͑2007͒. 4B. J. Tromberg, A. Cerussi, N. Shah, M. Compton, A. Durkin, D. Hsiang, 21G. Boverman, Q. Fang, S. A. Carp, E. L. Miller, D. H. Brooks, J. Selb, R. J. Butler, and R. Mehta, “Imaging in breast cancer: Diffuse optics in H. Moore, D. B. Kopans, and D. A. Boas, “Spatio-temporal imaging of breast cancer: Detecting tumors in pre-menopausal women and monitor- the hemoglobin in the compressed breast with diffuse optical tomogra- ing neoadjuvant chemotherapy,” Breast Cancer Res., 7͑6͒, 279–285 phy,” Phys. Med. Biol. 52͑12͒, 3619–3641 ͑2007͒. ͑2005͒. 22Q. Zhang, T. J. Brukilacchio, A. Li, J. J. Stott, T. Chaves, E. Hillman, T. 5N. Shah, J. Gibbs, D. Wolverton, A. Cerussi, N. Hylton, and B. J. Trom- Wu, M. Chorlton, E. Rafferty, R. H. Moore, D. B. Kopans, and D. A. berg, “Combined diffuse optical spectroscopy and contrast-enhanced Boas, “Coregistered tomographic x-ray and optical breast imaging: Initial magnetic resonance imaging for monitoring breast cancer neoadjuvant results,” J. Biomed. Opt. 10͑2͒, 024033 ͑2005͒. chemotherapy: A case study,” J. Biomed. Opt. 10͑5͒, 051503 ͑2005͒. 23Q. Zhu, S. H. Kurtzma, P. Hegde, S. Tannenbaum, M. Kane, M. Huang, 6R. Choe, A. Corlu, K. Lee, T. Durduran, S. D. Konecky, M. Grosicka- N. G. Chen, B. Jagjivan, and K. Zarfos, “Utilizing optical tomography Koptyra, S. R. Arridge, B. J. Czerniecki, D. L. Fraker, A. DeMichele, B. with ultrasound localization to image heterogeneous hemoglobin distribu- Chance, M. A. Rosen, and A. G. Yodh, “Diffuse optical tomography of tion in large breast cancers,” Neoplasia 7͑3͒, 263–270 ͑2005͒. breast cancer during neoadjuvant chemotherapy: A case study with com- 24Q. Zhu, “Optical tomography with ultrasound localization: Initial clinical parison to MRI,” Med. Phys. 32͑4͒, 1128–1139 ͑2005͒. results and technical challenges,” Technol. Cancer Res. Treat. 4͑3͒, 235– 7D. B. Jakubowski, A. E. Cerussi, F. Bevilacqua, N. Shah, D. Hsiang, J. 244 ͑2005͒. Butler, and B. J. Tromberg, “Monitoring neoadjuvant chemotherapy in 25Q. Zhu, M. Huang, N. Chen, K. Zarfos, B. Jagjivan, M. Kane, P. Hedge, breast cancer using quantitative diffuse optical spectroscopy: A case and S. H. Kurtzman, “Ultrasound-guided optical tomographic imaging of study,” J. Biomed. Opt. 9͑1͒, 230–238 ͑2004͒. malignant and benign breast lesions: Initial clinical results of 19 cases,” 8N. Shah, A. Cerussi, C. Eker, J. Espinoza, J. Butler, J. Fishkin, R. Hor- Neoplasia 5͑5͒, 379–388 ͑2003͒. nung, and B. Tromberg, “Noninvasive functional optical spectroscopy of 26V. Ntziachristos, A. G. Yodh, M. Schnall, and B. Chance, “Concurrent human breast tissue,” Proc. Natl. Acad. Sci. U.S.A. 98͑8͒, 4420–4425 MRI and diffuse optical tomography of breast after indocyanine green ͑2001͒. enhancement,” Proc. Natl. Acad. Sci. U.S.A. 97͑6͒, 2767–2772 ͑2000͒. 9N. Shah, A. E. Cerussi, D. Jakubowski, D. Hsiang, J. Butler, and B. J. 27V. Ntziachristos, A. G. Yodh, M. D. Schnall, and B. Chance, “MRI- Tromberg, “The role of diffuse optical spectroscopy in the clinical man- guided diffuse optical spectroscopy of malignant and benign breast le- agement of breast cancer,” Dis. Markers 19͑2-3͒, 95–105 ͑2003͒. sions,” Neoplasia 4͑4͒, 347–354 ͑2002͒. 10F. Bevilacqua, A. J. Berger, A. E. Cerussi, D. Jakubowski, and B. J. 28S. P. Poplack, K. D. Paulsen, A. Hartov, P. M. Meaney, B. W. Pogue, T. Tromberg, “Broadband absorption spectroscopy in turbid media by com- D. Tosteson, M. R. Grove, S. K. Soho, and W. A. Wells, “Electromagnetic bined frequency-domain and steady-state methods,” Appl. Opt. 39͑34͒, breast imaging: Average tissue property values in women with negative 6498–6510 ͑2000͒. clinical findings,” Radiology 231͑2͒, 571–580 ͑2004͒. 11R. Cubeddu, C. D’Andrea, A. Pifferi, P. Taroni, A. Torricelli, and G. 29B. W. Pogue, S. P. Poplack, T. O. McBride, W. A. Wells, K. S. Osterman,

Medical Physics, Vol. 35, No. 6, June 2008 2451 Tromberg et al.: Diffuse optical imaging technologies for breast cancer management 2451

U. L. Osterberg, and K. D. Paulsen, “Quantitative hemoglobin tomogra- tion of a hybrid frequency domain/continuous wave clinical system for phy with diffuse near-infrared spectroscopy: Pilot results in the breast,” breast imaging,” Med. Phys. 30͑2͒, 235–247 ͑2003͒. Radiology 218͑1͒, 261–266 ͑2001͒. 31S. A. Carp, T. Kauffman, Q. Fang, E. Rafferty, R. Moore, D. Kopans, and 30J. P. Culver, R. Choe, M. J. Holboke, L. Zubkov, T. Durduran, A. Slemp, D. Boas, “Compression-induced changes in the physiological state of the V. Ntziachristos, B. Chance, and A. G. Yodh, “Three-dimensional diffuse breast as observed through frequency domain photon migration measure- optical tomography in the parallel plane transmission geometry: Evalua- ments,” J. Biomed. Opt. 11͑6͒, 064016 ͑2006͒.

Medical Physics, Vol. 35, No. 6, June 2008 Vision 20/20: Increased image resolution versus reduced radiation exposure ͒ Erik L. Ritmana Department of Physiology & Biomedical Engineering, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905 ͑Received 6 December 2007; revised 8 April 2008; accepted for publication 8 April 2008; published 27 May 2008͒ This is a review of methods, currently and potentially, available for significantly reducing x-ray exposure in medical x-ray imaging. It is stimulated by the radiation exposure implications of the growing use of helical scanning, multislice, x-ray computed tomography for screening, such as for coronary artery atherosclerosis and cancer of the colon and lungs. Screening requires high- throughput imaging with high spatial and contrast resolution to meet the need for high sensitivity and specificity of detection and classification of specific imaged features. To achieve this goal beyond what is currently available with x-ray imaging methods requires increased x-ray exposure, which increases the risk of tissue damage and ultimately cancer development. These consequences limit the utility of current x-ray imaging in screening of at-risk subjects who have not yet developed the clinical symptoms of disease. Current methods for reducing x-ray exposure in x-ray imaging, mostly achieved by increasing sensitivity and specificity of the x-ray detection process, may still have potential for an up-to-tenfold decrease. This could be sufficient for doubling the spatial resolution of x-ray CT while maintaining the current x-ray exposure levels. However, a spatial resolution four times what is currently available might be needed to adequately meet the needs for screening. Consequently, for the proposed need to increase spatial resolution, an additional order of magnitude of reduction of x-ray exposure would be needed just to keep the radiation exposure at current levels. This is conceivably achievable if refraction, rather than the currently used attenuation, of x rays is used to generate the images. Existing methods that have potential for imaging the consequences of refracted x ray in a clinical setting are ͑1͒ by imaging the edge enhancement that occurs at the interfaces between adjacent tissues of different refractive indices, or ͑2͒ by imaging the changes in interference patterns resulting from moving grids which alter the refraction of x rays, that have passed through the body, in a predictable fashion, and ͑3͒ theoretically, by an image generated from the change in time-of-flight of x-ray photons passing through the body. Imaging phase shift or change in time-of-flight, rather than attenuation, of x-ray photons through tissues presents formidable technological problems for whole-body 3D imaging. However, if achievable in a routine clinical setting, these approaches have the potential for greatly expanding the use of x-ray imaging for screening. This overview examines the increased contrast resolution and reduced radiation exposure that might be achievable by the above-mentioned methods. © 2008 American Association of Physicists in Medicine. ͓DOI: 10.1118/1.2919112͔

Key words: screening, x-ray refractive index, x-ray attenuation

I. INTRODUCTION and this is raising some concern. The following discussion Shortly after its introduction to clinical practice in 1973, explores both the probable image resolution requirements for computed tomography was rapidly shown to greatly increase effective screening and its implications for associated radia- the specificity and sensitivity of image information content.1 tion exposure, and how this may be minimized by modifica- Since the mid 1990s fast, multislice, helical scanning mul- tions of attenuation-based x-ray scanning as well as by use of tidetector, or multislice, computed tomography ͑MDCT or non-attenuation-based x-ray imaging. MSCT͒,2,3 which generates a 3D array of tiny cubic picture elements ͑voxels͒, has advanced to include screening appli- II. BACKGROUND cations. Examples include CT colonography,4 lung imaging II.A. Increasing concern about x-ray exposure for early detection of cancer,5 and coronary artery calcification.6 In general, the duration during which the patient profits Because of the clinical appeal of these developments, from any treatment ͑resulting from the image-based diagno- there is considerable pressure for further technological im- sis͒ should not be curtailed by the onset of undesirable del- provement to increase the spectrum of clinical applications, eterious consequences of the radiation exposure. Some esti- especially in screening for early stages of disease. This, how- mate of that time interval in which deleterious consequences ever, is likely to increase the radiation exposure involved, develop can be deduced from previous studies of the tempo-

2502 Med. Phys. 35 „6…, June 2008 0094-2405/2008/35„6…/2502/11/$23.00 © 2008 Am. Assoc. Phys. Med. 2502 2503 Erik L. Ritman: Reduced x-ray exposure for screening 2503 ral relationship between radiation exposure and consequences. For instance, Imaizumi et al.7 recently showed that a signiﬁcant linear radiation dose response for thyroid nodules, including malignant tumors and benign tumors, exists in the survivors of atom bomb exposure. With the introduction of 3D imaging CT scanners, radiation exposures are increasingly being expressed as volume computed tomography dose index ͑CTDIvol in mGy͒ and dose-length product ͑DLP in mGycm͒. Although rarely experienced in clinical diagnostic or interventional practices, after a 2 Gy single dose, skin reddening occurs.8 However, because not all tissues are equally radiosensitive, gonads, for instance, are more sensitive than bone marrow ͑Ϸcolon ϷlungϷstomach͒ and these are more sensitive than bladder, liver, and thyroid, which in turn are more sensitive than skin.

A reasonable approximation of the more biologically mean- FIG.1. K is the kinetic energy released in matter and ␾ is the area exposed. ingful effective dose ͑E͒ can be obtained by the equation Extrapolation of these data to 511 keV indicates that use of the positron ͑ ͒ annihilation method would involve almost ten times higher KERMA than E = K · DLP, 1 that at 60 keV. ͑With permission from Ref. 51.͒ where K=0.017 mSv/͑mGy cm͒ for a thorax scan9 and DLP is the dose length product–– the length typically being 30 cm As one standard deviation of the quantum noise=I0.5, then for a thorax. the signal ⌬I has to be greater than ͑1.5ϫ10−2I ͒0.5. This A typical multislice heart/calcification CT scan involves o condition is met if I Ͼ6·7ϫ109 photons/exposure of a approximately 30 mSv and a CT coronary angiogram scan o 1mm2 resolution unit. According to Motz et al.,15 this up to 60 mSv.10 The National Radiological Protection Board would involve an exposure of 0.3 Gy, more than an order of of the U.K. ͑Ref. 11͒ showed that effective radiation doses in magnitude higher than the exposure with a current CT scan. patients 0–1-year-old were typically higher than correspond- In order to achieve higher spatial resolution at constant ing values in adults. This is particularly worrisome in the contrast resolution, the x-ray exposure needs to increase by cases such as congenital heart diseases, which are often emi- at least the cube of the resolution, i.e., by decreasing voxel nently treatable provided an accurate diagnosis is available size from 1 to 0.5 mm3, the exposure should increase at least and x-ray imaging is often the method of choice. A complex eightfold.16 Low-energy x-ray photons ͑i.e., Ͻ50 keV͒ pro- diagnostic study of congenital heart disease or an electro- vide more contrast because each photon is more likely to physiological interventional study could involve as much as interact with matter by virtue of the photoelectric effect. a 600 mSv exposure.12 To put this in perspective, for a popu- However, at this photon energy fewer primary photons are lation in which each person is exposed to 100 mSv it is likely transmitted through the body, so that the signal-to-noise ratio that the chance of developing cancer increases from 20 in a in the x-ray image is poorer for a given x-ray photon flux nonexposed population to 20.01%.13 exposure. On the other hand, when an x-ray photon’s energy The ability to discriminate between different tissues in a increases beyond 50 keV, it is less likely to interact with CT image depends on the difference in attenuation coeffi- matter but when it does interact the damage potential per cient of tissue in two adjacent voxels being greater than the photon increases as illustrated in Fig. 1. This trade-off be- noise in the detected x-ray signal ͑at best this is the quantum tween exposure and x-ray photon energy results in an opti- noise͒. Thus, to distinguisha1mmdiameter cubic voxel of mal x-ray photon energy, in terms of minimum number of muscle tissue with attenuation coefficient ␮=0.212/cm at 60 photons per unit x-ray interaction with tissue, at about 60 keV ͑Ref. 14͒ from a 1 mm ͑x͒ diameter voxel of blood ͑␮ keV in clinically relevant conditions. =0.222/cm͒ within a 20 cm diameter, water-equivalent, torso ͑␮=0.210/cm͒, the signal is given by the Beer- Lambert law, which relates the transmitted flux ͑I͒ to the II.B. Proposed image resolution requirements for ͑ ͒ medical screening illuminating flux Io by −␮x ͑ ͒ Because the radiation exposure required to achieve a de- I = Ioe 2 sired image quality depends so strongly on the desired image ء ء ͑ ͒ −0.222 0.1 −0.210 20 resolution, the pathophysiological rationale for the level of I thru blood voxel = Ioe e image resolution likely to be needed for screening purposes ء ء ͑ ͒ −0.212 0.1 −0.210 20 I thru muscle voxel = Ioe e needs to be established. ء ء ء ء І⌬ −0.210 20 −0.222 0.1 −0.210 20 −0.212 0.1 Screening for a disease requires both low false negative I = Ioe e − Ioe e and false positive detections as well as high true positive and = 1.5 ϫ 10−5I , o high true negative detections, i.e., high specificity and sensi- ⌬ where Io is the x-ray exposure and I is the difference in tivity. For imaging this requires spatial, contrast, and/or tem- transmitted x ray through a voxel of blood and of muscle. poral resolutions depending on the type of pathological pro-

Medical Physics, Vol. 35, No. 6, June 2008 2504 Erik L. Ritman: Reduced x-ray exposure for screening 2504 cess to be detected, the stage in the evolution of that II.B.3. Volume that needs to be imaged pathological process, as well as where in the body that pro- The volume that needs to be imaged is determined by the cess is occurring. As spatial, contrast, and temporal resolu- need to image an entire organ. This is because the absence of tions are generally interdependent, it is important to know a detected abnormality in an organ will only then have mean- the upper limits of these resolutions that are necessary for a ing in the case of a cancer or some other disease process that desired sensitivity and specificity. starts as focal pathology. Thus, the gut would require that the entire abdomen be imaged and the lung requires that the II.B.1. Spatial resolution entire thorax be imaged––both being approximately 30–40 The basic functional unit ͑BFU͒ of organs seems like a cm in cephalocaudal height and in transverse diameter. This reasonable goal for the highest spatial resolution of clinical is currently achieved with multislice helical scanning CT at whole-body CT imagers used for screening. BFUs are the approximately ͑0.6 mm͒3 resolution. ͑Note that spatial reso- smallest accumulations of diverse cells that function like the lution cannot be better than twice the size of a voxel.͒ organ they are in, e.g., the hepatic lobule in the liver or nephron in the kidney. Generally, they occupy about II.B.4. Temporal resolution 0.01 mm3, i.e., about 200 ␮m in diameter. The volume of a BFU is essentially the upper limit of a spherical assembly of In addition to 3D anatomy, the rate, amplitude, synchrony, cells, immersed in a suitable nutrient medium, which can and the spatial distribution of the movement attributes of survive without its own blood supply. However, each BFU some organs and of the blood flow within organs are impor- ͑ ͒ has its own capillary blood supply to support the extra en- tant indicators of the organs’ function s . Even if the dynam- ergy needed for the physiological function ͑e.g., secretion or ics is not of direct clinical interest, the minimizing of blur- filtration͒ of the BFU. Similarly, early “solid” cancers could ring of anatomic features due to motion is of direct interest. grow to this size in perfused tissues before a blood supply is Moreover, temporal and spatial resolutions are directly inter- 17 related in that increasing one often involves reducing the needed to sustain further growth. However, once a blood 18 supply to the small aggregation of cancerous cells is formed, other if x-ray exposure is kept constant. There are two then growth into larger tumors, as well as dissemination of types of organ motion; one can be predictively cyclic, such cancer cells throughout the body, is facilitated. Thus, an iso- as the normal heart beat or breathing, and the other is unpre- tropic voxel resolution of 100 ␮m seems like a reasonable dictable and therefore, generally not reproducible, such as goal because it would allow us to detect, measure the num- the peristaltic movement of the bowel or the passage of a ber, size, and perhaps functional status ͑especially as re- bolus of injected contrast agent through the blood stream. flected in its perfusion, but this would generally require use These physiological factors raise three issues: one is the need of a contrast agent͒ of individual BFUs or of early cancers. to image fast enough to stop the motion blurring i.e., the 3D Unfortunately, due to x-ray photon statistics alone, this spa- imaging “shutter” time, which would need to be fast enough tial resolution would require almost two decades more in to stop-action the fastest moving phase of the motion. In the x-ray exposure than is delivered by current MSCT scanners. heart this requires that CT scan data be acquired within 100 Additional x-ray exposure may be needed depending on the ms even in the “slow” diastolic filling phase of the heart contrast differential between a BFU and its surrounding cycle at heart rates less than 70 beats/min. Unless a priori ͑ stroma. Additional radiation may also be needed to overcome knowledge of the time at which the quiescent or most dy- ͒ the “noise” generated by x-ray beam hardening and x-ray namic phase of the cyclic activity occurs, continuous obser- scatter contamination of the primary x-ray image data. vation is needed at a rate required to ensure adequate imaging of the most dynamic phase. This approach generally results in retrospective selection of the desired image͑s͒ and II.B.2. Contrast resolution discarding the remaining images––which often represent the BFUs differ little in x-ray contrast from surrounding tis- majority of those images. This approach results in consider- sues because they are elementally not very different from the able x-ray exposure that ultimately does not contribute to- connective tissue in which they are embedded. Similarly, dis- ward information extracted from the available x-ray image crimination of some macroscopic tissue components that are data. of particular clinical interest, such as the cartilage in joints, and tissues that are starting to be infiltrated by pathological II.C. Enhancement of exposure-to-information content proteins ͑e.g., amyloid in heart muscle͒ or elements ͑e.g., of x-ray images iron in the liver͒, also is difficult for attenuation-based x-ray CT imaging. With current attenuation-based x-ray imaging, A goal is to have the modulation of the transmitted x-ray exploitation of any attenuation-based contrast difference signal be greater than the noise in that signal for unequivocal would require either very high radiation exposures to provide detection of the signal.19 However, this needs to be achieved the signal-to-noise ratio needed for discriminating these tiny without increasing radiation exposure. Contrast resolution20 BFUs from their surrounding tissue matrix, or would require depends on signal noise ͑especially in x-ray quantum-limited administering a contrast-enhancing agent generally involving images͒ and contamination by scattered x rays which add a high-Z element such as iodine that selectively accumulates noise21 and reduce the dynamic range of the electronic image in ͑or avoids͒ BFUs. gray scale available for detecting small changes of contrast

Medical Physics, Vol. 35, No. 6, June 2008 2505 Erik L. Ritman: Reduced x-ray exposure for screening 2505 in the x-ray image. Another contributor to altered gray-scale II.C.2. Contrast media ͑ values is beam hardening due to a polychromatic brems- The use of contrast media,32 primarily iodine-based, re- ͒ ͑ strahlung x-ray beam becoming “hardened” i.e., less at- duces the x-ray exposure needed to differentiate an “opaci- tenuating͒ as it traverses tissue, especially bone, which is ͑ ͒ 22 fied’ physiological space e.g., blood vessel lumen from its highly attenuating. surrounding tissues ͑e.g., brain tissue͒. The impact of the Radiation exposure has been, and is continuing to be, de- selective “opacification” may be limited in certain organs creased by increasing the sensitivity of x-ray detection by when intravenous injections are used, as this also opacifies ͑ improved detector technology i.e., make every transmitted the microcirculation in overlying tissues or cardiac chambers ͒ x-ray photon count and by increasing specificity by selec- and thereby reduces the desired signal. Zeman et al.33 tively rejecting scatter without use of antiscatter grids and by showed that, for a tissue thickness equivalent to 20 cm of use of beam filtration to generate a narrow spectrum or ide- water, the element providing optimal image contrast should ally the use of monochromatic radiation. The following sum- have a Z value ranging from 60 to 70 ͑iodine Z=53͒. How- marizes some present and ongoing developments. ever, use of contrast media in screening applications is gen- However, as will be shown, these approaches are unlikely erally not indicated because of logistic implications and be- to adequately reduce radiation exposure, and some of them cause of occasional side effects such as hematoma at the are likely to be technically impractical to implement in, or injection site, embolism downstream to the injection site, with, clinical CT scanners used in a screening mode. aggravation of kidney disease or allergic reaction.34

II.C.3. Prospective “gated” image acquisition II.C.1. Reduce x-ray scatter Prospective “gated” image acquisition, used in the case of The scatter component in an x-ray image has been shown the predictable cyclic motion such as occurs in the heart, can to double when the x-ray photon energy is reduced from 100 also reduce radiation exposure. This method involves acquir- to 20 keV, and also to double if “body” diameter is increased ing incremental sets of partial-scan data ͑only during a fixed from5to20cm.23 These two opposing factors are traded off phase of that cyclic motion͒ progressively over many se- by selecting higher x-ray voltages for greater body diam- quential heart cycles during one breath-hold. Total radiation eters. Partial removal of scattered x rays from the x-ray im- exposure/scan sequence can thereby be reduced fourfold ager has been achieved by two methods. The most com- relative to retrospectively gated tomographic reconstruction, monly used method involves increasing the distance between in which the x-ray exposure is continuous during the entire 35 the subject and the detector.24 Use of a large object-to- breath-hold duration of the scan. detector distance can greatly reduce the scatter that is detected, but with finite focal spot dimensions this is at the cost II.C.4. Hardware and software “tricks” of reduced spatial resolution.25 Use of a mechanical “Vene- Hardware and software “tricks” can also be used to re- tian blind”-like collimator26 preferentially reduces the x-ray duce patient exposure. The simplest method is to merely re- scatter contamination of the image and thereby increases the duce the x-ray source current. This so-called “low-dose CT” contrast resolution, but at the cost of loss of signal due to the 36 can reduce exposure to 1/5, but at the cost of reduced im- collimator’s vanes stopping some of the transmitted primary age quality. This approach is probably suitable for monitor- x-ray photons.27 This latter aspect can be partially overcome ing an abnormality known to be present, rather than for de- by using software to model the scatter and subtracting that tecting new ones. Another method involves varying the computed scatter signal from the detected signal28 instead of radiation exposure at different angles of view around the using a mechanical collimator. However, this approach usu- subject so as to keep the transmitted x-ray signal constant at ally degrades the spatial resolution of the scatter-corrected 37 the level needed for the desired signal-to-noise ratio. image. 38 Harpen showed the use of a “bow tie”-type of beam shap- Other methods that might possibly be used are technically ing filter to better match the dynamic range in the transmitted and/or economically more challenging. A method used in x-ray image gray scale to the image detector dynamic range. nuclear medicine imaging involves detecting the x-ray pho- This can decrease noise power in a CT image by up to 25%, tons with an energy-sensitive detector. If a monochromatic especially in larger diameter fields-of-view. Another ap- x-ray source can be used, the contribution of the lower en- proach is to restrict the x-ray exposure to only the organ of ergy scattered photons can be eliminated from the x-ray interest ͑e.g., the heart͒. This would reduce the amount of transmission image data. Another, potential, method borrows tissue exposed but requires use of special “limited data set” from positron emission tomography ͑PET͒ technology29 by tomographic reconstruction algorithms to provide usable using time-of-flight information to eliminate scattered pho- 39,40 images. tons by virtue of them generally being delayed in their arrival at the detector relative to the “ballistic,” nonscattered, photons. This approach requires knowledge of the time of II.C.5. Monochromatic x rays launch of a very brief pulse of x-ray photons, such as it Use of monochromatic x rays instead of polychromatic might be possible to generate with field-emission x-ray ͑bremsstrahlung͒ x rays41 would limit the radiation exposure sources30 or with a pulsed laser/electron-beam interaction.31 to just the useful x-ray photons, and also make the image

Medical Physics, Vol. 35, No. 6, June 2008 2506 Erik L. Ritman: Reduced x-ray exposure for screening 2506 contrast information more quantitative by eliminating beam hardening. In favorable circumstances this may reduce x-ray exposure. Simulations by Baldelli et al.42 indicated the reduction of radiation in the chest and abdomen to be by 10%–40%, but actually an increase in the head and lumbar spine by up to 45%. This latter effect may well have been due to a suboptimal match between the x-ray photon energy and the average x-ray path length through the body.

III. MINIMIZING X-RAY EXPOSURE BY USE OF NONATTENUATION ASPECTS OF X-RAY/ MATTER INTERACTION TO GENERATE IMAGES Instead of the gray scale within an image corresponding to the traditional attenuation coefﬁcient of tissue within a pixel or voxel, it can also be made to correspond to a param- FIG. 2. Complex refractive index ͑n͒ of breast tissue, where ␦ is contribu- eter related to the refractive index of that piece of tissue, tion by photon refraction and ␤ is contribution from attenuating factors. which can be expressed as the difference from the refractive Note that at 60 keV ␦ contributes 104 times the value of ␤. ͑Figure modiﬁed index of water. with permission from Ref. 51.͒

III.A. Complex refractive index cially at lower energy x-ray photon energy, are currently The complex refractive index ͑n͒ of x rays passing used to convey this small difference in refractive index. through matter can be expressed43 as Figure 2 illustrates that the refractive index for clinically relevant x rays through ͑breast͒ tissue theoretically provides n =1−␦ − i · ␤, ͑3͒ orders of magnitude greater contrast than does attenuation, 49 where the “imaginary” part represents the attenuation ͑␤͒, especially of low atomic weight elements. Moreover, the ͑␦͒ amount of x-ray exposure needed to obtain a usable image and the real part represents refraction . The refractive in- 50 ␧ should also be greatly reduced relative to attenuation-based dex of x ray in matter is very close to unity. If is the 15 dielectric function of matter, then imaging. However, because phase is a concept which as- ͱ ͱ sumes an ensemble of x-ray photons, its use inevitably in- n = ␧ = 1−␹ Ӎ 1−␹/2, ͑4͒ volves a number of photons per image pixel. The reduction in radiation exposure, therefore, may not be as great as might where ␹ is the susceptibility, which is very small because be expected from the magnitudes of ␦ versus ␤ when change ␹=e2␳/͑␲m␯2͒, e is the electron charge, ␳ is electron density in phase is used to make an image. in the material, m is electron mass, and ␯ is the frequency of Although monochromatic x rays emitted from a very the x ray. small focal spot or from a large, but very distant x-ray source Refraction should not be confused with diffraction,44 ͑such as can be achieved with a synchrotron͒ can generate which typically involves change of direction of the x-ray the coherent x-ray needed for phase-interference-based im- photon by many degrees ͑depending on the spacing between aging, conventional polychromatic x ray generated with rela- atoms encountered by the x-ray photons͒, rather than very tively large focal spots can be used.51 small fractions of a degree as occurs with refraction.45 None- Four general approaches to utilizing x-ray refraction are theless, the two are related.46 The refractive index of x ray is ͑␷ ͒ as follows: directly related to the phase velocity phase of x ray, ͑␷ ͒ ͑ ͒ whereas the group velocity group of radiation is the velocity i Refraction of the x rays, especially at sites of very with which energy propagates. Group velocity relates to rapid change in refractive index ͑such as occurs at the phase velocity as47 edges of tissue fibers or at surfaces of small ducts and blood vessel walls͒52 results in edge enhancement ␷ = c2/␷ , ͑5͒ group phase ͑e.g., much like an optical caustic͒ at some distance ␷ ͑ ϫ −6͒ ␷ ͑ 45 so that if phase=c 1+1.5 10 at 60 keV, then group=c 1 beyond the refraction site. This approach, called by −1.5ϫ10−6͒. some diffraction enhanced imaging ͑DEI͒, is probably This means that as an x-ray photon traverses 1 mm of a limited to imaging several centimeters of tissue depths vacuum in approximately 3.3ϫ10−12 s, i.e., 3.3 picosec- and tissues in which adjacent tissues have marked dif- onds, the delay to be expected after a 60 keV x-ray photon ferences in refractive index properties, such as can be traverses 1 mm of water is 5ϫ10−18 s, and at 511 keV this the case in cartilage in joint spaces of fingers or toes, difference is 2ϫ10−21 s! Because of this minuscule differ- and in fibro-vascular microstructures of breast ence, phase interference, as may be manifested in Moiré pat- tissue.53 terns or as development of optical caustics48 ͑much like the ͑ii͒ Differences in phase shift that occur due to passage bright lines at the bottom of a wavy swimming pool͒, espe- through materials of different refractive indices can be

Medical Physics, Vol. 35, No. 6, June 2008 2507 Erik L. Ritman: Reduced x-ray exposure for screening 2507

used to cause Moiré-type patterns when “mixed” with III.B. Direct measurement of spatial distribution of a reference beam such as in the Bonse-Hart interfer- transit times ometer principle.54 The Moiré pattern can be mathematically “unraveled” to provide a map of the phase The fourth, and perhaps the ultimate, goal might be to shift distribution. This works well for a small thick- directly measure the spatial distribution of the transit times ness of tissue in which a relatively small number ͑e.g., of individual x-ray photons. As the velocity of x ray through less than ten͒ of phase shifts occur ͑and hence can be water differs little from that through air, then imaging of just accounted for͒ but, after passage through 30 cm of the presence or absence of tissue at 1 mm resolution would tissue the amount of phase shift, combined with the require time discriminations in the attosecond ranges, and shorter photon wavelength needed to provide ad- that is not technologically practical at the clinical x-ray level equate penetration of the body, would make “unravel- at present. Nonetheless, this approach seems to have poten- ing” of the phase shift quite challenging. tial for so dramatically expanding use of clinical x-ray imaging that it is worth exploring in some detail, especially as A variant of this method involves use of Talbot grating technology continues to develop rapidly at the rate described interferometers placed on the detector side, but adjacent by Moore’s law, i.e., doubling in speed or capacity every ͑ ͒ to, the person i.e., the phase grating and the other just year and a half.56 State-of-the-art streak cameras have tem- ͑ ͒ 55 in front of the detector i.e., the absorption grating . poral resolution of 200–300 femtoseconds,57 so development The phase interference may be finer than the pixel reso- of a technique to decrease this a thousand-fold would require lution of an area detector, so that an additional absorp- 15 years to achieve if Moore’s law is also applicable to this tion grating with a suitable pitch put in front of the de- technology and holds over that period of time. tection plane would allow the detection of intensity The overwhelming advantage of velocity measurement variations that correspond to the derivative of the wave would be that only one transmitted photon would provide front phase taken along the direction perpendicular to this measurement ͑although, as will be shown later, the delay the grating lines. This technique can be combined with a of arrival of several transmitted photons would need to be phase-stepping method, which involves several expo- measured to provide an acceptable degree of certainty͒, sures which differ in phase such that any nonuniform whereas attenuation estimation needs more than 104 photons intensities and in-line phase contrast causing edge- to be transmitted to provide a useful ͑signal-to-noise͒ mea- enhancement are eliminated. surement per picture element ͑pixel͒ in the detector.15 Hence, ͑iii͒ A third, conceivable, approach is to cyclically modu- the exposure for time-of-flight-delay imaging could poten- late the illuminating x-ray flux with a cycle duration tially require only one ten-thousandth the radiation needed ͑i.e., wavelength͒ very much longer ͑e.g., ϫ1010͒ than for conventional, attenuation-based x-ray imaging. an x-ray photon wavelength. The Moiré pattern result- Two ways in which time-of-flight measurements might be ing from the refraction of these waves would be more made are illustrated in Fig. 3. One is to launch a very brief, manageable in terms of fewer phase “wraparounds.” well-characterized x-ray pulse at a precisely known time and The downside of this approach is that a sufficient then measure the precise arrival time at a detector. The other number of photons ͑N͒ would be needed, per modu- is to use a positron annihilation source of gamma rays which lation wavelength, to provide the needed sensitivity to launches two photons at exactly the same time in essentially detect the small phase shift ͑⌬␾͒. To measure the opposite directions, one to a reference detector and the other phase difference between the two trains of n x-ray through the subject and then to the imaging detector. In both pulses ͑for the purposes of illustration, each with a cases, the difference in time between the launch and detec- Gaussian distribution of N photons͒, the number of tion of the x-ray photon then provides the time-of-flight de- photons needed to detect a phase difference ͑⌬␾͒ be- lay of the photon. However, the positron/electron annihila- tween the two identical trains of pulses is tion approach using a “mirror image” reference detector array is almost certainly not practical for two reasons. One is that at that photon energy there is only a very small difference in the photon velocity as it passes through matter and ⌬␾ =FWHM/͑2.355ͱN · n͒, ͑6͒ second, the fact that the gamma ray photon pairs do not travel in exactly opposite directions. This deviation from where FWHM is the duration of the pulse of x ray at the 180° can be as much as 30 m radians which at 60 cm ͑if a half-maximum intensity of each pulse. Thus, for a point source is used to illuminate a 30 cm diameter torso͒ phase-shift through 1 mm water to be detected ͑5 translates to 18 mm ͑although statistically this might be half ϫ10−18 s͒, this can be achieved with a train of ten that͒––resulting in an unacceptable blurring of the image, let pulses, each with a 10−15 s FWHM x-ray pulse dura- alone the added uncertainty in time delay resulting from the tion containing N=1000 photons. This involves detec- up to 0.27 mm longer path length. However, if the reference tion of 10,000 photons/detector pixel––which is the detector is positioned close to the gamma ray source, then it same as regular attenuation-based imaging. The only could be used to provide a timing signal for individual anni- advantage with this method would be that there would hilations, resulting in a gamma ray pair. In this approach, a be increased contrast between low-Z elements. source generating 6ϫ1010 photons/s would ensure illumi-

Medical Physics, Vol. 35, No. 6, June 2008 2508 Erik L. Ritman: Reduced x-ray exposure for screening 2508

FIG. 3. Two approaches to time-of-ﬂight x-ray imaging. Left panel: a very brief x-ray pulse is launched and the change in time of arrival of the x ray at the detector used to generate the image. Right panel: a positron annihilation results in two gamma ray photons which are launched simultaneously in opposite directions. The difference in time of detection between the reference and imaging detector pair is the signal used to generate the image.

nation of each pixel in the detector array with at least five to have several “hits” before others have even one hit. If the photons within 100 ms ͑see the next sections for details of number of detected hits in a detection pixel follows a Pois- several issues related to characteristics of the x-ray detection son distribution with a mean dependent on the number of process which require x-ray exposure to be greater than photons that survive and are detected, then needed to just overcome the attenuation by the body͒. P͑x͒ = e−NdNdx/x !, ͑7͒ There are three major reasons why more than a single photon needs to enter a detector pixel, thereby somewhat where Nd is the mean number of photons detected in each reducing the exposure advantage of the time-of-flight pixel, and x is the thickness of the transradiated object. method. The number detected follows a binomial distribution, dependent on the number that survive ͑Nd͒ so that the prob- III.B.1. Spatial heterogeneity of illumination of the ability of detection ͑P͒ is x-ray detector areas P͑Nd͒ =pdNd͑1−pdN−Nd͒, ͑8͒ If the x-ray or positron-emitting source is effectively a single point source of x ray generating a random distribution where pd=detection probability ͑or detector efficiency͒, and of photons in 4␲ steradians, then, as illustrated schematically N is the number of photons that survive with the number that in Fig. 4, some detector pixels in the detector array are likely survive passing through the chest following a binomial dis- ␮ tribution, then, depending on No, the absorption parameter , and the thickness x, then ␮ ␮ P͑N͒ = ͑e− x͒N͑1−e− x͒No−N. ͑9͒ Table I shows how the combination of attenuation by body thickness, the efficiency of the detector, and launched number of photons combine to influence the percentage of pixels that detect fewer than 5 photons. If we tolerate that 0.01% of Ͻ / FIG. 4. If each pixel in this 9-pixel detector array has an equal chance of the detector pixels detect 5 photons pixel, this means that being hit by a random x-ray photon emitted from a point x-ray source, and a 10002 array of detector elements would have 100 pixels detection efficiency is 100%, then approximately double the number of pho- each receiving less than 5 photons. For this array, an x-ray tons are needed to be reasonably sure that each pixel receives at least one detection efficiency of 70% and imaging through a 10 cm photon. The panels show the distribution of the number of detected photons that might occur after the array is exposed by the indicated number of tissue path length, this would mean that if we accept 100 photons. pixels with less than five detections would require launching,

Medical Physics, Vol. 35, No. 6, June 2008 2509 Erik L. Ritman: Reduced x-ray exposure for screening 2509

TABLE I. Each detector pixel should detect at least one photon to prevent “dead” spots in the image. The random spatial distribution of photons ͑see Fig. 4͒, attenuation of photon flux by the body, and the inefficiency of the detector combine to decrease the chance of a detector pixel detecting an x-ray photon. This decrease is mitigated by increasing the x-ray flux destined for each typical detector pixel. The numbers in bold indicate those conditions for which less than 0.01% of detector pixels each detect less than five photons.

X-ray ﬂux mean number of photons aimed at 1 detector pixel 60 80 100

Efﬁciency of detector fraction of 0.5 0.7 0.9 0.95 0.5 0.7 0.9 0.95 0.5 0.7 0.09 0.95 transmitted photons detected by detector Attenuation by body thickness Percent of detector pixels with Ͻ5 detections 5 cm 0.4 0.01 0.00 0.00 0.02 0.00 0.00 0.00 0.00 0.00 0.00 0.00 10 cm 9.7 1.4 0.14 0.08 2.2 0.12 0.00 0.00 0.42 0.00 0.00 0.00 15 cm 41 18 6.4 4.9 21.0 5.6 1.17 0.77 9.7 1.53 0.18 0.10 20 cm 73 52 32 30 57 33 17 15 42 19 8 6 25 cm 97 87 62 60 76 66 48 33 73 52 36 32

on average, 100 photons at each detector pixel, i.e., 1% of annihilation case, the detection in the reference detector͒ the number of photons needed for attenuation-based imag- triggers the stop-clock of the detection device. If the launch ing. This random pixel exposure effect can be largely elimi- time of each x-ray photon also turns off the detection process nated if a scanning x-ray source illuminates one detection after a preset time interval, then for a number of photons pixel pair at the time and it moves to the next pixel imme- with a time distribution of the chance ͑P͑t͒͒ that a photon is diately after an x-ray photon is detected. However, if a me- detected at time t is chanical scanning process is involved, this would almost cer- ␮␷ tainly incur a clinically unacceptable increase in the duration P͑t͒ = k͑1−e− gt͒, ͑10͒ required to acquire such an image. where k is a constant related to the detection efficiency of the detector mechanism, ␮ is attenuation coefficient of the de- III.B.2. X-ray detector time-of-detection uncertainty ␷ ͑ tector crystal, g is the group velocity of x ray i.e., photon A second issue is that the detectors have an inherent delay velocity͒ in the detecting mechanism, and t is the time after between x ray entering into the detector and its detection. entry into the crystal. This delay overwhelms the temporal resolution of a detected The change in probability of detection, resulting from a ␮␷ event. Figure 5 schematically illustrates the problem in terms delayed arrival by ␦t,is␦P=ke− gt␦t. If the detector crystal of the probability of detection in a detector as a function of is 1 cm in length, ␮=10 cm−1, the velocity of the x ray ␷ ϫ 10 / depth into the detector Fig. 5. Hence, we have uncertainty in through the crystal is g =3 10 cm s, and a time differ- the time of detection due to this trade-off between depth of ential of 10−15 s is to be determined, then the difference in penetration and probability of detection with depth. If, how- number of counts due to the delay in the difference “signal” ever, the detection duration is kept fixed from the time of is approximately 3ϫ104. Hence, at least 104 detections x-ray launch, then the situation depicted schematically in would be needed, which requires at least as many photons as Fig. 6 results if each photon’s launch ͑or in the positron would attenuation-based x-ray imaging. Moreover, this is an ambiguous situation because this approach cannot distinguish between a decrease in detected photons due to increased attenuation by the subject or whether there is an increased delay of the photon arrival. However, as illustrated in Fig. 7, if we use a detector system that can detect the depth of penetration of the photon, such as would be func- tionally equivalent to a CCD coupled to a microchannel plate intensifier ͑which is exposed to x ray side-on͒, we can have an effectively infinitely thick detector that captures all photons entering it, but without loss of timing information because each depth of interaction can be accounted for in terms of added delay due to passage through that distance within the detector. The time uncertainty is now largely determined by the thickness of each microchannel and the size of the CCD detection pixel––which can be of the order of 10 ␮m, and by the delay between the interaction of the x-ray photon FIG. 5. As detector thickness increases the probability of a photon being ␮ and the microchannel and subsequent electron transfer into detected increases in a ͑1−e− x͒ relationship, where ␮ is the attenuation ϫ −14 coefficient of the detector material. However, the thicker the detector, the the CCD pixel. This could therefore result in 3 10 s accuracy of the estimated arrival time of the photon falls off hyperbolically. time-resolution steps. This time discrimination alone may be

Medical Physics, Vol. 35, No. 6, June 2008 2510 Erik L. Ritman: Reduced x-ray exposure for screening 2510

FIG. 8. If a brief bunch of x-ray photons is allocated a time of occurrence FIG. 6. If the x-ray detection process of a detector is cut off after a short with a clock cycle time ͑that is greater than the time between photons͒, then time interval ␶ from a selected time zero, then the total number of photons a “binning” transformation of the bunch’s frequency/time distribution occurs ͑area under curve͒ detected decreases with delay of the x-ray pulse ͑left which affects the computed mean time of arrival of the photons. However, if panel͒. Hence, the difference in the area under the curves is related both to the x-ray photon bunch’s time distribution is well known, then the transfor- delay of the pulse due to any difference in attenuation ͑right panel͒ within mation of the time distribution allows computation of the arrival time with the subject. subcycle time precision. enough to distinguish different x-ray transit times through hilation approach, then one time-of-flight explains 64% of the torso, but not quite enough to detect a 100 ␮m differ- the variability in the other. Table II shows that a tenfold ence in tissue path length. increase of temporal resolution can be achieved with an exposure sufficient to result in an average of 128 detected III.B.3. Precision of time-delay detection photons/detector element. Thus, even if extra photons are A third issue is the need for increased number of x-ray needed to increase the clock-cycle precision by one order of photon detections if the precision of the “time-of-detection” magnitude, this two decade “inefficiency,” combined with a has to be better than one clock cycle interval ͑e.g., 3 25-fold ͑128/5͒ increase needed to ensure at least 128 pho- −14 ϫ10 s͒. Super-resolution has been achieved with analog- tons for each detector pixel, would still result in a 40-fold to-digital converter systems by “dithering” the input signal ͑105 /250͒ lower x-ray exposure than achievable with current with a well-described signal perturbation, e.g., by the addi- attenuation-based systems. If a sufficiently fast clock cycle is 58 tion of a Gaussian distribution of noise. The duration and available ͑thereby eliminating the need to use the dithering time-intensity profile of the x-ray pulse, whether due to a principle͒, then a 200-fold lower x-ray exposure would be 29 field-emission burst or due to the time-intensity character- plausible––which would allow reducing the voxel size to istics of a combined laser pulse and electron beam system, or ͑100 ␮m͒3 without an increase in x-ray exposure currently due to the finite thickness of the positron emitter source, experienced with MDCT scanners. transforms ͑by virtue of the temporal discretization͒ into a postdigitized time-intensity profile as illustrated schematically in Fig. 8. For situations in which the time difference of III.B.4. Temporal resolution interest is less than the clock precision, we can use the Temporal resolution requirements are the same as those known time distribution of sequential photons to provide for attenuation-based x-ray imaging. However, as the radia- “super-resolution” time difference detection as follows. If the tion exposure needed is reduced several fold, the exposure stochasticity in the time-of-flight for the multiple pairs of time needed to generate an image should potentially also be particles is approximated by a Gaussian distribution––with a reduced, although this and the repetition rate of image gen- standard deviation equal to a constant times the clock preci- eration would depend very much on the technology involved sion, and we assume a correlation of 0.80 between the refer- in implementing the time-of-flight-based x-ray imaging ence and imaging detectors in the case of the positron anni- method.

IV. CONCLUSION Current, attenuation-based x-ray imaging methods cannot be expected to increase much more in spatial and contrast resolution due to the undesirable x-ray exposure conse- FIG. 7. If the depth ͑x͒ of x-ray interaction into a detector can be detected, quences. If time-of-ﬂight x-ray imaging can be developed for /␷ ␷ then the time of entry into the detector can be calculated as x g, where g clinical applications, the power of x-ray imaging could be is the speed of x ray through the detector. The precision of this distance measurement would be less than 10 ␮m ͑i.e., Ͻ33 fs͒ if a microchannel greatly enhanced by virtue of its potential for a two decade platelike arrangement were used. reduction of radiation exposure at current image resolutions

Medical Physics, Vol. 35, No. 6, June 2008 2511 Erik L. Ritman: Reduced x-ray exposure for screening 2511

TABLE II. For the positron annihilation approach a pair of photons is emitted in opposite directions from a source of ﬁnite thickness such that the arrival times of the photons at the detector pixel has a Gaussian distribution. As the number of detected event pairs is increased, the discrimination of time differences ͑⌬t͒ between the reference detector pixel and “imaging” detector pixel can be a fraction of the time resolution ͑␦t͒ of the clock used to measure the times of the event occurrences.

# Observed events pairs 2 4 8 16 32 64 128 Discrimination ⌬t/␦t 0.75 0.55 0.4 0.3 0.2 0.15 0.10

or its potential for resolution down to 100 ␮m without in- Medical Devices Agency, London, 2000. 13 creasing the radiation exposure beyond that currently expe- “Statistical research and applications. Probability of developing or dying ␮ of cancer,” National Cancer Institute: http://srab.cancer.gov/devcan, Na- rienced at 600 m voxel resolution. tional Cancer Institution Vol. 206, pp. 541–545 ͑1983͒. 14D. R. White, L. H. Peaple, and T. J. Crosby, “Measured attenuation coefficients at low photon energies ͑9.88–59.32 keV͒ for 44 materials and ACKNOWLEDGMENTS tissues,” Radiat. Res. 84, 239–252 ͑1980͒. 15 The author thanks Professor Dr. Ulrich Bonse, Technical J. W. Motz and M. Danos, “Image information content and patient exposure,” Med. Phys. 5, 8–22 ͑1978͒. University Dortmund, Dortmund, Germany; Professor Dr. 16L. Grodzins, “Optimal energies for x-ray transverse tomography of small Winfried Schuelke, Institute of Physics, University of Dort- samples,” Nucl. Instrum. Methods 206, 541–545 ͑1983͒. mund, Dortmund, Germany; Professor James L. Ritman, 17M. J. Friedrich, “Studying cancer in 3 dimensions: 3-D models foster new University of Bochum and Research Center Jülich, Institute insights into tumorigenesis,” JAMA 290, 1977–1979 ͑2003͒. 18T. Behrenbeck, J. H. Kinsey, L. D. Harris, R. A. Robb, and E. L. Ritman, for Nuclear Physics, Jülich, Germany, for their input on some “Three-dimensional spatial, density and temporal resolution of the dy- of the x-ray/matter interaction issues; Dr. Vernon S. Pankratz namic spatial reconstructor,” J. Comput. Assist. Tomogr. 6, 1138–1147 and Mr. Jeffrey Slezak of the Mayo Clinic Biostatistics Sec- ͑1982͒. 19 tion for performing the statistical analysis underlying the A. Rose, “Sensitivity performance of the human eye on an absolute scale,” J. Opt. Soc. Am. 38, 196 ͑1948͒. analysis illustrated in Tables I and II, and Ms. Mara Lukenda 20D. A. Chesler, S. J. Riederer, and N. J. Pelc, “Noise due to photon count- for typing and formatting this manuscript. ing statistics in computed tomography,” J. Comput. Assist. Tomogr. 1, 64–74 ͑1977͒. ͒ 21 a Telephone: 507-255-1939; Fax: 507-255-1935. Electronic mail: P. D. Johns and M. Yaffe, “Scattered radiation in fan beam imaging sys- [email protected] tems,” Med. Phys. 9, 231–239 ͑1982͒. 22 1H. L. Baker, Jr., “The impact of computed tomography on neurological P. S. Rao and R. J. Alfidi, “The environmental density artifact: A beam- practice,” Radiology 116, 637–640 ͑1975͒. hardening effect in computed tomography,” Radiology 141, 223–227 2H. Nishimura and O. Miyazaki, “CT system for spirally imaging subject ͑1981͒. on a moveable bed synchronized to x-ray tube revolution,” U.S. Patent 23A. L. C. Kwan, J. M. Boone, and N. Shah, “Evaluation of x-ray scatter 4,789,929 ͑1988͒. properties in a dedicated cone-beam CT breast CT scanner,” Med. Phys. 3C. Kondo, S. Mori, M. Endo, K. Kusakabe, K. Suzuki, N. Hattori, and M. 32, 2967–2975 ͑2005͒. Kusakabe, “Real-time volumetric imaging of human heart without elec- 24J. Persliden and G. A. Carlsson, in Developments in Radiography and trocardiographic gating by 256-detector row computed tomography: Ini- Fluoroscopy Imaging, edited by H. Cole and C. P. Lawinski ͑British tial experience,” J. Comput. Assist. Tomogr. 29, 694–698 ͑2005͒. Institute of Radiology, London, 2006͒, Vol. 18, pp. 75–81. 4P. J. Pickhardt, J. R. Choi, I. Hwang, J. A. Butler, M. L. Puckett, H. A. 25E. N. C. Milne, “The role and performance of minute focal spots in Hildebrandt, R. K. Wong, P. A. Nugent, and P. A. Mysliwiec, “Computed roentgenology with special references to magnification,” CRC Crit. Rev. tomographic virtual colonoscopy to screen for colorectal neoplasia in as- Radiol. Sci. 2, 269–310 ͑1971͒. ymptomatic adults,” N. Engl. J. Med. 349, 2191–2200 ͑2003͒. 26G. Bucky, Über die Ausschaltung der Sekunderstrahlen ͑Verhandlung der 5D. F. Yankelevitz, R. Gupta, B. Zhao, and C. I. Henschke, “Small pulmo- Deutsch Rtg Gesellsch, Leipzig: GeorgThieme Verlag, 1913͒, Vol. 9, pp. nary nodules: Evaluation with repeat CT–preliminary experience,” Radi- 30–32. ology 212, 561–566 ͑1999͒. 27R. F. Wagner, G. T. Barnes, and B. S. Askins, “Effect of reduced scatter 6B. Ohnesorge, T. Flohr, R. Fischbach, A. F. Kopp, A. Knez, S. Schroder, content on radiographic information, contrast and patient exposure: A U. J. Schopf, A. Crispin, E. Klotz, M. F. Reiser, and C. R. Becker, “Re- qualitative demonstration,” Med. Phys. 7, 13–18 ͑1980͒. producibility of coronary calcium quantification in repeat examinations 28R. Ning, X. Tang, and D. Conover, “X-ray scatter correction algorithm for with retrospectively ECG-gated multisection spiral CT,” Eur. Radiol. 12, cone beam CT imaging,” Med. Phys. 31, 1195–1202 ͑2004͒. 1532–1540 ͑2002͒. 29S. Surti, J. S. Karp, L. M. Popescu, M. E. Duabe-Witherspoon, and M. 7M. Imaizumi et al., “Radiation dose-response relationships for thyroid Werner, “Investigation of time-of-flight benefit for fully 3-D PET,” IEEE nodules and autoimmune diseases in Hiroshima and Nagasaki Atomic Trans. Med. Imaging 25, 529–538 ͑2006͒. Bomb survivors 55–58 years after radiation exposure,” JAMA, J. Am. 30W. P. Dyke, “Advances in field emission,” Sci. Am. 210, 108–116 ͑1964͒. Med. Assoc. 295, 1011–1022 ͑2006͒. 31W. Leemans, R. Schoenlein, A. Chin, E. Glover, R. Govil, P. Volfbeyn, S. 8L. K. Wagner, P. J. Eifel, and R. A. Geise, “Potential biological effects Chattopadhyay, K.-J. Kim, and C.V. Shank. “Femtosecond x-rays from following high x-ray dose interventional procedures,” J. Vasc. Interv. Ra- 90° Thomson scattering,” Proc. IEEE Particle Accelerator Conf. 1, 174– diol. 5, 71–84 ͑1994͒. 176 ͑1995͒. 9R. L. Morin, T. C. Gerber, and C. H. McCollough, “Physics and dosim- 32Z. Parvez, R. Moncada, and M. Sovak, Contrast Media: Biologic Effect etry in computed tomography,” Cardiol. Clin. 21, 515–520 ͑2003͒. and Clinical Application ͑CRC Press Inc., Baton Rouge, 1987͒, Vol. I–III. 10A. J. Einstein, M. J. Henzlova, and S. Rajagopalan, “Estimating risk of 33H. D. Zeman and D. P. Siddons, “Contrast agent choice for intravenous cancer associated with radiation exposure from 64-slice computed tomog- coronary angiography,” Nucl. Instrum. Methods Phys. Res. A 291, 67–73 raphy coronary angiography,” JAMA 298, 317–323 ͑2007͒. ͑1990͒. 11P.C. Shrimpton, M.C. Hillier, M.A. Lewis, M. Dunn, “Doses from com- 34W. H. Shehadi and G. Toniolo, “Adverse reactions to contrast media,” puted tomography ͑CT͒ examination in the UK–2003 Review,” National Radiology 137, 299–302 ͑1980͒. Radiological Protection Board, Chilton, Dideo, Oxon OX110RQ, 2003. 35H. T. Abada, C. Larchez, B. Daoud, A. Sigal-Cinqualbre, and J. F. Paul, 12N. L. Keat, “Real time CT and CT fluoroscopy. Report MDA/00/10,” “MDCT of the coronary arteries: Feasibility of low-dose CT with ECG-

Medical Physics, Vol. 35, No. 6, June 2008 2512 Erik L. Ritman: Reduced x-ray exposure for screening 2512

pulsed tube current modulation to reduce radiation dose,” AJR, Am. J. 1361–1368 ͑2004͒. Roentgenol. 186, S387–S390 ͑2006͒. 47G. Woan, The Cambridge Handbook of Physics Formulas ͑Cambridge 36W. Huda, E. M. Scalzetti, and G. Levin, “Technique factors and image University Press, Cambridge, 2000͒, p. 219. quality as functions of patient weight at abdominal CT,” Radiology 217, 48Van Nostrand’s Scientiﬁc Encyclopedia, 5th ed., edited by D. M. Consi- 430–435 ͑2000͒. dine ͑Van Nostrand Reinhold Co., New York, 1976͒. 37 W. A. Kalender, H. Wolf, C. Suess, M. Gies, H. Greess, and W. A. Bautz, 49A. Momose and J. Fukuda, “Phase-contrast radiographs of nonstained rat “Dose reduction in CT by on-line tube current control: Principles and cerebellar specimen,” Med. Phys. 22, 375–379 ͑1995͒. ͑ ͒ 50 validation on phantoms and cadavers,” Eur. Radiol. 9, 323–328 1999 . T. J. Davis, D. Gao, T. E. Gureyev, A. W. Stevenson, and S. W. Wilkins, 38 M. D. Harpen, “A single theorem relating noise and patient dose in com- “Phase-contrast imaging of weakly absorbing materials using hard puted tomography,” Med. Phys. 26, 2231–2234 ͑1999͒. ͑ ͒ ͑ ͒ 39 x-rays,” Nature London 373, 595–598 1995 . R. M. Lewitt, “Processing of incomplete measurement data in computed 51R. A. Lewis, “Medical phase contrast x-ray imaging: Current status and tomography,” Med. Phys. 6,412–417͑1979͒. ͑ ͒ 40 future prospects,” Phys. Med. Biol. 49, 3573–3583 2004 . A. Faridani, F. Keinert, F. Naterrer, E. L. Ritman, and K. T. Smith, in 52T. Weitkamp, C. David, C. Kottler, O. Bunk, and F. Pfeiffer, “Tomogra- Signal Processing Part II (IMA Control Theory and Applications), edited phy with grating interferometers at low-brilliance sources,” Proc. SPIE by F. A. Grunbaum, J. W. Helton, and P. Khargonekar ͑Springer-Verlag, 6318, 63180S ͑2006͒. New York, 1990͒, Vol. 23, pp. 241–255. 53T. Takeda, A. Momose, J. Wu, Q. Yu, T. Zeniya, T.-T. Lwin, A. 41F. A. Dilmanian, “Computed tomography with monochromatic x-rays,” Yoneyama, and Y. Itai, “Vessel imaging by interferometric phase-contrast Am. J. Physiol. Imaging 7, 175–193 ͑1992͒. 42 x-ray technique,” Circulation 105, 1708–1712 ͑2002͒. P. Baldelli, A. Taibi, A. Tuffanelli, and M. Gambaccini, “Dose compari- 54 son between conventional and quasi-monochromatic systems for diagnos- F. Beckmann, U. Bonse, F. Busch, and O. Günnewig, “X-ray microto- ͑ ͒ tic radiology,” Phys. Med. Biol. 49, 4135–4146 ͑2004͒. mography microCT using phase contrast for the investigation of organic 43 matter,” J. Comput. Assist. Tomogr. 21, 539–553 ͑1997͒. B. L. Henke, E. M. Gullikson, and J. C. Davis, “X-ray interactions: pho- 55 toabsorption, scattering, transmission, and reﬂection at E T. Weitkamp, A. Diaz, B. Nöhammer, F. Pfeiffer, T. Rohbeck, P. Cloetens, =50–30 000 eV , Z=1–92,” At. Data Nucl. Data Tables 54, 181–342 M. Stampanoni, and C. David, “Hard x-ray phase imaging and tomogra- ͑ ͒ ͑1993͒. phy with a grating interferometer,” Proc. SPIE 5535, 137–142 2004 . 56 44J. Kosanetzky, B. Knoerr, G. Harding, and U. Neitzel, “X-ray diffraction G. E. Moore, “Cramming more components onto integrated circuits,” measurements of some plastic materials and body tissues,” Med. Phys. Electronics 38, 114–117 ͑1965͒. 57 14, 526–553 ͑1987͒. C. Martel, S. Fourmaux, L. Lecherbourg, H. Bandulet, and J. C. Kieffer, 45M. N. Wernick, O. Wirjadi, D. Chapman, Z. Zhong, N. P. Galatsanos, Y. “New ultra fast x-ray streak camera for the advanced laser light source Yang, J. G. Brankov, O. Oltulu, M. A. Anastasio, and C. Muehleman, facility,” Proc. SPIE 6703, 67030K ͑2007͒. “Multiple-image radiography,” Phys. Med. Biol. 48, 3875–3895 ͑2003͒. 58H. Shimizu, Y. Iikura, Y. Sasano, and N. Takeuchi, “Resolution improve- 46A. M. Anastasio and D. Shi, “On the relationship between intensity dif- ment in an analog-to-digital converter by the superposed dither signal,” fraction tomography and phase-contrast tomography,” Proc. SPIE 5535, Electron. Commun. Jpn. 64,1–8͑1981͒.

Medical Physics, Vol. 35, No. 6, June 2008 Targeted radionuclide therapy ͒ Lawrence E. Williamsa Radiology Division, City of Hope National Medical Center, Duarte, California 91010 ͒ Gerald L. DeNardob Internal Medicine, University of California Davis Medical Center, 1508 Alhambra Boulevard, Suite 3100, Sacramento, California 95816 ͒ Ruby F. Meredithc Department of Radiation Oncology, Wallace Tumor Institute WTI No. 117, University of Alabama at Birmingham, Birmingham, Alabama 35294 ͑Received 4 March 2008; revised 22 April 2008; accepted for publication 10 May 2008; published 12 June 2008͒ Targeted radionuclide therapy ͑TRT͒ seeks molecular and functional targets within patient tumor sites. A number of agents have been constructed and labeled with beta, alpha, and Auger emitters. Radionuclide carriers spanning a broad range of sizes; e.g., antibodies, liposomes, and constructs such as nanoparticles have been used in these studies. Uptake, in percent-injected dose per gram of malignant tissue, is used to evaluate the specificity of the targeting vehicle. Lymphoma ͑B-cell͒ has been the primary clinical application. Extension to solid tumors will require raising the macroscopic absorbed dose by several-fold over values found in present technology. Methods that may effect such changes include multistep targeting, simultaneous chemotherapy, and external sequestration of the agent. Toxicity has primarily involved red marrow so that marrow replacement can also be used to enhance future TRT treatments. Correlation of toxicities and treatment efficiency has been limited by relatively poor absorbed dose estimates partly because of using standard ͑phantom͒ organ sizes. These associations will be improved in the future by obtaining patient-specific organ size and activity data with hybrid SPECT/CT and PET/CT scanners. © 2008 American Association of Physicists in Medicine. ͓DOI: 10.1118/1.2938520͔

Key words: radionuclide therapy, antibodies, absorbed dose

I. PRESENT CLINICAL SITUATION curs postsurgery. For example, intraperitoneal applications of antibodies to ovarian cancer1 and directly into brain tumor A possible imaging result with a cancer patient is shown in 2 sites are currently being evaluated. Fig. 1, whereby multiple lesions appear using nuclear ͑or Many agents have been investigated as possible tumor- other͒ technology. It is important to find a method to target targeting vehicles. Some, such as antibodies, may also have both seen and unseen tumor locations anywhere in the body. intrinsic antitumor effects. While the following will describe It would be desirable that this strategy be as specific as pos- radionuclide-effected therapy, antitumor chemical species sible to the tumor with minimal collateral toxicity. Targeting may also be loaded into some tumor seekers such as lipo- of this sort is measured in units of percent-injected dose per somes. A partial list is given in Table I that includes the gram of tissue ͑% ID/g͒. The mouse would generally be the traditional use of the 131I ion as postsurgery treatment of test species for preclinical development of radiopharmaceu- choice for some types of thyroid cancer. This compilation is ticals for targeted radionuclide therapy ͑TRT͒. Following IV injection into a 20 g animal, nonspecific uptake should be capable of expansion using either further engineering of the agents listed, direct invention of novel entities, or combinations of multiple technologies; e.g., liposomes with antibod- 100% ID/20 g=5% ID/g ͑1͒ ies on their outer surface. Optimization of tumor targeting is complicated due to the for any of the tissues. Extrapolating the calculation to a number of possible agents. Using an antibody as an example, 70-kg man, the comparable nontargeting value is a single amino acid exchange can cause order-of-magnitude 13 1.4% ID/kg. Tumor uptakes ͑u͒ exceeding these respective variation in blood circulation times of the mutated protein. tissue sample numbers can then be taken as evidence of spe- Since there are several thousand amino acids in the original cific targeting of the agent of interest. Tumor absorbed dose antibody sequence and essentially 20 possible amino acid rate for particulate emissions is also proportional to the tu- inserts at each location, the number of variations is astro- mor u value so that applicability of uptake to radiotherapy is nomical. Thus, only a very limited subset of all possible direct. agents will ever be investigated experimentally. While intravenous injection is probably the only way to Only four agents have progressed to FDA-approved clini- target lesions at any site, direct injections may be used to cal therapies as shown in Table II. Note that two of these enhance tumor accumulation. Typically, this intervention oc- therapies involve direct catheter injection into tumor sites in

͑ ͒ Increasing injected total activity A0 cannot be used to arbitrarily raise tumor absorbed doses because of limits set by normal organ toxicities.17 Bone marrow is the most probable absorbed dose-limiting tissue in TRT when the activity is injected IV. Presently, red marrow ͑RM͒ absorbed dose is difﬁcult to estimate due to uncertainty in patient-speciﬁc information. Recall that internal emitter absorbed dose ͑D͒ is usually estimated by the simple vector equation

A, ͑2͒˜ ء D = S

FIG. 1. Anterior gamma camera image of a medullary thyroid cancer patient. Image obtained at 48 h post-IV injection of 5 mCi ͑185 MBq͒ of 111In-cT84.66 anti-CEA antibody. Multiple bone lesions are seen in the pel- where S is a rectangular matrix relating source organs to vis and both femurs. Part of the right lobe of liver appears superiorly ͑see targets and Ã is a vector containing the integrals of source ͒ Ref. 37 . organ activities ͑A͒ over time. S contains information on the radionuclide’s emission energies and probabilities as well as the geometry of the source and target organs. For particulate the liver. Intravenous injections have been limited to treat- emitters that stop in the source, we concern ourselves with ment of lymphoma using anti-B cell ͑anti-CD20͒ monoclonal diagonal elements of S where source and target are the same antibodies. tissue. In this case, S matrix elements are inversely proportional to the total organ mass. For red marrow, this parameter II. CURRENT LIMITATIONS is unknown since the individual patient has genetic, age- Because of the small number of FDA-approved agents, it related, and therapy-associated variability. One would expect is clear that significant constraints have hindered develop- that the RM mass would be significantly different from—and ment of TRT. Primarily, the limitation has been relatively probably lower than—values found in phantom-based ab- poor tumor uptake. This has led to correspondingly low absorbed dose estimation algorithms. There is no present-day sorbed doses and lack of tumor response. Table III contains routinely used method for estimating this unknown tissue estimated absorbed doses for a standard phase III lymphoma mass value. Thus, phase I TRT trial escalation has generally trial14 and an experimental colon cancer therapy.16 These not been based on absorbed dose toxicity but usually on the protocols were at previously determined maximal values of injected activity per meter squared or activity per total body activity per body mass14 or per body surface area.16 Notice mass. Neither of these parameters, which are based on tradi- that both lymphoma and colon cancer regimens have tional chemotherapy treatment planning, has correlated well achieved similar numerical tumor absorbed dose values. with patient marrow toxicity.18 Clinical application of TRT to the former disease state has Given the above constraints, an approximate formula to followed from the relatively high sensitivity of B-cells to estimate the circulating blood contribution to marrow ab- ionizing radiation. sorbed dose has been developed by the AAPM task group19

TABLE I. A partial list of tumor-targeting agents.

Agent Molecular weight ͑Da͒ or physical size Application Representative radiolabels

NaI 154 Da Thyroid cancer ͑follicular and papillary͒ 131I MIBGa 130 Da Neuroendocrine tumors 131I Octreotideb 100 Da As above 90Y, 111In SHALsc Ͻ2 kDa Lymphoma 131I Nucleotidesd 10 kDa Solid tumors 99mTc, 111In Antibodiese 25–150 kDa Lymphomas, solid tumors 90Y and 131I Liposomesf 100 nm Solid tumors 111In, 99mTc Nanoparticlesg 10 nm Solid tumors Morpholinosh 2 kDa Solid tumors 188Re Spheresi 30 ␮m Hepatic lesions 90Y

f aSee Ref. 3. See Ref. 8. g bSee Ref. 4. See Ref. 9. cSee Ref. 5. hSee Ref. 10. d See Ref. 6. iSee Refs. 11 and 12. eSee Ref. 7.

Medical Physics, Vol. 35, No. 7, July 2008 3064 Williams, DeNardo, and Meredith: Targeted radionuclide therapy 3064

TABLE II. FDA-Approved TRT protocols.

Agent Label Disease Method

SIR spheresa ͑plastic͒ 90Y ͑99mTc MAA for images͒ Metastatic liver cancer Catheter via hepatic artery Theraspheresb ͑glass͒ 90Y ͑99mTc MAA for images͒ Primary liver cancer Catheter via hepatic artery Zevalinc ͑Ibritumomab͒ 90Y ͑111In for images͒ B-cell lymphoma IV injection Bexxard ͑Tositumomab͒ 131I B-cell lymphoma IV injection aSee Ref. 11. bSee Ref. 12. cSee Ref. 14. dSee Ref. 15.

Ã͑RM͒ = f Ã͑blood͒ 1500/5000, ͑3͒ ing, testing, and generally enhancing the tumor-targeting ca- * * pability of radiopharmaceuticals. Computer modeling of bio- where f is a fraction on the order of 0.3 and the ratio repre- distributions and comparisons of figures of merit are aspects sents the correction for marrow mass ͑1500 g in a particular of this work relevant to the physicist. This is particularly standard phantom20͒ in a patient with an assumed 5000 g important for solid tumors. Beyond the engineering and in- total blood mass. In the ideal case of no direct marrow tar- ventive phase will be the necessity of establishing improved geting of the radioactive agent or its label, the result of Eq. methods of patient-specific absorbed dose calculations. ͑3͒ is used as an input into Eq. ͑2͒ to estimate total RM These estimates will become more useful when they relate to absorbed dose. voxels rather than whole organ values as indicated above. Issues of accurate absorbed dose estimation have been at Among target tissue calculations, red marrow absorbed dose the heart of TRT since its inception in the 1950s; e.g., there is estimates will continue to be the most important. little knowledge of the absorbed dose to remnant thyroid 131 tissue during I treatment. While MIRD-type calculations III.A. Pharmaceutical development and testing are often used to justify clinical trials to the FDA, use of the associated phantom mass values contained in programs like Engineering is the operative word for the future. TRT MIRDOSE3 ͑Ref. 20͒ and OLINDA ͑Ref. 21͒ cannot be directly agents of the present time are usually constructed by crude applied to a given patient. It has been shown, for example, analogy to naturally occurring entities in the bloodstream of that hepatic and splenic masses may differ by factors of two- common mammals. Protein configurations appear to be one and threefold in individuals undergoing TRT of colon of the most likely for future manipulation. After in vitro test- cancer.22 Patient-specific treatment planning23 requires actual ing, the putative tumor seekers would be evaluated via se- knowledge of patient anatomy ͑organ separations͒ and organ quential animal three-dimensional imaging rather than by sizes ͑masses͒. This problem is thus one of image fusion biodistribution studies as are done today. One particularly whereby the activity found using quantitative nuclear imag- fruitful area of this research would be the use of mouse-sized ing can be assigned correctly to a particular anatomic PET or SPECT scanners to obviate the need for large num- structure. bers of animals being sacrificed at each time point in the biodistribution evaluation. Statistically, this method is also preferred since the same animals are being followed serially. III. FUTURE DEVELOPMENTS Flexibility of usage may favor SPECT over PET in that more Medical physicists can be expected to contribute directly radionuclide labels are available for the former technique. to the growth of TRT in the next 7–10 years. Advances Use of PET scanners requires availability of suitable pos- would be of two distinctly different but complementary itron emitters as labels. Two types of labeling may be antici- types. Initially there will have to be a strategy for develop- pated: Radioiodine and radiometal. In the case of proteins,

90 TABLE III. Comparison of two TRT clinical antibody protocols involving Y. Absorbed doses were computed using the MIRD formalism ͑Refs. 20 and 21͒ and refer to whole organ mean values. Ranges are shown in parentheses. The clinical protocols were at maximum activity per body mass ͑Ref. 14͒ or body surface area ͑Ref. 16͒ determined from previously established hematological toxicity levels.

Tumor absorbed dose RM absorbed dose Liver absorbed dose Agent Disease ͑cGy͒ ͑cGy͒ ͑cGy͒

Zevalina NHL 1484 71 532 ͑61−24 300͒͑18−221͒͑234−1856͒ Ant-CEAb Colon cancer 1320 64 912 ͑46−6400͒͑19−198͒͑534−1719͒ aSee Ref. 14. bSee Ref. 16.

Medical Physics, Vol. 35, No. 7, July 2008 3065 Williams, DeNardo, and Meredith: Targeted radionuclide therapy 3065 there is a developmental advantage in using radioiodines. ciently depleted. It has become conventional to replace plate- Iodine can be directly attached to tyrosine moieties in the lets and white cells in patients undergoing TRT when these amino acid sequence with protein amounts as small as cells are below certain limits. In the future, such procedures 100 ␮g. This is in contrast to the radiometal case where may become economical enough such that the marrow is no milligram amounts are required since a chelator must be first longer the activity-limiting tissue. In that case, other solid attached to the protein. For iodines, the physical half-life of organs such as the kidneys or liver may be considered limit- 124I is 100 h and appears to be a good theoretical choice for ing. This strategy may lead to greater total activities being PET. Limitations of availability and accurate quantitation injected and larger tumor absorbed doses being achieved. have stymied extensive use. Recent work24 has shown that As in the case of external beam, one anticipates that con- measurement of the amount of 124I is possible with a com- siderable effort will be expended to enhance TRT-induced mercial PET imager and human-scale phantoms. absorbed dose by means of circulating chemotherapeutic and Iodination of tumor-tracking agents has one disadvantage. radiation-enhancing agents.28 At present, it is unclear what Because of thyroid needs, multiple enzymes have evolved to chemical dose levels and what timing relative to the IV in- extract iodine atoms from sites on proteins and other agents. jection of the radiotherapeutic agent are optimal. Again, pre- Using an iodinated species for extended periods in vivo may clinical and phase I trials will be needed to evaluate the lead to unwanted targeting of freed activity to stomach, gut, effectiveness of this approach. Because of the multiple pos- and thyroid. Because of this limitation, use of radiometal sible combinations of enhancing and TRT agents, extensive labels of proteins and other entities is expected to increase. animal testing will become more important in the near term. This will require production facilities for 64Cu and 86Y, for Following from the above multiple agent therapies, it is example. With their relatively simple gamma spectra, these probable that future collaborations would be expanded be- labels will probably become the marker of choice in many tween medical oncology and radiation oncology. Historically, preclinical and clinical trials that study entities with rela- chemotherapeutic drugs have been studied using only blood tively rapid biological targeting ͑i.e., biological half-life and excreta chemical measurements. In the next 7–10 years, Ͻ12 h͒. Species that remain in the blood for periods exceed- it would be anticipated that present-day and future chemo- ing one day, however, will remain difficult to label with these therapeutic drugs would be radiolabeled and then followed, radiometals and may require use of 124I. probably with PET scanning, in patients. Because of concern Several ideas have shown promise in the enhancement of that the radioactive tag may affect the biodistribution, label- tumor therapy using IV-injected agents. One of these is the ing will preferably be done by substituting radioactive iso- use of a sequence of steps to optimize the placement of ac- topes into the chemical structure. While organic isotopes 11C, tivity on or within the tumor.25 In this strategy, a large unla- 15O, and 13N are of primary importance, there will be other beled molecule, which is at least partially an antibody to the possible labels such as 18F in the case of 5FU. Availability of tumor-associated antigen, is injected initially. After some local cyclotrons is implicit in this approach due to the short time, and perhaps a clearance step, a low-mass radiolabeled half-lives of the positron labels required. entity is injected. The labeled agent would be an antibody fragment or other small ligand that reacts to the complex of III.B. Improved absorbed dose estimation original antigen and the first large molecule. Since the labeled molecule would be of relatively low molecular weight, Improvement in patient-specific absorbed dose estimates it would diffuse more rapidly to the lesion sites. Such quick will be one outcome achievable by medical physicists in the movement would reduce red marrow absorbed dose induced immediate time frame. This result may be termed a type-II by the circulating activity in the blood.26 Limitations to the absorbed dose estimate whereas the MIRD ͑phantom͒ result 29 method involve the possible increase in the renal absorbed is a type-I calculation. Phantom results will still be needed dose due to the anticipated urinary excretion of the radiola- for FDA approval of the trial; patient-specific calculations beled entity. will evolve to be used to assess clinical outcomes for an A second targeting variation that manipulates the blood individual. In order to achieve such specificity, knowledge of curve of the radiotracer shows significant promise for reduc- the patient’s organ masses and their spatial separations will ing bone marrow toxicities as estimated via Eq. ͑3͒. Here the be essential. clinicians would use an antigen-bearing protein column lo- Instrumentation enhancements, now common in nuclear cated outside the patient.27 Blood would be shunted from the medicine, will make it possible to directly improve patient patient to the column at a calculated time when the estimated absorbed dose estimates. This follows from the two uncer- marrow absorbed dose approached toxic limits. At that point, tainties implicit in Eq. ͑2͒: Evaluating Ã and S for an indi- the activity level in the bloodstream would essentially be set vidual. Considering the present difficulty of estimating the to zero such that no further bone marrow toxicity would be activity ͑A͒ at depth, it is important to realize that there are at anticipated. Note that this method requires that the patient be least six different techniques30 that have been applied to this placed into an external circulatory system. long-standing physics problem. With hybrid scanners such as Other invasive strategies have been proposed. If the mar- SPECT/CT and PET/CT, gamma attenuation factors will be row is expected to be the absorbed dose-limiting tissue, the evaluated directly without the need for external transmission patient may have a marrow sample sequestered prior to the sources or complicated fusions of different modality images. therapy with subsequent transplantation if the RM is suffi- Additionally, the activity being imaged will be assignable to

Medical Physics, Vol. 35, No. 7, July 2008 3066 Williams, DeNardo, and Meredith: Targeted radionuclide therapy 3066 a specific anatomic structure in the body; a structure that will IV. CONCLUSIONS also have a definite geometric volume and location relative Continued growth in lymphoma treatment using TRT is to other tissues. As a result, uncertainties using the phantom expected with more patients being entered into RIT trials as calculations in OLINDA ͑Ref. 21͒ will be reduced and the true part of a first-line therapy. Helping to expedite this expansion organ ͑or tumor͒ size obtained. Koral and co-workers have is the unexplained, growing incidence of B-cell lymphomas. 31 demonstrated that quantitative SPECT permits tumor ab- We would anticipate that T-cell antibodies would become sorbed dose estimates that do correlate with lymphoma out- available within the next 5 years. While 90Y facilitates outcomes. With hybrid scanners, we expect that such improved patient treatments, the utilization of 131I as a label is ex- correlations will occur for other tumor types. pected to continue due to lower radionuclide cost and the Variation of tumor mass during therapy is a feature of possibility of directly imaging therapeutic administrations to TRT that has been observed in clinical lymphoma trials.32 verify treatment planning. This result cannot be anticipated from prior imaging sessions With better dosimetry, repeat TRT procedures would be- since the effect arises out of the relatively high magnitude of come possible. In the next 5–7 years, repeated lymphoma the therapeutic absorbed dose. In the future, simple relation- therapies would become a topic of importance to patients ships such as Eq. ͑2͒ will not generally be valid for tumors. who have recurrence or were originally undertreated. Patient- Instead, dosimetrists will use the differential form of the specific normal organ absorbed doses would be tabulated to make sure that the relevant total is within the levels deter- equality whereby absorbed dose rate is evaluated over a set 17 of time intervals during the therapy regimen. A mathematical mined in external beam therapy. It is likely that the toxicity model of the target mass variation over time can be used in levels due to TRT-derived absorbed doses will be found to be different from those seen in external beam therapies. the determination of S in this case. We can also expect extensive use of engineering and in- Equation ͑2͒ has other important limitations. As defined vention to contribute a number of new targeting above, it refers to average total organ or tumor absorbed pharmaceuticals.36 Improvement in chelates will enable doses. While of gross interest, such single value representa- greater control of radiometals so that direct targeting of the tions of the ionizing radiation would not be as useful as freed label to the marrow becomes improbable. absorbed dose-volume histograms that have been popular- Improved patient-specific absorbed dose estimates will ized in external beam work. In this case, a voxel-based set of lead to better control of toxicities and improved clinical resources would be introduced and a voxel-by-voxel result cal- sults for lymphomas and, eventually, solid tumors. The culated by convolution. This result, when available, will lead present tenuous connection between estimated marrow ab- to greater absorbed dose heterogeneity and make treatment sorbed dose and its clinical toxicity will become more statis- planning a more complicated task. A technical problem in tically significant as the marrow mass becomes available via this context would be the tracking of individual regions from marrow tracers used as adjuncts prior to the TRT protocols. one imaging session to the next during the imaging or sub- As a result, escalation in phase I and other FDA-approved sequent therapy. For beta emitters, brake radiation effects can trials would occur with normal organ absorbed doses as the be included in this formulation. control variables and not simplistic parameters such as total It has been shown in both murine and some human studies activity or total activity per body surface area or body mass. that tumor uptake is an inverse function of tumor mass—at Labeling and tracking of chemotherapeutics will evolve out least for radiometal-labeled entities.33,34 We would anticipate of this work and lead to greater understanding and safety of that this result would become more important in future clini- their administration to individual patients. Combinations of cal trials implying adjuvant treatment of patients postsurgery. radiation-enhancing compounds with TRT will expand Applications of this idea to occult lesions would also be of within these two converging threads of knowledge. Patient- interest since these sites would probably have relatively specific treatment is one logical outcome of this work. small sizes. One colon cancer trial involving unlabeled antibodies has been reported.35 Like politics, absorbed dose is essentially a local phenom- ACKNOWLEDGMENTS enon. Given surgical specimens and information on cellular This work was partially supported by NIH Grant Nos. localization, an optimal radionuclide label for a given tumor PO1-43904 and CA 33572 ͑L.W.͒. type can also become possible. Proof of localization within ͒ a Author to whom correspondence should be addressed. Telephone: 626- tumor cell nuclei or at least at their surfaces would imply use 359-8111 X61488; Fax: 626-930-5451; Electronic mail: 213 111 of alpha emitters such as Bi or Auger emitters as In. [email protected] ͒ Heterogeneous distributions of activity throughout the tumor, b Telephone: 916-734-3787; Fax: 916-451-2857; Electronic mail: [email protected] on the other hand, would indicate longer-range beta produc- c͒ 90 Telephone: 205-975-0222; Fax: 205-975-0784; Electronic mail: ers such as Y to enhance cross-fire effects. Similar argu- [email protected] ments can be applied to normal tissue toxicity. Thus, future 1A. J. Jacobs, M. Fer, F. M. Su, H. Breitz, J. Thompson, H. Goodgold, J. improvement in therapy will depend upon greater coopera- Cani, J. Heap, and P. Weiden, “A phase I trial of rhenium-186-labeled ͑ ͒ monoclonal antibody administered intraperitoneally in ovarian carcinoma: tion between surgeons and pathologists , radiation oncolo- Toxicity and clinical response,” Obstet. Gynecol. ͑N.Y., NY, U. S.͒ 82, gists, and therapy physicists. 586–593 ͑1993͒.

Medical Physics, Vol. 35, No. 7, July 2008 3067 Williams, DeNardo, and Meredith: Targeted radionuclide therapy 3067

2P. Riva, A. Arista, V. Tison, C. Sturiale, G. Francheschi, A. Spinelli, N. J. Macey, and K. R. Lamborn, “Factors affecting 131-I-Lym-1 pharma- Riva, M. Casi, G. Moscatelli, and M. Frattarelli, “Intralesional radioim- cokinetics and radiation dosimetry in patients with non-Hodgkin’s lym- munotherapy of malignant gliomas: An effective treatment in recurrent phoma and chronic lymphocytic leukemia,” J. Nucl. Med. 40, 1317–1326 tumors,” Cancer 73, 1076–1082 ͑1994͒. ͑1999͒. 3 B. Shapiro, J. C. Sisson, D. M. Wieland, T. J. Mangner, S. M. Zempel, E. 19J. A. Siegel, B. W. Wessels, E. E. Watson, M. G. Stabin, H. M. Vriesen- Mudgett, M. D. Gross, J. E. Carey, K. R. Zasadny, and W. H. Beier- dorp, E. W. Bradley, C. C. Badger, A. B. Brill, C. S. Kwok, D. R. Stick- waltes, “Radiopharmaceutical therapy of malignant pheochromocytoma ney, K. F. Eckermann, D. R. Fisher, D. J. Buchsbaum, and S. E. Order, with 131I metaiodobenzylguanidine: Results from ten years of experi- “Bone marrow dosimetry and toxicity in radioimmunotherapy, “Anti- ence,” J. Nucl. Biol. Med. 35, 269–276 ͑1991͒. ͑ ͒ 4 body, Immunoconjugates, Radiopharm. 3, 213–233 1990 . A. Frilling, F. Weber, V. Cicinnati, and C. Broelsch, “Role of radiolabeled 20 M. G. Stabin, “MIRDOSE: Personal computer software for internal ab- octreotide therapy in patients with metastatic neuroendocrine neoplasms,” sorbed dose assessment in nuclear medicine,” J. Nucl. Med. 37, 538–546 Exp. Rev. Endocrinology Metabolism 2, 517–527 ͑2007͒. 5 ͑1996͒. G. L. DeNardo, A. Natarajan, S. Hok, J. Perkins, M. Cosman, S. J. De- 21 Nardo, F. C. Lightstone, G. L. Mirick, L. A. Miers, and R. L. Balhorn, M. G. Stabin, R. B. Sparks, and E. Crowe, “OLINDA/EXM: The second- “Pharmacokinetic characterization in xenografted mice of a series of first- generation personal computer software for internal absorbed dose assess- ͑ ͒ generation mimics for HLA-DR antibody, Lym-1, as carrier molecules to ment in nuclear medicine,” J. Nucl. Med. 46, 1023–1027 2005 . 22 image and treat lymphoma,” J. Nucl. Med. 48, 1338–1347 ͑2007͒. L. E. Williams, A. Liu, A. A. Raubitschek, and J. Y. C. Wong, “A method 6B. J. Hicke, A. W. Stephens, T. Gould, Y.-F. Chang, C. K. Lynott, J. Heil, for patient-specific absorbed dose estimation for internal beta emitters,” S. Borkowski, C.-S. Hilger, G. Cook, S. Warren, and P. G. Schmidt, Clin. Cancer Res. 5, 3015s–3019s ͑1999͒. “Tumor targeting by an aptamer,” J. Nucl. Med. 47, 668–678 ͑2006͒. 23G. Akabani, W. G. Hawkins, M. B. Eckblade, and P. K. Leichner, 7T. A. Waldmann, “Monoclonal antibodies in diagnosis and therapy,” Sci- “Patient-specific dosimetry using quantitative SPECT imaging and three- ence 252, 1657–1662 ͑1991͒. dimensional discrete Fourier transform convolution,” J. Nucl. Med. 38, 8 J. W. Park, “Liposome-based drug delivery in breast cancer treatment,” 308–314 ͑1997͒. Breast Cancer Res. 4, 95–99 ͑2002͒. 24C. H. Holdsworth, M. Dahlbom, A. Liu, L. Williams, C. S. Levin, M. 9 J. F. Kukowska-Latallo, K. A. Candido, Z. Cao, S. S. Nigavekar, I. J. Janecek, and E. J. Hoffman, “Expanding the versatility of a more accurate Majoros, T. P. Thomas, L. P. Balogh, M. K. Khan, and J. R. Baker, Jr., accelerated Monte Carlo simulation for 3D PET: Data correction of PET “Nanoparticle targeting of anticancer drug improves therapeutic response emission scans using 124-I,” Nuclear Science Symposium Conference in animal model of human epithelial cancer,” Cancer Res. 65, 5317–5324 Record 2001 IEEE ͑2002͒, Vol. 4, pp. 2105–2109. ͑2005͒. 25D. A. Goodwin, “Tumor pretargeting: Almost the bottom line,” J. Nucl. 10G. Liu, S. Dou, G. Mardirossian, J. He, S. Zhang, X. Liu, M. Rusckowski, Med. 36, 876–879 ͑1995͒. and D. J. Hnatowich, “Successful radiotherapy of tumor in pretargeted 26 mice by 188Re-radiolabeled phosphorodiamidate morpholino oligomer, D. M. Goldenberg and R. M. Sharkey, “Novel radiolabeled antibody con- ͑ ͒ as synthetic DNA analogue,” Clin. Cancer Res. 12, 4958–4964 ͑2006͒. jugates,” Oncogene 26, 3734–3744 2007 . 27 11R. J. Lewandowski, K. G. Thurston, J. E. Goin, C. Y. Wong, V. L. Gates, O. Linden, J. Kurkus, M. Garkavij, E. Cavallin-Stahl, M. Ljungberg, R. M. Van Buskirk, J. F. Geschwind, and R. Salem, “90Y microsphere Nilsson, T. Ohlsson, B. Sandberg, S.-E. Strand, and J. Tennvall, “A novel ͑TheraSphere͒ treatment for unresectable colorectal cancer metastases of platform for radioimmunotherapy: Extracorporeal depletion of biotiny- the liver: Response to treatment at targeted absorbed doses of 135 lated and 90Y-labeled rituximab in patients with refractory B-cell lym- −150 Gy as measured by 18F fluorodeoxyglucose positron emission to- phoma,” Cancer Biother. Radiopharm. 20, 457–466 ͑2005͒. mography and computer tomographic imaging,” J. Vasc. Interv. Radiol. 28S. Welt, G. Ritter, C. Williams, Jr., L. S. Cohen, A. Jungbluth, E. A. 16, 1641–1651 ͑2005͒. Richards, L. J. Old, and N. E. Kemeny, “Preliminary report of a phase I 12 A. S. Kennedy, D. Coldwell, C. Nutting, R. Murthy, D. E. Wertman, Jr., study of combination chemotherapy and humanized A33 antibody immu- S. P. Loehr, C. Overton, S. Meranze, J. Niedzwecki, and S. Sailer, “Resin notherapy in patients with advanced colorectal cancer,” Clin. Cancer Res. 90 Y-microsphere brachytherapy for unresectable colorectal liver me- 9, 1347–1353 ͑2003͒. tastases: Modern USA experience,” Int. J. Radiat. Oncol., Biol., Phys. 65, 29L. E. Williams, A. Liu, D. M. Yamauchi, G. Lopatin, A. A. Raubitschek, 412–425 ͑2006͒. and J. Y. C. Wong, “The two types of correction of absorbed dose esti- 13V. Kenanova, T. Olafsen, L. E. Williams, N. H. Ruel, J. Longmate, P. J. mates for internal emitters,” Cancer 94, 1231–1234 ͑2002͒. Yazaki, J. E. Shively, D. Colcher, A. A. Raubitschek, and A. M. Wu, 30D. J. Macey, L. E. Williams, H. B. Breitz, A. Liu, T. K. Johnson, and P. “Radioiodinated versus radiometal-labeled anti-carcinoembryonic antigen single-chain Fv-Fc antibody fragments: Optimal pharmacokinetics for B. Zanzonico, A Primer for Radioimmunotherapy and Radionuclide ͑ ͒ therapy,” Cancer Res. 67, 718–726 ͑2007͒. Therapy AAPM Report No. 71 Medical Physics, Madison, WI, 2001 . 31 14G. A. Wiseman, C. A. White, R. B. Sparks, W. D. Erwin, D. A. Podoloff, K. F. Koral, Y. Dewaraja, L. A. Clarke, J. Li, R. Zasadny, S. G. Rommel- D. Lamonica, N. L. Bartlett, J. A. Parker, W. L. Dunn, S. M. Spies, R. fanger, I. R. Francis, M. S. Kaminski, and R. L. Wahl, “Tumor-absorbed Belanger, T. L. Witzig, and B. R. Leigh, “Biodistribution and dosimetry dose estimates versus response in tositumomab therapy of previously un- results from a phase III prospectively randomized controlled trial of Zeva- treated patients with follicular non-Hodgkin’s Lymphoma: Preliminary lin radioimmunotherapy for low-grade, follicular, or transformed B-cell report,” Cancer Biother. Radiopharm. 15, 347–355 ͑2000͒. non-Hodgkin’s lymphoma,” Crit. Rev. Oncol. Hematol. 39, 181–194 32C. Hindorf, O. Linden, L. Stenberg, J. Tennvall, and S.-E. Strand, ͑2001͒. “Change in tumor-absorbed dose due to decrease in mass during fraction- 15 J. M. Vose, R. L. Wahl, M. Saleh, A. Z. Rohatiner, S. J. Knox, J. A. ated radioimmunotherapy in lymphoma patients,” Clin. Cancer Res. 1, Radford, A. D. Zelenetz, G. F. Tidmarsh, R. J. Stagg, and M. S. Kamin- 4003S–4006S ͑2003͒. ski, “Multicenter phase II study of iodine I-131 tositumomab for 33L. E. Williams, R. B. Duda, R. T. Proffitt, B. G. Beatty, J. D. Beatty, J. Y. chemotherapy-relapsed/refractory low-grade and transformed low-grade C. Wong, J. E. Shively, and R. J. Paxton, “Tumor uptake as a function of B-cell non-Hodgkin’s lymphoma,” J. Clin. Oncol. 18, 1316–1323 ͑2000͒. tumor mass: A mathematic model,” J. Nucl. Med. 29, 103–109 ͑1988͒. 16J. Y. C. Wong, S. Shibata, L. E. Williams, C. S. Kwok, A. Liu, D. Z. Chu, 34D. J. Macey, S. J. DeNardo, G. DeNardo, J. L. Goodnight, and M. W. D. M. Yamauchi, S. Wilcznski, D. N. Ikle, A. M. Wu, P. J. Yazaki, J. E. Unger, “Uptake of In-111 labeled monoclonal antibody ZME018 as a Shively, J. H. Doroshow, and A. A. Raubitschek, “A phase I trial of 90Y-anti-carcinoembryonic antigen chimeric T84.66 radioimmunotherapy function of tumor size in a patient with melanoma,” Am. J. Physiol. ͑ ͒ with 5-fluorouracil in patients with metastatic colorectal cancer,” Clin. Imaging 3,1–6 1988 . 35 Cancer Res. 9, 5842–5852 ͑2003͒. G. Riethmuller, E. Schneider-Gadicke, G. Schlimok, W. Schmiegel, R. 17B. Emami, J. Lyman, A. Brown, L. Coia, M. Goitein, J. E. Munzenrider, Raab, K. Hoffken, R. Gruber, H. Pichlmaier, H. Hirche, R. Pichlmayr, P. B. Shank, L. J. Solin, and M. Wesson, “Tolerance of normal tissue to Buggisch, and J. Witte, “Randomised trial of monoclonal antibody for therapeutic irradiation,” Int. J. Radiat. Oncol., Biol., Phys. 21, 109–122 adjuvant therapy of resected Dukes’C colorectal carcinoma,” Lancet 343, ͑1991͒. 1177–1183 ͑1994͒. 18G. L. DeNardo, S. J. DeNardo, S. Shen, D. A. DeNardo, G. R. Mirick, D. 36J. Carlsson, E. Aronsson Forsell, S. O. Hietala, T. Stigbrand, and T.

Medical Physics, Vol. 35, No. 7, July 2008 3068 Williams, DeNardo, and Meredith: Targeted radionuclide therapy 3068

Tennvall, “Tumor therapy with radionuclides: Assessment of progress and A. Liu, J. M. Esteban, M. Neumaier, S. Dresse, A. M. Wu, F. J. Primus, problems,” Radiother. Oncol. 66, 107–117 ͑2003͒. J. E. Shively, and A. A. Raubitschek, “Clinical evaluation of indium-111- 37Reprinted by permission of the Society of Nuclear Medicine from J. Y. C. labeled chimeric anti-CEA monoclonal antibody,” J. Nucl. Med. 38, Wong, G. E. Thomas, D. Yamauchi, L. E. Williams, T. L. Odom-Maryon, 1951–1959 ͑1997͒.

Medical Physics, Vol. 35, No. 7, July 2008 The role of photodynamic therapy „PDT… physics ͒ Timothy C. Zhua and Jarod C. Finlay Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 ͑Received 14 April 2008; revised 7 May 2008; accepted for publication 8 May 2008; published 16 June 2008͒ Photodynamic therapy ͑PDT͒ is an emerging treatment modality that employs the photochemical interaction of three components: light, photosensitizer, and oxygen. Tremendous progress has been made in the last 2 decades in new technical development of all components as well as understanding of the biophysical mechanism of PDT. The authors will review the current state of art in PDT research, with an emphasis in PDT physics. They foresee a merge of current separate areas of research in light production and delivery, PDT dosimetry, multimodality imaging, new photosensitizer development, and PDT biology into interdisciplinary combination of two to three areas. Ulti- mately, they strongly believe that all these categories of research will be linked to develop an integrated model for real-time dosimetry and treatment planning based on biological response. © 2008 American Association of Physicists in Medicine. ͓DOI: 10.1118/1.2937440͔

Key words: PDT, spectroscopy, implicit dosimetry, explicit dosimetry, dynamic process

I. INTRODUCTION II. THE PROBLEMS IN CLINICAL PDT II.A. Modeling the dynamic process of PDT Photodynamic therapy ͑PDT͒ is an emerging cancer treatment modality based on the interaction of light, a photosen- 1 Photodynamic therapy is inherently a dynamic process. sitizing drug, and oxygen. PDT has been approved by the There are three principal components: photosensitizer, light, U.S. Food and Drug Administration for the treatment of mi- and oxygen, all of which interact on time scales relevant to a croinvasive lung cancer, obstructing lung cancer, and ob- single treatment. The distribution of light is determined by structing esophageal cancer, as well as for premalignant ac- the light source characteristics and the tissue optical proper- tinic keratosis and age-related macular degeneration. Studies ties. The tissue optical properties, in turn, are influenced by have shown some efficacy in the treatment of a variety of the concentration of photosensitizer and the concentration malignant and premalignant conditions including head and and oxygenation of the blood. The distribution of oxygen is neck cancer,2,3 lung cancer,4–6 mesothelioma,7 Barrett’s altered by the photodynamic process, which consumes oxy- esophagus,8,9 prostate,10–12 and brain tumors.9,13–15 Unlike ra- gen. Finally, the distribution of photosensitizer may change diation therapy, PDT uses nonionizing radiation and can be as a result of photobleaching, the photodynamic destruction administered repeatedly without cumulative long-term com- of the photosensitizer itself. To account for these interactions, a dynamic model of the photodynamic process is re- plications since it does not appear to target DNA. quired. There has been tremendous progress made in the last 2 At the most fundamental level, the photodynamic process decades in new technologies and in understanding of the depends on the photosensitizer molecule itself. Figure 1 basic biophysical mechanisms of PDT. The most important shows the energy level, or Jablonski, diagram for a typical question to be answered is: “What determines PDT efficacy type-II photosensitizer. The photochemical reaction is initi- for a particular patient, photosensitizer, and treatment proto- ated by the absorption of a photon of light by a photosensi- ͑ ͒ col?” Answering this question will require a unified under- tizer molecule in its ground state S0 , promoting it to an ͑ ͒ standing of the interactions of the three basic components: excited state S1 . Both this state and the ground state are light, photosensitizer, and tissue oxygenation. We have cat- spectroscopic singlet states. One essential property of a good egorized the current basic research in PDT into five areas: ͑1͒ photosensitizer is a high intersystem crossing ͑ISC͒ yield, light sources, light transport, and light delivery in tissue; ͑2͒ i.e., a high probability of transition from S1 to an excited ͑ ͒ PDT dosimetry; ͑3͒ optical and anatomic imaging; ͑4͒ new triplet state T1 .IntheT1 state, the photosensitizer can transfer energy to molecular oxygen ͑3O ͒, exciting it to its photosensitizers; and ͑5͒ PDT biology. Among these, the de- 2 highly reactive singlet state ͑1O ͒. The details of this energy velopment of new photosensitizers and PDT biology is tra- 2 transfer process are beyond the scope of this article but have ditionally considered outside of the realm of PDT physics been an area of active study.16 and will only be briefly described for completeness. All five Two approaches have been used to study PDT dynamics. areas are linked by a quantitative understanding of the dy- First, a microscopic model takes into account diffusion of namic processes involved in the photochemical interaction oxygen and photosensitizer from blood vessels and can de- that drives PDT. In the next section, we will describe these termine the singlet oxygen concentration in cells microscopi- areas separately. cally. Foster et al. were the first to propose such a quantita-

Energy tion. Development of more powerful and cheaper laser transfer to oxygen sources, e.g., fiber lasers, which couple more efficiently into S1 ISC optical fiber, is an active area of research. T 1 The invention of optical fiber allowed light to be directed 1 O2 easily to deliver irradiation to desired regions without the Photon absorption requirement of a straight light path and is another enabler of PDT. Currently, most PDT procedures are performed with optical fibers. By attaching diffuse scattering tips of various

S 3O geometrical shapes at the exit end of the fiber, point, linear, 0 2 25 Sensitizer Oxygen and planar light sources can be produced. Further development in light delivery devices that produce a light field with FIG. 1. Energy level diagram for a typical type II photosensitizer and oxy- ͑ ͒ various geometrical shapes and in power distribution modu- gen. The sensitizer in its ground state S0 absorbs a photon of light and is ͑ ͒ excited to its first singlet state S1 . It spontaneously decays to its excited lation that covers a larger area and has higher power is still ͑ ͒ triplet state T1 via ISC. From T1, energy is transferred to ground state an active area of research. ͑3 ͒ ͑1 ͒ molecular oxygen O2 , creating reactive singlet oxygen O2 . Light distributions can be modeled using the diffusion approximation to radiative transport.26 The finite-element method is commonly used to solve the diffusion equation27 in an optically heterogeneous medium with arbitrary geom- tive model and to verify its results in multicell tumor 17,18 etry. Various boundary conditions are used to describe vari- spheroid models. These models demonstrate that the ous tissue-tissue, tissue-air, and tissue-water interfaces.26,28 dominant effect of the fluence rate in photodynamic therapy However, the solution is often inaccurate in regions without arises because the photochemical process itself consumes a sufficient number of multiple scattering ͑near the light oxygen. If the rate of photochemical oxygen consumption is source or nonscattering medium͒. In these regions Monte greater than the rate at which oxygen can be resupplied by Carlo simulation provides more accurate results but is much the vasculature or ambient medium, an induction of transient slower.29 Active research is on going to solve the Boltzmann hypoxia by PDT can result. This effect has been modeled 17 equation of light transport directly to provide accurate result theoretically and has been demonstrated in cell spheroids, while improve the speed of calculation.26,30 animals,19 and human tissues,20 and continues to be an area of active research.21 A second, macroscopic model has also been developed.22,23 This is an empirical model that does not II.B.2. PDT dosimetry take into account the actual oxygen and photosensitizer dif- Three general strategies have been developed for dosim- fusion processes microscopically but instead approximates etry based on the cumulative dose of singlet oxygen, which them with simpler functions. It does, however, explicitly ac- is presumed to be predictive of tissue damage. Explicit do- count for the larger-scale spatial variation in fluence rate simetry refers to the prediction of singlet oxygen dose on the based on the diffusion approximation. This model provides a basis of measurable quantities that contribute to the photo- ͑ ͒ quantity reacted singlet oxygen that can be used directly for dynamic effect.31 The quantities of interest are typically the clinical PDT dosimetry, and that relates directly to the three- distributions of light, photosensitizer, and oxygen. The dis- dimensional distribution of photosensitizers, light fluence 22,23 tributions of photosensitizer and oxygenation can be mea- rate, and a mean tissue oxygenation distribution. sured via optical spectroscopy, as described above. In current clinical practice, however, the quantity most straightforward to measure is the light dose. Flat photodiode detectors have II.B. Current areas of basic PDT research been used to measure the incident irradiance at the tissue surface in intraoperative PDT.32 These measurements, how- II.B.1. Light source, transport, and delivery ever, may not accurately reflect the fluence rate in the tissue PDT became popular after the invention of the laser, itself because they neglect contribution of backscattered which allowed the production of monochromatic light that light. Detectors based on optical fibers overcome this prob- could be easily coupled into optical fibers. The wavelength lem by collecting light isotropically.33 The effect on the mea- of light used for PDT is typically in the wavelength range sured fluence rate is significant.34 Because these probes col- between 600–800 nm, the so called “therapeutic window.”24 lect light via multiple scattering, the interface between the In this wavelength range, the energy of each photon ͑h␯͒ is scattering tip and the surrounding medium can change the high enough ͑Ͼ1.5 eV͒ to excite the photosensitizer and yet sensitivity of the detector by as much as a factor of 2, requir- is low enough so that the light has sufficient penetration into ing careful calibration.35 the tissue. Early lasers were based on either argon gas lasers Because complete explicit dosimetry requires measure- ͑488 and 514.5 nm͒ or frequency doubled Nd:yttrium- ment of three different parameters, it is inherently challeng- aluminun-garnet solid state lasers ͑532 nm͒, which were ing. Two alternatives have been suggested that require mea- then used to pump a dye laser to produce light in the desired surement of only a single parameter. Direct dosimetry relies wavelength range. With the development of the diode laser, on the detection of singlet oxygen itself, either through its the laser source has become portable and a turn-key opera- own phosphorescence emission or via singlet-oxygen-

Medical Physics, Vol. 35, No. 7, July 2008 3129 T. C. Zhu and J. C. Finlay: PDT physics 3129 sensitive chromophores. Implicit dosimetry31 uses a quan- concentration in the blood using the Hill curve.57 This mea- tity such as fluorescence photobleaching of the photosensi- surement does not directly measure the concentration of oxy- tizer, which is indirectly predictive of the production of gen in the tissue itself, however, it is possible to model the singlet oxygen. Strategies for direct and implicit dosimetry relationship between the vascular and tissue oxygenation. are under development and will be discussed in later sec- This concept has been investigated in animal models in tions. which the blood flow and/or oxygenation were monitored and changes correlated with outcome.58,59 II.B.3. Anatomic and optical imaging II.B.4. New photosensitizers The most commonly used medical imaging modalities in- Various photosensitizing drugs have been developed. The clude ultrasound, computer tomography ͑CT͒, magnetic first-generation photosensitizer, hematoporphyrin derivative, resonance, magnetic resonance spectroscopy, single photon is a mixture of porphyrin monomers and oligomers that is emission computer tomography, and positron emission to- partially purified to produce the commercially available mography ͑PET͒. The first three modalities produce excellent product, porfimer sodium, marketed under the tradename anatomical images, while the latter three provide functional Photofrin®. Photofrin® was approved for treatment of early information ͑e.g., oxygen perfusion or tissue metabolism͒ at stage lung cancer in 1998 and for Barrett’s esophagus in the expense of image resolution. Diffuse optical tomography 2003. The clinical applicability of Photofrin® has been lim- ͑DOT͒ is a viable new biomedical imaging modality.36 This ited by two factors. First, its absorption peak occurs at too technique images the absorption and scattering properties of short a wavelength ͑630 nm͒ to allow deep penetration in biological tissues and has been explored as a diagnosis tool tissue. Second, administration of Photofrin® results in cuta- in breast,37–42 brain,43,44 and bones and joints.45 Some pre- neous photosensitivity lasting up to 6 weeks. These limita- liminary attempts have been made to perform DOT for tions have inspired the development of a second generation prostate.46–49 DOT at the treatment wavelength can be used of photosensitizers with longer-wavelength absorption peaks as input to calculate light fluence rate distribution for PDT. and more rapid clearance from skin. Among these was ben- In addition, it provides access to a variety of physiological zoporphyrin derivative monoacid A ͑BPD-MA͒, or vertepor- parameters that cannot otherwise be measured easily. An- fin. In preclinical trials, it was observed that verteporfin pref- other modality, optical coherence tomography ͑OCT͒ uses erentially targeted neovasculature. This selectivity has been coherent light to obtain high resolution images. However, exploited for the treatment of choroidal neovascularization OCT is rarely used in PDT because of the limitation of pen- ͑CNV͒, an abnormal growth of vessels in the retina associ- etration depth ͑ϳ1mm͒.50 ated with age-related macular degeneration ͑AMD͒, the lead- Most image reconstruction of DOT is based on solving ing cause of blindness in the developed world. Verteporfin the inverse problem for the diffusion equation.27 This is an was approved in the U.S. under the tradename Visudyne for ill-posed problem because of the strong scattering in the tur- CNV treatment in 2000. Tetra ͑m-hydroxyphenyl͒ chlorin bid medium. As a result, the image resolution of DOT is ͑mTHPC, Foscan®͒ is another second generation photosen- limited when compared with other imaging modalities, such sitizer, a pure synthetic chlorin compound, which is activated as magnetic resonance imaging ͑MRI͒ or CT. The use of by 652 nm light.60 The major advantages of mTHPC are a spectroscopic information and/or a priori anatomic informa- short duration of skin photosensitivity ͑15 days͒, a high tion is common to provide additional constraint to produce quantum yield for singlet oxygen, and depth of tumor necro- reliable DOT reconstruction. Interested readers can find more sis of up to 10 mm in preclinical models.61 mTHPC has been information from some excellent review articles.51,52 used for treatment of pleural mesothelioma,7 head-and-neck The concept of absorption and fluorescence spectroscopy cancers,62,63 esophagus,64,65 prostate,10,66 pancreas,67 arthritic as a modality for the diagnosis of disease dates back several joints,68 and skin cancers69 and was approved in Europe for decades.53 In recent years, the potential for spectroscopy to PDT of head-and-neck and varieties of other tumors in 2001. diagnose cancer54 and to monitor the progress of cancer Another development of note is the prodrug treatment55 has been increasingly appreciated. In addition to ␦-aminolevulinic acid ͑ALA͒. Unlike other PDT drugs, ALA its role in diagnosis, spectroscopy is particularly applicable itself is not a photosensitizer. When taken up by cells, how- to PDT in determining the local drug and oxygen ever, it is converted by a naturally occurring biosynthetic concentrations.56 process into the photosensitizer protoporphyrin IX ͑PpIX͒. Photodynamic therapy can cause changes in the concen- ALA can be applied topically, and was approved by the FDA tration and oxygenation of blood in tissue both directly, in 1999 for the treatment of actinic keratosis ͑AK͒. Table I through photochemical oxygen consumption, and indirectly, summaries several of the more widely used photosensitizers through effects on the vasculature and general physiological currently available. responses. The monitoring of these responses may, therefore, be predictive of treatment outcome. For oxygen monitoring, the difference in absorption spectra between oxy- and deoxy- II.B.5. PDT biology hemoglobin is used to determine the hemoglobin oxygen From the point of view of biological response, PDT is saturation, i.e., the fraction of total hemoglobin that is in its fundamentally different from other cancer therapies. Unlike oxygenated state. This quantity can be related to the oxygen ionizing radiation, PDT achieves its cytotoxic effects prima-

Medical Physics, Vol. 35, No. 7, July 2008 3130 T. C. Zhu and J. C. Finlay: PDT physics 3130

TABLE I. An incomplete list of photosensitizers currently undergoing human clinical trials.

Excitation Drug-light Clearance Photosensitizer Trade name Approval ͑nm͒ interval time Sites

Porfimer sodium Photofrin 1998, 2003 ͑FDA͒ 630 48–150 h 4–6 weeks Lung, Barrett’s esophagus ALA-PpIX Levulan Keratastick 1999 ͑FDA͒ 405, 635 14–18 h ϳ2 days AK Methyl aminolevulate-PpIX Metvix 2004 ͑FDA͒ 405, 635 3 h ϳ2 days AK Hexyl aminolevulate-PpIX Hexvix 2005 ͑EU͒ 405 1–3 h ϳ2 days Detection of bladder tumors BPD-MA Verteporfin, Visudyne 2000 ͑FDA͒ 689 15 min 5 days CNV mTHPC Foscan Phase I trials, 2001 ͑EU͒ 652 48–110 h 15 days Head and neck, prostate, pancreas, esophagus, mesothelioma Motexafin Lutetium MLu, Lutex, Lutrin Phase I trials 732 3 h Prostate, atherosclerosis Pd-bacteriopheophorbide Tookad Phase I trials 762 ϳ30 min ϳ2 h Prostate Taloporfin sodium LS11 Phase I and II trials 664 1 h CNV, liver and colorectal metastasis ͑mono-L-aspartyl chlorin e6͒ Silicon pthalocyanine 4 PC-4 Phase I trials 672 24–36 h Skin

rily though damage to targets other than DNA. The specific long times after injection.72 An additional level of complex- subcellular targets damaged by PDT depend on the photosen- ity arises from the fact that the response to PDT is not con- sitizer’s localization within the cell, which varies among fined to the cells where the singlet oxygen is deposited but photosensitizers and cell lines. Different types of damage can can involve physiological73 and immunological74,75 re- lead to different mechanisms of cell death. Damage to mito- sponses as well. chondria in particular can lead to apoptosis even at relatively low light doses.70 Recently, the role of autophagic cell death in PDT has been increasingly recognized.71 In addition to the III. CURRENT DEVELOPMENTS variation among photosensitizers in their subcellular targets, Much of the research in the early decades of PDT and its there is considerable variability in the macroscopic targeting related fields proceeded in five almost independent areas, as of photosensitizers. Photosensitizers that are retained in the illustrated in the top row of Fig. 2. The problems associated vasculature can destroy tumors via vascular damage rather with light source and light delivery system development, do- than direct cell killing. Some photosensitizers may act as simetry, and optical imaging were treated as physics prob- vascular agents at short times after injection and at high flu- lems, while photosensitizer development and PDT biology ence rates, where only the vasculature is sufficiently oxygen- were treated as problems of chemistry and biology, respec- ated, and produce direct cell kill at low fluence rates and tively. In recent years, however, the most promising ad-

Light Delivery Dosimetry Imaging Photosensitizer PDT Development Biology

Light Dosimetry Explicit and, Biomarkers Targeted with Feedback Implicit Molecular Photosensitizer, Dosimetry, Beacons Photo- SOLD immunotherapy

Complex PMB, dose- Biological Dosimetry with responsive Response Feedback, imaging Imaging Real-time TPS

Real-time dosimetry and treatment planning based on biological response

FIG. 2. Diagram illustrating the progress of PDT development from a set of disparate fields ͑top row͒ to a collaborative effort unifying the contributions of biologists, chemists, physicists, and engineers. The second row illustrates the current state of art of research and represents integration of two separate fields. The third row illustrates the future research direction and the fourth row is the ultimate integration of all disparate fields. See text for a complete description.

Medical Physics, Vol. 35, No. 7, July 2008 3131 T. C. Zhu and J. C. Finlay: PDT physics 3131 vances have come out of interdisciplinary collaborations simetry using photobleaching has been developed for use in among these areas. The systems and strategies currently in clinical trials84 and work to extend the spheroid models to preclinical and clinical trials are examples of such realistic tissues is ongoing.85 collaborations. Fluorescence photobleaching is relatively inexpensive and straightforward to implement, however, its quantitative inter- III.A. Light dosimetry with real-time feedback pretation involves several challenges. First, fluorescence measurement in vivo must always account for the confound- It is very difficult to assess the efficacy and toxicity of any ing effects of light scattering and absorption. Second, the treatment in a clinical trial without a rigorous quantitative validity of the relationship between fluorescence pho- measurement of the treatment given. One reason that radio- tobleaching and reacted singlet oxygen dose assumes that the therapy has become an accepted locoregional therapy is that photobleaching is mediated primarily by singlet oxygen re- the dose to tissues has been quantified accurately and cura- action with the photosensitizer. There is experimental evi- tive doses can be delivered safely. In our current clinical dence to suggest that other bleaching mechanisms may be trials, we deliver a dose of light to the treatment sites based important for the commonly used photosensitizers upon measurements made from implanted isotropic light Photofrin®82 and ALA-induced PpIX,86 and the in vivo pho- detectors.34,76 These detectors allow us to prescribe the light tobleaching of mTHPC exhibits features that are not readily dose based upon actual measurements in the prostate rather interpretable.81 Care should therefore be exercised in using than the output of the laser. This dosimetric approach also photobleaching as a dose metric. ensures that the same amount of light energy ͑as measured Two methods have been developed for the detection of by the isotropic detectors͒ is deposited uniformly in the pros- singlet oxygen itself. Qin et al. have demonstrated a tate within each cohort of patients as a specific dose level. chemoluminescent compound that emits light in the presence The measurement of light fluence in vivo is necessary but of singlet oxygen.87 The translation of this technology into not sufficient to optimize the light fluence distribution. Opti- patients will require the development of a nontoxic, singlet- mization of the light fluence depends upon accurate calcula- oxygen-specific chemoluminescent probe that distributes tion of the light fluence rate in the entire prostate volume, uniformly in tissue. which in turn requires accurate characterization of the in vivo Direct measurement of singlet oxygen can be accom- prostate optical properties as input. Many studies have been plished via detection of its 1270 nm phosphorescence emis- conducted to determine the in vivo optical properties of hu- sion, a technique known as singlet oxygen luminescence do- man prostate.77–79 These light fluence measurements show simetry ͑SOLD͒.88 Detection of this signal presents that the optical properties of the prostate vary substantially significant technical challenges due to the long wavelength within a prostate gland as well as among separate prostate of the emission and the weak signal. Jarvi et al.88 have de- glands. The optical properties of prostate tissue may also veloped a system based on a photomultiplier tube capable of vary over time during a PDT procedure. detecting the long-wavelength emission of singlet oxygen. The state of the art for prostate PDT uses only in vivo The emission is stimulated by a pulsed laser at the treatment light fluence rate monitoring to determine the light fluence wavelength, and a time-resolved measurement of the emitted using equal weight of linear light sources. This is not suffi- signal allows determination of the singlet oxygen lifetime in cient since light fluence at only selected points are known. the system being measured. An additional challenge is the Integrating ultrasound imaging and the PDT dose calculation interpretation of the singlet oxygen phosphorescence signal. engine into the PDT delivery system, with input of tissue The phosphorescence emission arises from a transition of optical properties and drug uptake, will allow the clinician to oxygen from its singlet state to its ground state. This process optimize the weight of each light-delivery fiber, and thus therefore competes with the reaction of singlet oxygen with improve the light fluence distribution in the prostate gland. cellular and extracellular substrates. This leads to an increase Adequate treatment planning often uses various optimization in phosphorescence emission in conditions where substrates engines to optimize the distribution of light source for singlet oxygen are not plentiful. To differentiate between intensities. the cellular signal corresponding to PDT effect and the extracellular signal, the time-resolved emission signal can be fit III.B. Implicit dosimetry and dosimetric imaging as a sum of signals with different lifetimes. The most commonly cited example of implicit dosimetry is fluorescence photobleaching. Wilson31 suggested that the III.C. Biomarkers and molecular beacons photobleaching of the photosensitizer, if moderated by the same mechanism as the photodynamic effect, could indicate Because the goal of PDT is ultimately to deliver the op- the extent of damage. The theoretical basis for quantitative timal treatment to the tumor, the idea of using noninvasive implicit dosimetry using fluorescence photobleaching was detection and imaging to determine the status of tumor cells formalized by Georgakoudi et al.18 for the case of multicell at the molecular level is very attractive. This concept has tumor spheroids. Fluorescence photobleaching has been used driven the development of molecular beacons, molecules that in animal models to investigate the fluence-rate dependence target specific molecular pathways that can be imaged using, of photodynamic therapy80–82 and has been shown to corre- for instance, near-infrared fluorescence. Steflova et al. have late with visible skin damage.83 A device for skin PDT do- developed a series of molecular beacons whose fluorescence

Medical Physics, Vol. 35, No. 7, July 2008 3132 T. C. Zhu and J. C. Finlay: PDT physics 3132 is quenched in their latent state and restored under the action lasers and light-emitting diodes. Diode light sources have of specific cellular processes of interest.89 Because these bea- already been made small enough to be implantable.97 We cons target specific molecules, it is likely that they will be predict that this trend will continue, with future light sources tumor-type specific, however, the variety of cellular pro- becoming ever smaller, cheaper, and more efficient. On the cesses that can potentially be imaged using this approach other hand, the increases in efficiency of these light sources makes it very promising. Molecular beacons are a subset of will also lead to lasers with greater total power output, al- the general category of cancer biomarkers, molecules which lowing the treatment of larger volumes of tissue using a allow imaging of specific biological processes via various single source. modalities including MRI, PET,90 and optical imaging. Simple increases in power are not the only advances we can expect from future light sources. New delivery systems III.D. Enhancement and targeting of photosensitizers will incorporate mechanisms to deliver a light distribution customizable to each patient’s treatment plan. In our group, Several researchers have developed methods for enhanc- we have developed a computer-controlled attenuator system ing the ability of a photosensitizer to target tumors. One for prostate PDT designed to adjust the intensities of up to 16 strategy to accomplish this is to optimize the timing the ad- implanted interstitial diffusing fibers independently and in ministration of light to coincide with the desired distribution 98 72 real time. Lilge et al. have investigated optical diffusing of the photosensitizer. This approach has been used to tar- fibers whose emission profiles along the fiber axis can be get vasculature by applying light while the photosensitizer is customized to deliver much more complex light distributions in circulation, for the treatment of AMD using Vertepofin and 99,100 12 than conventional diffusers. We expect further develop- the prostate using Tookad. In cases where the rate of pro- ments in this direction to allow more and more precise con- duction of singlet oxygen is limited by the vascular resupply trol of the in vivo light distribution during PDT. of oxygen, changes in the light fluence rate can change the distribution of deposited singlet oxygen, with higher fluence IV.B. Real-time oxygen monitoring rates leading to preferential targeting of vascular-adjacent tissue. Thus, the combination of drug-light interval and fluence While it has long been recognized that oxygenation of the rate can be adjusted to enhance the treatment of the desired target tissue is essential to PDT, measurements of oxygen- tissue type. ation are now starting to be implemented in preclinical and A more direct approach to photosensitizer targeting is the clinical trials. We anticipate that future clinical protocols in- conjugation of the photosensitizer to a tumor-selective mol- volving real-time dosimetry will also include real-time oxy- ecule or particle.91 The last 2 decades have seen tremendous gen monitoring, both to prevent PDT-induced hypoxia and to progress in the development of tumor-targeted therapeutic take advantage of the predictive value of PDT-induced 58 and imaging agents for cancer in general.92,93 These innova- changes in blood flow and hemoglobin oxygen saturation. tions will continue to inform the development of new photo- The monitoring of hemoglobin saturation and blood flow has 101 sensitizers targeted to specific tumor types. been demonstrated in clinical trials. The translation of Recent research has shown PDT induced increases of measurements of hemoglobin oxygenation into a determina- VEGF, MMPs, and/or COX-2 in tumor microenvironment tion of the cellular oxygen concentration requires a model of that cause resistance to standard treatment. As a result, com- oxygen diffusion and consumption. The development of such bination of therapy that suppresses these growth factors has models is ongoing and will inform future dosimetry 85 been proposed to enhance the therapeutic efficacy of PDT. developments. C225, a monoclonal antibody that inhibits the receptor ty- An alternative to hemoglobin monitoring is the use of rosine kinase activity of EGFR, has been shown to enhance time-resolved SOLD measurements. A sufficiently sophisti- the PDT treatment in ovarian cancer.94,95 Other combined cated analysis of the time dependence of the SOLD signal modalities seek to target treatment-induced angiogenesis allows determination of the photosensitizer triplet lifetime, and/or inflammation to enhance the effectiveness of PDT.96 which is related to the local oxygen concentration. Hence, SOLD has the potential to provide both a measure of reacted singlet oxygen dose and a measure of the molecular oxygen IV. FUTURE DEVELOPMENTS AND concentration at the point of singlet oxygen generation.88 PREDICTIONS This approach has the additional advantage from the point of We predict that future developments in PDT will continue view of explicit dosimetry of providing an intermediate veri- the trend toward interdisciplinary work and the inclusion of fication of the triplet lifetime predicted by the dosimetric more technologies and subfields, such as imaging, novel model. drug design, and biological modeling into the treatment planning and dosimetry processes. Below are a few predictions of IV.C. Multifunctional, multimodality photosensitizers future PDT physics research directions: Another area of active research in photodynamic therapy is the development of photosensitizers and photosensitizer IV.A. Light sources: Faster, cheaper, larger, smaller delivery systems that enhance the functionality of the A significant driver in the development of new light photosensitizer.102 For instance, a photosensitizer may be sources has been the advent of inexpensive, reliable diode linked to a fluorescent molecule to enhance its delectability

Medical Physics, Vol. 35, No. 7, July 2008 3133 T. C. Zhu and J. C. Finlay: PDT physics 3133 under fluorescence imaging.103 Pandey et al.104 have pro- tion of photosensitizer, it does not consider the effect of tis- posed combining photosensitizers with contrast agents for sue oxygenation on the quantum yield of oxidative radicals. optical, MRI and PET imaging, allowing image-guided PDT Thus, it is only applicable in cases where ample oxygen sup- treatment. Zheng et al. have combined the “molecular bea- plies exist. It is anticipated that new dosimetry quantities ͓1 ͔ con” concept with a photosensitizer to produce photody- based on reacted singlet oxygen O2 rx, e.g., a product of namic molecular beacons.105 These molecules exhibit singlet oxygen quantum yield and PDT dose, can be used to 1 quenching that suppresses their production of O2 in their account for kinetics of the oxygen consumption during PDT latent state. They can be activated by interaction with a process.23 Foster et al. have determined most of fundamental tumor-specific molecular marker, in this case the matrix met- parameters necessary for microscopic model of the oxygen alloproteinase MMP-7. The clinical implementation of strat- consumption during PDT.18,82,106,112 However, when apply- egies such as these has the potential to dramatically improve ing models developed in the microscopic scale to a macro- the targeting of the photosensitizer to the tumor. An essential scopic environment, the values of many parameters may component of any targeting strategy will be the ability to change, and many parameters may be observable only in the verify the targeting of the drug to the desired target. The volume average, so extensive study will be required to deter- distribution of the photosensitizer can be determined opti- mine the values for each specific photosensitizer. cally using fluorescence or absorption imaging. In addition, detailed models of the distributions and kinetics of light, IV.F. Physiological effects of PDT will be exploited to photosensitizer, and oxygen will provide a quantitative rela- develop systemic therapy tionship between the microscopic distribution and photo- The ability of PDT to elicit an immune response has been chemical properties of the drug and the macroscopically ob- recognized for some time.75 The past decade has seen dra- served treatment response.106 In cases where the drug is matic progress in our understanding of the mechanisms of activated by an endogenous agent, the results will be predict- PDT-induced immune response.74,113 In addition it has been able only using such sophisticated models. demonstrated that PDT can be used to generate vaccines against specific tumor types.114,115 This strategy is particu- IV.D. Treatment planning integrated with dosimetry, larly attractive for the treatment of cancer, where it is likely imaging, and light delivery devices to allow that PDT will be used in combination with radiation and adaptive treatment chemotherapy, both of which can have immunosuppressive The integration of dosimetry systems with multimodality effects. imaging ͑anatomic and DOT͒ and light delivery devices into As the details of the mechanisms of the immune response an integrated system has drawn great interest recently. Sev- are better understood, it is likely that new photosensitizers eral groups are developing integrated systems to control light and delivery mechanisms will be developed for the express delivery, real-time light monitoring, and volumetric light flu- purpose of enhancing the immunological response and/or ence calculation. The group in Lund, Sweden is developing a moderate treatment induced angiogenesis and inflammation. multiple channel system of point sources that can be used as Furthermore, the parameters which optimize immune re- either light sources or detectors.107 A personal computer con- sponse to PDT will be different from those that maximize trols the position and duration of the point sources to opti- singlet oxygen dose or direct cell killing.116 Therefore, there mize light fluence distribution. Another group in Toronto, will be an increasing need for the incorporation of these ef- Canada has commercialized a four-channel light source with fects into PDT treatment planning and dosimetry. We predict computerized power control in each channel. Our group has that PDT vaccines will find a use as an adjuvant therapy, developed an integrated system that incorporates PDT do- even in cases where the tumor location or geometry pre- simetry that include light fluence rate at multiple points,108 a cludes conventional PDT as a primary treatment. In these three-dimensional map of optical properties,46 drug concen- cases, it may be possible to perform PDT on ex vivo tissue or tration distribution,56 and tissue oxygenation.98 A kernel- cell cultures, in which case the problems of light propagation based algorithm was developed to calculate light fluence rate and tumor physiology are greatly simplified, allowing a level distribution in the optically heterogeneous prostate gland,109 of treatment optimization not feasible in vivo. which, coupled with an optimization engine allows optimization of light source powers to achieve a uniform light flu- V. CONCLUSIONS ence distribution.110,98 This area of research will evolve into We have predicted that PDT research will increasingly a totally computerized delivery, monitoring, and dosimetry rely on combinations of widely varied fields, leading to more system for real-time feedback control. and more sophisticated treatment protocols. It is tempting to assume that such therapies will become so complex that they IV.E. New dosimetry quantities based on modeling of can only be modeled empirically, and that the role of physics the dynamic system will diminish. However, the history of PDT research demon- The current state of art in PDT dosimetry is to explicitly strates that many advances in the field are made not by determine the quantity PDT dose, defined as the number of avoiding the complexity of the problem but by embracing it. photons absorbed by photosensitizing drug per gram of As we exploit our growing knowledge of the underlying pho- tissue.111 While this quantity takes into account the consump- tochemistry, biology, and physiology of PDT to develop new

Medical Physics, Vol. 35, No. 7, July 2008 3134 T. C. Zhu and J. C. Finlay: PDT physics 3134 and better treatments, it will be more important than ever to Photobiol. Sci. 4, 438–442 ͑2005͒. 16 understand and optimize those treatment parameters over M. J. Paterson, O. Christiansen, F. Jensen, and P. R. Ogilby, “Overview of theoretical and computational methods applied to the oxygen-organic which we have direct control. In the future, as in the past, it molecule photosystem,” Photochem. Photobiol. 82, 1136–1160 ͑2006͒. will be the understanding of the physics of PDT that will 17T. H. Foster, D. F. Hartley, M. G. Nichols, and R. Hilf, “Fluence rate allow us to take advantage of our scientific understanding effects in photodynamic therapy of multicell tumor spheroids,” Cancer ͑ ͒ and translate it into improved clinical treatments. Res. 53, 1249–1254 1993 . 18I. Georgakoudi, M. G. Nichols, and T. H. Foster, “The mechanism of Photofrin photobleaching and its consequences for photodynamic dosimetry,” Photochem. Photobiol. 65, 135–144 ͑1997͒. ACKNOWLEDGMENTS 19S. L. Gibson, K. R. VanDerMeid, R. S. Murant, R. F. Raubertas, and R. This work is supported by the National Institute of Health Hilf, “Effects of various photoradiation regimens on the antitumor effi- ͑ ͒ cacy of photodynamic therapy for R3230AC mammary carcnimoas,” NIH Grant Nos. P01 CA87971 and R01 CA109456. Cancer Res. 50, 7236–7241 ͑1990͒. 20B. W. Henderson, T. M. Busch, L. A. Vaughan, N. P. Frawley, D. Babich, ͒ a Electronic mail: [email protected] T. A. Sosa, J. D. Zollo, A. S. Dee, M. T. Cooper, D. A. Bellnier, W. R. 1T. J. Dougherty, C. J. Gomer, B. W. Henderson, G. Jori, D. Kessel, M. Greco, and A. R. Oseroff, “Photofrin photodynamic therapy can signifi- Korbelik, J. Moan, and Q. Peng, “Photodynamic therapy,” J. Natl. Cancer cantly deplete or preserve oxygenation in human basal cell carcinomas Inst. 90, 889–905 ͑1998͒. during treatment, depending on fluence rate,” Cancer Res. 60, 525–529 2M. A. Biel, “Photodynamic therapy and the treatment of head and neck ͑2000͒. cancers,” J. Clin. Laser Med. Surg. 14, 239–244 ͑1996͒. 21B. W. Henderson, T. M. Busch, and J. W. Snyder, “Fluence rate as a 3W. E. Grant, P. M. Speight, C. Hopper, and S. G. Bown, “Photodynamic modulator of PDT mechanisms,” Lasers Surg. Med. 38,489–493͑2006͒. therapy: an effective, but non-selective treatment for superficial cancers 22X. H. Hu, Y. Feng, J. Q. Lu, R. R. Allison, R. E. Cuenca, G. H. Downie, of the oral cavity,” Int. J. Cancer 71, 937–942 ͑1997͒. and C. H. Sibata, “Modeling of a type II photofrin-mediated photody- 4J. S. Friedberg, R. Mick, J. P. Steveson, T. Zhu, T. M. Busch, D. Shin, D. namic therapy process in a heterogeneous tissue phantom,” Photochem. Smith, M. Culligan, A. Dimofte, E. Glatstein, and S. M. Hahn, “A phase Photobiol. 81, 1460–1468 ͑2005͒. II trial of pleural photodynamic therapy ͑PDT͒ and surgery for patients 23T. C. Zhu, J. C. Finlay, X. Zhou, and J. Li, “Macroscopic modeling of the with non-small cell lung cancer ͑NSCLC͒ with pleural spread,” J. Clin. singlet oxygen production during PDT,” Proc. SPIE 6427, 642708– Oncol. 22, 2192–2201 ͑2004͒. 642720͑2007͒. 5T. L. Moskal, T. J. Dougherty, J. D. Urschel, J. G. Antkowiak, A. M. 24B. C. Wilson and M. S. Patterson, in Photodynamic Therapy of Neoplas- Regal, D. L. Driscoll, and H. Takita, “Operation and photodynamic tic Disease, edited by D. Kessel ͑CRC Press, Boca Raton, 1990͒, Vol. 1, therapy for pleural mesothelioma: 6-year follow-up,” Ann. Thorac. Surg. pp. 129–144. 66, 1128–1133 ͑1998͒. 25P. R. Almond, Photodynamic Therapy Equipment and Dosimetry ͑Ameri- 6H. I. Pass et al., “Intrapleural photodynamic therapy: Results of a phase I can Institute of Physics, Woodbury, NY, 1992͒. trial,” Ann. Surg. Oncol. 1,28–37͑1994͒. 26A. Ishimaru, Wave Propagation and Scattering in Random Media ͑IEEE, 7J. S. Friedberg, R. Mick, J. Stevenson, J. Metz, T. Zhu, J. Buyske, D. H. New York, 1997͒. Sterman, H. I. Pass, E. Glatstein, and S. M. Hahn, “A phase I study of 27W. Cong, L. V. Wang, and G. Wang, “Formulation of photon diffusion Foscan-mediated photodynamic therapy and surgery in patients with me- from spherical bioluminescent sources in an infinite homogeneous mesothelioma,” Ann. Thorac. Surg. 75, 952–959 ͑2003͒. dium,” Biomed. Eng. Online 3,12͑2004͒. 8R. Ackroyd, N. J. Brown, M. F. Davis, T. J. Stephenson, S. L. Marcus, C. 28R. C. Haskell, L. O. Svaasand, T.-T. Tsay, T.-C. Feng, M. S. McAdams, J. Stoddard, A. G. Johnson, and M. W. Reed, “Photodynamic therapy for and B. J. Tromberg, “Boundary conditions for the diffusion equation in dysplastic Barrett’s esophagus: A prospective, double blind, randomised, radiative transfer,” J. Opt. Soc. Am. A 11, 2727–2741 ͑1994͒. placebo controlled trial,” Gut 47, 612–617 ͑2000͒. 29L. Wang, S. L. Jacques, and L. Zheng, “MCML-Monte Carlo modeling of 9M. Panjehpour, B. F. Overholt, J. M. Haydek, and S. G. Lee, “Results of light transport in multi-layered tissues,” Comput. Methods Programs photodynamic therapy for ablation of dysplasia and early cancer in Bar- Biomed. 47, 131–146 ͑1995͒. rett’s esophagus and effect of oral steroids on stricture formation,” Am. J. 30J. J. Duderstadt and W. R. Martin, Transport Theory ͑Wiley, New York, Gastroenterol. 95, 2177–2184 ͑2000͒. 1979͒. 10T. R. Nathan, D. E. Whitelaw, S. C. Chang, W. R. Lees, P. M. Ripley, H. 31B. C. Wilson, M. S. Patterson, and L. Lilge, “Implicit and explicit dosim- Payne, L. Jones, M. C. Parkinson, M. Emberton, A. R. Gillams, A. R. etry in photodynamic therapy: A new paradigm,” Lasers Med. Sci. 12, Mundy, and S. G. Browen, “Photodynamic therapy for prostate cancer 182–199 ͑1997͒. recurrence after radiotherapy: A phase I study,” J. Urol. 168, 1427–1432 32S. K. Hendren, S. M. Hahn, F. R. Spitz, T. W. Bauer, S. C. Rubin, T. Zhu, ͑2002͒. E. Glatstein, and D. L. Fraker, “Phase II trial of debulking surgery and 11D. Stripp, R. Mick, T. C. Zhu, R. Whittington, D. Smith, A. Dimofte, J. C. photodynamic therapy for disseminated intraperitoneal tumors,” Ann. Finlay, J. Miles, T. M. Busch, D. Shin, A. Kachur, Z. Tochner, S. B. Surg. Oncol. 8, 65–71 ͑2001͒. Malkowicz, E. Glatstein, and S. M. Hahn, “Phase I trial of Motexfin 33J. P. Marijnissen and W. M. Star, “Performance of isotropic light dosim- Lutetium-mediated interstitial photodynamic therapy in patients with lo- etry probes based on scattering bulbs in turbid media,” Phys. Med. Biol. cally recurrent prostate cancer,” Proc. SPIE 5315, 88–99 ͑2004͒. 47, 2049–2058 ͑2002͒. 12R. A. Weersink, A. Bogaards, M. Gertner, S. R. Davidson, K. Zhang, G. 34T. G. Vulcan, T. C. Zhu, C. E. Rodriguez, A. Hsi, D. L. Fraker, P. Baas, Netchev, J. Trachtenberg, and B. C. Wilson, “Techniques for delivery and L. H. Murrer, W. M. Star, E. Glatstein, A. G. Yodh, and S. M. Hahn, monitoring of TOOKAD ͑WST09͒-mediated photodynamic therapy of “Comparison between isotropic and nonisotropic dosimetry systems dur- the prostate: clinical experience and practicalities,” J. Photochem. Photo- ing intraperitoneal photodynamic therapy,” Lasers Surg. Med. 26, 292– biol. B 79, 211–222 ͑2005͒. 301 ͑2000͒. 13M. A. Rosenthal, B. Kayar, J. S. Hill, D. J. Morgan, R. L. Nation, S. S. 35J. P. Marijnissen and W. M. Star, “Calibration of isotropic light dosimetry Stylli, R. L. Basser, S. Uren, H. Geldard, M. D. Green, S. B. Kahl, and A. probes based on scattering bulbs in clear media,” Phys. Med. Biol. 41, H. Kaye, “Phase I and pharmacokinetic study of photodynamic therapy 1191–1208 ͑1996͒. for high-grade gliomas using a noval boronated porphyrin,” J. Clin. On- 36A. H. Hielscher, A. Y. Bluestone, G. S. Abdoulaey, A. D. Klose, J. col. 19, 519–524 ͑2001͒. Lasker, M. Stewart, U. Netz, and J. Beuthan, “Near-infrared diffuse op- 14T. T. Goodell and P. J. Muller, “Photodynamic therapy: A novel treatment tical tomography,” Dis. Markers 18, 313–337 ͑2002͒. for primary brain malignancy,” J. Neurosci. Nurs. 33, 296–300 ͑2001͒. 37A. Li, E. L. Miller, M. E. Kilmer, T. J. Brukilacchio, T. Chaves, J. Stott, 15A. Bogaards, A. Varma, K. Zhang, D. Zach, S. K. Bisland, E. H. Q. Zhang, T. Wu, M. Chorlton, R. H. Moore, D. B. Kopans, and D. A. Moriyama, L. Lilge, P. J. Muller, and B. C. Wilson, “Fluorescence image- Boas, “Tomographic optical breast imaging guided by three-dimensional guided brain tumour resection with adjuvant metronomic photodynamic mammography,” Appl. Opt. 42, 5181–5190 ͑2003͒. therapy: Pre-clinical model and technology development,” Photochem. 38J. P. Culver, R. Choe, M. J. Holboke, L. Zubkov, T. Durduran, A. Slemp,

Medical Physics, Vol. 35, No. 7, July 2008 3135 T. C. Zhu and J. C. Finlay: PDT physics 3135

V. Ntziachristos, B. Chance, and A. G. Yodh, “Three-dimensional diffuse 59H. W. Wang, M. E. Putt, M. J. Emanuele, D. B. Shin, E. Glatstein, A. G. optical tomography in the parallel plane transmission geometry: Evalua- Yodh, and T. M. Busch, “Treatment-induced changes in tumor oxygen- tion of a hybrid frequency domain/continuous wave clinical system for ation predict photodynamic therapy outcome,” Cancer Res. 64, 7553– breast imaging,” Med. Phys. 30, 235–247 ͑2003͒. 7561 ͑2004͒. 39M. J. Holboke, B. J. Tromberg, X. Li, N. Shah, J. Fishkin, D. Kidney, J. 60M. C. Berenbaum, S. L. Akande, R. Bonnett, H. Kaur, S. Ioannou, R. D. Butler, B. Chance, and A. G. Yodh, “Three-dimensional diffuse optical White, and U. J. Winfield, “Meso-tetra͑hydroxyphenyl͒porphyrins, a new mammography with ultrasound localization in a human subject,” J. class of potent tumour photosensitisers with favourable selectivity,” Br. J. Biomed. Opt. 5, 237–247 ͑2000͒. Cancer 54, 717–725 ͑1986͒. 40S. Srinivasan, B. W. Pogue, S. Jiang, H. Dehghani, C. Kogel, S. Soho, J. 61I. P. van Geel, H. Oppelaar, Y. G. Oussoren, M. A. van der Valk, and F. A. J. Gibson, T. D. Tosteson, S. P. Poplack, and K. D. Paulsen, “In vivo Stewart, “Photosensitizing efficacy of mTHPC-PDT compared to hemoglobin and water concentrations, oxygen saturation, and scattering photofrin-PDT in the RIF1 mouse tumour and normal skin,” Int. J. Cancer estimates from near-infrared breast tomography using spectral reconstruc- 60, 388–394 ͑1995͒. tion,” Acad. Radiol. 13, 195–202 ͑2006͒. 62W. Rauschning, I. B. Tan, and G. Dolivet, “Photodynamic therapy ͑PDT͒ 41B. Brooksby, S. Jiang, H. Dehghani, B. W. Pogue, K. D. Paulsen, J. with mTHPC in the palliation of advanced head and neck cancer in pa- Weaver, C. Kogel, and S. P. Poplack, “Combining near-infrared tomog- tients who have failed prior therapies and are unsuitable for radiatio- raphy and magnetic resonance imaging to study in vivo breast tissue: therapy, surgery or systemic chemotherapy,” J. Clin. Oncol. 22͑14͒, 5596 implementation of a Laplacian-type regularization to incorporate mag- ͑2004͒. netic resonance structure,” J. Biomed. Opt. 10, 051504–051514͑2005͒. 63M. Biel, “Advances in photodynamic therapy for the treatment of head 42B. W. Pogue, S. P. Poplack, T. O. McBride, W. A. Wells, K. S. Osterman, and neck cancers,” Lasers Surg. Med. 38, 349–355 ͑2006͒. U. L. Osterberg, and K. D. Paulsen, “Quantitative hemoglobin tomogra- 64L. B. Lovat, N. F. Jamieson, M. R. Novelli, C. A. Mosse, C. Selvasekar, phy with diffuse near-infrared spectroscopy: Pilot results in the breast,” G. D. Mackenzie, S. M. Thorpe, and S. G. Bown, “Photodynamic therapy Radiology 218, 261–266 ͑2001͒. with m-tetrahydroxyphenyl chlorin for high-grade dysplasia and early 43J. P. Culver, A. M. Siegel, J. J. Stott, and D. A. Boas, “Volumetric diffuse cancer in Barrett’s columnar lined esophagus,” Gastrointest. Endosc. 62, optical tomography of brain activity,” Opt. Lett. 28, 2061–2063 ͑2003͒. 617–623 ͑2005͒. 44J. P. Culver, T. Durduran, D. Furuya, C. Cheung, J. H. Greenberg, and A. 65J. Etienne, N. Dorme, G. Bourg-Heckly, P. Raimbert, and J. F. Flejou, G. Yodh, “Diffuse optical tomography of cerebral blood flow, oxygen- “Photodynamic therapy with green light and m-tetrahydroxyphenyl chlo- ation, and metabolism in rat during focal ischemia,” J. Cereb. Blood Flow rin for intramucosal adenocarcinoma and high-grade dysplasia in Barrett’s Metab. 23, 911–924 ͑2003͒. esophagus,” Gastrointest. Endosc. 59, 880–889 ͑2004͒. 45Y. Xu, N. Iftimia, H. Jiang, L. L. Key, and M. B. Bolster, “Three- 66C. M. Moore, T. R. Nathan, W. R. Lees, C. A. Mosse, A. Freeman, M. dimensional diffuse optical tomography of bones and joints,” J. Biomed. Emberton, and S. G. Bown, “Photodynamic therapy using meso tetra Opt. 7,88–92͑2002͒. hydroxy phenyl chlorin ͑mTHPC͒ in early prostate cancer,” Lasers Surg. 46T. C. Zhu and J. C. Finlay, “Prostate PDT dosimetry,” Photodiagnosis Med. 38, 356–363 ͑2006͒. Photodynamic Therapy 3, 234–246 ͑2006͒. 67S. P. Pereira, L. Ayaru, A. Rogowska, A. Moose, A. R. Hatfield, and S. G. 47X. Zhou, T. C. Zhu, J. C. Finlay, J. Li, A. Dimofte, and S. Hahn, “Two- Bown, “Photodynamic therapy of malignant biliary strictures using meso- dimensional/three dimensional hybrid interstitial diffuse optical tomogra- tetrahydroxyphenylchlorin,” Eur. J. Gastroenterol. Hepatol. 19,479–485 phy of human prostate during photodynamic therapy: Phantom and clini- ͑2007͒. cal results,” Proc. SPIE 6434, 64341Y–64352Y ͑2007͒. 68A. Hansch, O. Frey, M. Gajda, G. Susanna, J. Boettcher, R. Brauer, and 48C. Li, R. Liengsawangwong, H. Choi, and R. Cheung, “Using a priori W. A. Kaiser, “Photodynamic treatment as a novel approach in the structural information from magnetic resonance imaging to investigate the therapy of arthritic joints,” Lasers Surg. Med. 40, 265–272 ͑2008͒. feasibility of prostate diffuse optical tomography and spectroscopy: A 69M. Triesscheijn, M. Ruevekamp, N. Antonini, H. Neering, F. A. Stewart, simulation study,” Med. Phys. 34, 266–274 ͑2007͒. and P. Baas, “Optimizing meso-tetra-hydroxyphenyl-chlorin-mediated 49X. Zhou and T. C. Zhu, “Interstitial diffuse optical tomography using an photodynamic therapy for basal cell carcinoma,” Photochem. Photobiol. adjoint model with linear sources,” Proc. SPIE 6845, 68450C– 82, 1686–1690 ͑2006͒. 68459C͑2008͒. 70N. L. Oleinick, R. L. Morris, and I. Belichenko, “The role of apoptosis in 50A. F. Low, G. J. Tearney, B. E. Bouma, and I. K. Jang, “Technology response to photodynamic therapy: What, where, why, and how,” Photo- Insight: optical coherence tomography–Current status and future develop- chem. Photobiol. Sci. 1, 1–21 ͑2002͒. ment,” Nat. Clin. Pract. Cardiovasc. Med. 3, 154–162 ͑2006͒. 71E. Buytaert, M. Dewaele, and P. Agostinis, “Molecular effectors of mul- 51B. W. Pogue, S. C. Davis, X. Song, B. A. Brooksby, H. Dehghani, and K. tiple cell death pathways initiated by photodynamic therapy,” Biochim. D. Paulsen, “Image analysis methods for diffuse optical tomography,” J. Biophys. Acta 1776, 86–107 ͑2007͒. Biomed. Opt. 11, 033001–033017 ͑2006͒. 72B. Chen, B. W. Pogue, P. J. Hoopes, and T. Hasan, “Vascular and cellular 52A. P. Gibson, J. C. Hebden, and S. R. Arridge, “Recent advances in targeting for photodynamic therapy,” Crit. Rev. Eukaryot. Gene Expr. 16, diffuse optical imaging,” Phys. Med. Biol. 50, R1–R43 ͑2005͒. 279–305 ͑2006͒. 53R. Richards-Kortum and E. Sevick-Muraca, “Quantitative optical spec- 73T. M. Busch, “Local physiological changes during photodynamic troscopy for tissue diagnosis,” Annu. Rev. Phys. Chem. 47, 555–606 therapy,” Lasers Surg. Med. 38, 494–499 ͑2006͒. ͑1996͒. 74M. Korbelik, “PDT-associated host response and its role in the therapy 54B. Swinson, W. Jerjes, M. El-Maaytah, P. Norris, and C. Hopper, “Optical outcome,” Lasers Surg. Med. 38, 500–508 ͑2006͒. techniques in diagnosis of head and neck malignancy,” Oral Oncol. 42, 75M. Korbelik, “Induction of tumor immunity by photodynamic therapy,” J. 221–228 ͑2006͒. Clin. Laser Med. Surg. 14, 329–334 ͑1996͒. 55I. J. Bigio and S. G. Bown, “Spectroscopic sensing of cancer and cancer 76P. Baas, L. Murrer, F. A. Zoetmulder, F. A. Stewart, H. B. Ris, N. van therapy: current status of translational research,” Cancer Biol. Ther. 3, Zandwijk, J. L. Peterse, and E. J. Rutgers, “Photodynamic therapy as 259–267 ͑2004͒. adjuvant therapy in surgically treated pleural malignancies,” Br. J. Cancer 56J. C. Finlay, T. C. Zhu, A. Dimofte, D. Stripp, S. B. Malkowicz, T. M. 76, 819–826 ͑1997͒. Busch, and S. M. Hahn, “Interstitial fluorescence spectroscopy in the 77L. K. Lee, C. Whiteburst, M. L. Pantelides, and J. V. Moore, “In situ human prostate during motexafin lutetium-mediated photodynamic comparison of 665 nm light and 633 nm wavelength light penetration in therapy,” Photochem. Photobiol. 82, 1270–1278 ͑2006͒. the human prostate gland,” Photochem. Photobiol. 62, 882–886 ͑1995͒. 57A. V. Hill, “The possible effects of the aggregation of the molecules of 78M. L. Pantelides, C. Whitehurst, J. V. Moore, T. A. King, and N. J. hemoglobin on its dissociation curves,” J. Physiol. ͑Proc.͒ 40, iv–vii Blacklock, “Photodynamic therapy for localised prostatic cancer: light ͑1910͒. penetration in the human prostate gland,” J. Urol. 143, 398–401 ͑1990͒. 58G. Yu, T. Durduran, C. Zhou, H. W. Wang, M. E. Putt, H. M. Saunders, C. 79T. C. Zhu, A. Dimofte, J. C. Finlay, D. Stripp, T. Busch, J. Miles, R. M. Sehgal, E. Glatstein, A. G. Yodh, and T. M. Busch, “Noninvasive Whittington, S. B. Malkowicz, Z. Tochner, E. Glatstein, and S. M. Hahn, monitoring of murine tumor blood flow during and after photodynamic “Optical properties of human prostate at 732 nm measured in vivo during therapy provides early assessment of therapeutic efficacy,” Clin. Cancer motexafin lutetium-mediated photodyanmic therapy,” Photochem. Photo- Res. 11, 3543–3552 ͑2005͒. biol. 81, 96–105 ͑2005͒.

Medical Physics, Vol. 35, No. 7, July 2008 3136 T. C. Zhu and J. C. Finlay: PDT physics 3136

80J. C. Finlay, D. L. Conover, E. L. Hull, and T. H. Foster, “Porphyrin dosimetry system for prostate photodynamic therapy,” Proc. SPIE 6845, bleaching and PDT-induced spectral changes are irradiance dependent in 68450Q–68458Q ͑2008͒. ALA-sensitized normal rat skin in vivo,” Photochem. Photobiol. 73, 99L. Vesselov, W. Whittington, and L. Lilge, “Design and performance of 54–63 ͑2001͒. thin cylindrical diffusers created in Ge-doped multimode optical fibers,” 81J. C. Finlay, S. Mitra, and T. H. Foster, “In vivo mTHPC photobleaching Appl. Opt. 44, 2754–2758 ͑2005͒. in normal rat skin exhibits unique irradiance-dependent features,” Photo- 100A. Rendon, R. Weersink, and L. Lilge, “Towards conformal light delivery chem. Photobiol. 75, 282–288 ͑2002͒. using tailored cylindrical diffusers: attainable light dose distributions,” 82J. C. Finlay, S. Mitra, and T. H. Foster, “Photobleaching kinetics of Phys. Med. Biol. 51, 5967–5975 ͑2006͒. Photofrin in vivo and in multicell tumor spheroids indicate multiple si- 101G. Yu, T. Durduran, C. Zhou, T. C. Zhu, J. C. Finlay, T. M. Busch, S. B. multaneous bleaching mechanisms,” Phys. Med. Biol. 49, 4837–4860 Malkowicz, S. M. Hahn, and A. G. Yodh, “Real-time in situ monitoring ͑2004͒. of human prostate photodynamic therapy with diffuse light,” Photochem. 83D. J. Robinson, H. S. de Bruijn, N. van der Veen, M. R. Stringer, S. B. Photobiol. 82, 1279–1284 ͑2006͒. Brown, and W. M. Star, “Fluorescence photobleaching of ALA-induced 102E. Clo, J. W. Snyder, P. R. Ogilby, and K. V. Gothelf, “Control and protoporphyrin IX during photodynamic therapy of normal hairless selectivity of photosensitized singlet oxygen production: challenges in mouse skin: The effect of light dose and irradiance and the resulting complex biological systems,” ChemBioChem 8, 475–481 ͑2007͒. biological effect,” Photochem. Photobiol. 67, 140–149 ͑1998͒. 103Y. Chen, A. Gryshuk, S. Achilefu, T. Ohulchansky, W. Potter, T. Zhong, 84W. J. Cottrell, A. Oseroff, and T. H. Foster, “Portable instrument that J. Morgan, B. Chance, P. N. Prasad, B. W. Henderson, A. Oseroff, and R. integrates irradiation with fluorescence and reflectance spectroscopies K. Pandey, “A novel approach to a bifunctional photosensitizer for tumor during clinical photodynamic therapy of cutaneous disease,” Rev. Sci. imaging and phototherapy,” Bioconjug. Chem. 16, 1264–1274 ͑2005͒. Instrum. 77, 064302 ͑2006͒. 104R. K. Pandey, L. N. Goswami, Y. Chen, A. Gryshuk, J. R. Missert, A. 85K. K.-H. Wang, S. Mitra, and T. H. Foster, “A comprehensive mathemati- Oseroff, and T. J. Dougherty, “Nature: A rich source for developing mul- cal model of microscopic dose deposition in photodynamic therapy,” tifunctional agents. Tumor-imaging and photodynamic therapy,” Lasers Med. Phys. 34, 282–293 ͑2007͒. Surg. Med. 38, 445–467 ͑2006͒. 86J. S. Dysart and M. S. Patterson, “Photobleaching kinetics, photoproduct 105G. Zheng, J. Chen, K. Stefflova, M. Jarvi, H. Li, and B. C. Wilson, formation, and dose estimation during ALA induced PpIX PDT of MLL “Photodynamic molecular beacon as an activatable photosensitizer based cells under well oxygenated and hypoxic conditions,” Photochem. Photo- on protease-controlled singlet oxygen quenching and activation,” Proc. biol. Sci. 5,73–81͑2006͒. Natl. Acad. Sci. U.S.A. 104, 8989–8994 ͑2007͒. 87Y. Qin, D. Xing, S. Luo, J. Zhou, X. Zhong, and Q. Chen, “Feasibility of 106S. Mitra and T. H. Foster, “Photophysical parameters, photosensitizer using fluoresceinyl Cypridina luciferin analog in a novel chemilumines- retention and tissue optical properties completely account for the higher cence method for real-time photodynamic therapy dosimetry,” Photo- photodynamic efficacy of meso-tetra-hydroxyphenyl-chlorin vs Photof- chem. Photobiol. 81, 1534–1538 ͑2005͒. rin,” Photochem. Photobiol. 81, 849–859 ͑2005͒. 88M. T. Jarvi, M. J. Niedre, M. S. Patterson, and B. C. Wilson, “Singlet 107A. Johansson, J. Axelsson, S. Andersson-Engels, and J. Swartling, “Re- oxygen luminescence dosimetry ͑SOLD͒ for photodynamic therapy: cur- altime light dosimetry software tools for interstitial photodynamic therapy rent status, challenges and future prospects,” Photochem. Photobiol. 82, of the human prostate,” Med. Phys. 34, 4309–4321 ͑2007͒. 1198–1210 ͑2006͒. 108T. C. Zhu, J. Li, J. C. Finlay, A. Dimofte, D. Stripp, B. S. Malkowicz, and 89K. Stefflova, J. Chen, and G. Zheng, “Using molecular beacons for cancer S. M. Hahn, “In vivo light dosimetry of interstitial PDT of human pros- imaging and treatment,” Front. Biosci. 12, 4709–4721 ͑2007͒. tate,” Proc. SPIE 6139, 61390L–61401L ͑2006͒. 90H. Minn, “PET and SPECT in low-grade glioma,” Eur. J. Radiol. 56, 109J. Li and T. C. Zhu, “Determination of in vivo light fluence distribution in 171–178 ͑2005͒. heterogeneous prostate during photodyanmic therapy,” Phys. Med. Biol. 91N. Solban, I. Rizvi, and T. Hasan, “Targeted photodynamic therapy,” 53, 2103–2114 ͑2008͒. Lasers Surg. Med. 38, 522–531 ͑2006͒. 110M. D. Altschuler, T. C. Zhu, J. Li, and S. M. Hahn, “Optimized interstitial 92D. Schrama, R. A. Reisfeld, and J. C. Becker, “Antibody targeted drugs PDT prostate treatment planning with the Cimmino feasibility algorithm,” as cancer therapeutics,” Nat. Rev. Drug Discov. 5, 147–159 ͑2006͒. Med. Phys. 32, 3524–3536 ͑2005͒. 93R. M. Sharkey and D. M. Goldenberg, “Targeted therapy of cancer: New 111M. S. Patterson, B. C. Wilson, and R. Graff, “In vivo tests of the concept prospects for antibodies and immunoconjugates,” Ca-Cancer J. Clin. 56, of photodynamic threshold dose in norma rate liver photosensitized by 226–243 ͑2006͒. aluminum chlorosulphonated phthalocyanine,” Photochem. Photobiol. 51, 94M. G. del Carmen, I. Rizvi, Y. Chang, A. C. Moor, E. Oliva, M. Sher- 343–349 ͑1990͒. wood, B. Pogue, and T. Hasan, “Synergism of epidermal growth factor 112I. Georgakoudi and T. H. Foster, “Singlet oxygen- versus nonsinglet receptor-targeted immunotherapy with photodynamic treatment of ova- oxygen-mediated mechanisms of sensitizer photobleaching and their ef- rian cancer in vivo,” J. Natl. Cancer Inst. 97, 1516–1524 ͑2005͒. fects on photodynamic dosimetry,” Photochem. Photobiol. 67, 612–625 95K. A. Cengel, S. M. Hahn, and E. Glatstein, “C225 and PDT combination ͑1998͒. therapy for ovarian cancer: the play’s the thing,” J. Natl. Cancer Inst. 97, 113A. P. Castano, P. Mroz, and M. R. Hamblin, “Photodynamic therapy and 1488–1489 ͑2005͒. anti-tumour immunity,” Nat. Rev. Cancer 6, 535–545 ͑2006͒. 96C. J. Gomer, A. Ferrario, M. Luna, N. Rucker, and S. Wong, “Photody- 114S. O. Gollnick, L. Vaughan, and B. W. Henderson, “Generation of effec- namic therapy: Combined modality approaches targeting the tumor mi- tive antitumor vaccines using photodynamic therapy,” Cancer Res. 62, croenvironment,” Lasers Surg. Med. 38, 516–521 ͑2006͒. 1604–1608 ͑2002͒. 97S. K. Bisland, L. Lilge, A. Lin, R. Rusnov, and B. C. Wilson, “Metro- 115M. Korbelik and J. Sun, “Photodynamic therapy-generated vaccine for nomic photodynamic therapy as a new paradigm for photodynamic cancer therapy,” Cancer Immunol. Immunother. 55, 900–909 ͑2006͒. therapy: Rationale and preclinical evaluation of technical feasibility for 116B. W. Henderson, S. O. Gollnick, J. W. Snyder, T. M. Busch, P. C. Kou- treating malignant brain tumors,” Photochem. Photobiol. 80, 22–30 sis, R. T. Cheney, and J. Morgan, “Choice of oxygen-conserving treat- ͑2004͒. ment regimen determines the inflammatory response and outcome of pho- 98J. Li, T. C. Zhu, X. Zhou, A. Dimofte, and J. C. Finlay, “Integrated light todynamic therapy of tumors,” Cancer Res. 64, 2120–2126 ͑2004͒.

Medical Physics, Vol. 35, No. 7, July 2008 Molecular imaging and the uniﬁcation of multilevel mechanisms and data in medical physics ͒ ͒ ͒ George C. Nikiforidis,a George C. Sakellaropoulos,b and George C. Kagadisc Department of Medical Physics, School of Medicine, University of Patras, GR 265 04, Rion, Greece ͑Received 18 February 2008; revised 29 May 2008; accepted for publication 29 May 2008; published 8 July 2008͒ Molecular imaging ͑MI͒ constitutes a recently developed approach of imaging, where modalities and agents have been reinvented and used in novel combinations in order to expose and measure biologic processes occurring at molecular and cellular levels. It is an approach that bridges the gap between modalities acquiring data from high ͑e.g., computed tomography, magnetic resonance imaging, and positron-emitting isotopes͒ and low ͑e.g., PCR, microarrays͒ levels of a biological organization. While data integration methodologies will lead to improved diagnostic and prognostic performance, interdisciplinary collaboration, triggered by MI, will result in a better perception of the underlying biological mechanisms. Toward the development of a unifying theory describing these mechanisms, medical physicists can formulate new hypotheses, provide the physical constraints bounding them, and consequently design appropriate experiments. Their new scientiﬁc and working environment calls for interventions in their syllabi to educate scientists with enhanced capabilities for holistic views and synthesis. © 2008 American Association of Physicists in Medi- cine. ͓DOI: 10.1118/1.2948321͔

Key words: molecular imaging, data integration, uniﬁcation

I. INTRODUCTION tomography ͑SPECT͒ in 1973.3,4 Until the early 1990s, the evolution of ideas and experiments within each modality oc- Over the last 30 years we have experienced a rapid evolution curred in a relative solitude to other modalities. It was an era of technology which has led to a transformation of biological in which continuous improvement of instrumentation speci- and medical sciences. Biological entities and mechanisms fications was the driving force behind the progress in diag- that the limitations of technology until recently did not allow nostic capabilities and effectiveness. us to observe have now become an object of routine mea- While the usefulness of combining anatomical and func- surement and reasoning. A typical field of application of this tional planar images was evident to physicians even in the change is medical imaging. Until the early 1970s, the study 1960s,5 preceding the invention of CT, the first prototypes of the human body was based on imaging modalities that combining two imaging modalities ͑SPECT/CT, PET/CT͒ produced projections, exploiting a variety of physical prop- capable of acquiring images within the same reference frame erties of the human tissues. Three dimensional ͑3D͒ repre- appeared only in the late 1990s.6,7 Ironically,8 while the presentations were rarely achieved through time-consuming and clinical designs and early clinical prototypes were received mainly experimental procedures, producing rather vague fi- with enthusiasm, the introduction of commercial PET/CT nal results. In contrast, modern routine medical diagnostic scanners into the clinic encountered a certain amount of re- imaging heavily relies on modalities that produce high- sistance. The technology was accused of being disruptive,9 resolution 3D representations of the human body featuring expensive,10 wasteful of resources, clinically unproven,11 both morphological and functional characteristics. The latter oversold ͑for treatment planning͒,12,13 and successful only as often require four dimensional images, by combining the a consequence of the marketing strategy of major equipment three dimensional spatial information with other types of in- vendors.11 It was, however, a manifestation of a new para- formation, e.g., temporal, spectroscopic, etc. digm in the field of medical imaging. Although computed tomography ͑CT͒ and magnetic reso- As computer power increased exponentially and became nance imaging ͑MRI͒ were initially considered to be ineffi- more readily available, medical physicists joined scientists cient, as it is vividly described in a recent article by Wagner,1 from other disciplines in their new perspective for tackling they proved to be indispensable medical diagnostic modali- with the primary clinical tasks; that of exploring and mea- ties. These modalities are mathematically ill-conditioned suring the benefit of combining the available information problems. As such, much experimentation and cultivation of that originated from apparently disjoint modalities and was ideas was necessary to make them appropriate for providing encapsulated into data of variable levels of complexity. The clinically useful images. Instrumentation for functional to- field of medical informatics attracted the spotlight since the mographic imaging evolved along a path distinct from that of combination of information attained its own distinctive role anatomical imaging devices ͑CT and MRI͒. The first human as a major factor for achieving better health care.14,15 tomographic images with positron-emitting isotopes ͑PET͒ In our time, the scientific vernacular of biology and medi- were presented in 1972,2 followed by single photon emission cine has been augmented with a multitude of new terms,

3444 Med. Phys. 35 „8…, August 2008 0094-2405/2008/35„8…/3444/9/$23.00 © 2008 Am. Assoc. Phys. Med. 3444 3445 Nikiforidis, Sakellaropoulos, and Kagadis: Molecular imaging and the uniﬁcation of multilevel mechanisms 3445

TABLE I. The advent of MI allows the design of structured experiments aiming to reveal/find the causal relationships among variables and mechanisms concerning various levels of biological organization. A unified biomedical theory may be built using top-down and bottom-up approaches ͑as well as combinations thereof͒ for diagnosis or prognosis. This theory could causally connect the mutations of specific genes ͑sequence analysis͒ with a characteristic pattern of gene coexpressions ͑analysis of microarrays͒, the abnormal value of some immunochemical parameters ͑flow cytometry, microscopy͒, the manifestation of certain macroscopic anatomical or functional anomalies ͑CT, SPECT, etc.͒ and finally with the observation of specific clinical signs and symptoms. All modalities are in vivo unless otherwise indicated.

describing the function of genes, proteins, and cells. The acterization and assessment of therapeutic response.18 More advances in mass spectrometry, cell sorting, and develop- importantly, it may become the means for a paradigm shift to ment of microarrays, with substantial contribution of physi- our mode of scientific reasoning, where interdisciplinary col- cists, are feeding the biomedical field with an abundance of laboration becomes fundamental toward a holistic view of data, driving it toward a molecular perspective. A formidable the biological mechanisms. number of variables are being recorded, pertaining to the In Sec. II we present how the attempt to combine the diverse biological mechanisms inherent to the function of a various fragments of information gave rise to data integra- living organism. Based on different levels of biological or- tion. Sections III and III A contain the current status and ganization, the data can be classified into: genetic, genomic future steps in MI technology. In Sec. IV we present how MI and proteomic, cellular, tissue, organ, and organism ͑Table I͒. can become the vehicle for a new paradigm shift in medical Within this continuum, data originating from higher levels of physics and our vision for the new scientific and working biological organization can be defined as high-level data, environment that the medical physicist is going to be part of whereas those originating from lower levels of biological in the years to come. organization can be defined as low-level data. Each level is studied with specific acquisition modalities and methods of analysis, giving rise to a large variety of “omics.”16 Unfor- II. DATA INTEGRATION tunately, these data cannot be directly utilized. The ocean of The medical diagnostic and prognostic tasks have moti- electronic data at our disposal is stored in a mosaic of het- vated researchers to integrate the available data, in an at- erogeneous database implementations, hindering the access tempt to combine the various fragments of information. Bio- to and aggregation of data across implementations and cre- medical data integration can be defined as the procedure for ating a large gap between their potential and effective the creation of a single, uniform interface to query the data value.17 The application of various measurement protocols stored in many heterogeneous databases. customized for the specific experimental conditions intro- Integration means much more than obtaining the data in duces another source of data inhomogeneity. digital form or even reducing diverse data to a common The advent of molecular imaging ͑MI͒ is further changing form. Care must be taken so that integrated data serve the our approach to research and patient care by directly target- end-users’ ͑clinicians’͒ requirements and reflect in a well ing the molecular, cellular, or physiologic defects responsible specified manner the medical hypothesis that warranted the for disease. It offers a promise for more precise disease char- specific examination. In general, integration can be the ag-

Medical Physics, Vol. 35, No. 8, August 2008 3446 Nikiforidis, Sakellaropoulos, and Kagadis: Molecular imaging and the unification of multilevel mechanisms 3446 gregation of semantically similar data from multiple hetero- III. MOLECULAR IMAGING geneous sources ͑vertical integration͒; the composition of semantically complementary data from multiple heterogeneous Since understanding is our goal, seeking optimal methods sources ͑horizontal integration͒; and the standardization of for production and analysis of integrated data might prove a access to semantically similar information at disparate futile task. Drawing an example from the field of machine sources ͑integration for application portability͒. For example, learning, one can find a number of methodologies that are with vertical integration morphology information can be ob- capable of performing efficient multivariate discrimination tained through the combination of data from both CT and of cases into classes but provide little or no insight on how ultrasound ͑US͒; horizontal integration would be beneficial these variables are semantically connected. Expanding our when both anatomy and physiology of a specific region are focus from a possibly blind analysis of integrated data to the sought for. Integration for application portability would quest for understanding the inter-relationship among the make comparable data originating from imaging apparatuses variables and governing biological mechanisms can allow us of different specifications, e.g., 512ϫ512 and 256ϫ256 im- to obtain a holistic view of human organism. age matrices. MI is the field of research that provides an opportunity for The attempts for data integration have comprised a strenu- convergence of two seemingly disparate interests: the clini- ous track of research within the field of medical informatics cal interest in providing better health care and the basic sci- and a number of issues still need to be addressed. Some of entists’ interest in explaining the biological mechanisms that these issues are the partial availability of databases, the con- give rise to the phenotypic manifestations. Based on this troversial privacy issues, the fact that useful information lies convergence, productive alliances between medical physi- in the natural language text of the scientific papers, and, per- cists and radiologists, on one hand, and molecular and cellu- haps most importantly, the lack of appropriate standards.19 It lar biochemists, on the other hand, are currently driving MI.20 was soon evident that obtaining multiple representations of MI can be broadly defined as the in vivo characterization the same entity, e.g., through CT, SPECT, or MRI, would and measurement of biologic processes at the cellular and enhance the ability of making better medical decisions. But molecular level.21 Receptors, transporters, extracellular en- the efficient combination of available variables toward better zymes, and intracellular macromolecules are all potential tar- medical diagnosis and prognosis had been a high-complexity gets for MI. MI encompasses a broad set of technologies that process, even when the available data were of the high-level couple imaging modalities and contrast agents with molecu- type, i.e., results of clinical and laboratory examinations. lar specificity. MI can be divided into two general ap- With the advent of molecular data, the combination of proaches for generation of image contrast. In the first ap- multimodality information reached a higher level of com- proach, contrast reagents are engineered to interrogate plexity. It became obvious that analytical approaches are un- endogenously expressed proteins or nucleic acids and in the able to compensate for such complexity. From the thousands second the reporter genes are transfected for expression regu- of variables stored in the integrated databases only the vari- lated by environmental or tissue factors.22 It is expected that ables relevant to specific clinical problems should be consid- chemically engineered exogenous reporters will be more use- ered. This calls for the development of efficient ways for ful than genetically encoded reporters.20 variable description and management. One such way is The contrast agents, called molecular probes or tracers, building additional data structures—called metadata—that consist of a signaling component that emits a detectable sig- describe the characteristics of stored variables. Metadata ar- nal and a targeting component that confers localization. Mo- ranged in schemata can represent the hierarchical structures dalities used in MI include nuclear imaging, i.e., SPECT and of these characteristics and help us build frameworks for the PET, anatomical imaging, i.e., CT and MR imaging, optical integration of contextual information from the clinician’s imaging and US.18 MI is possible with the existing imaging point of view. Statistical modeling and procedures for statis- modalities because some degree of tissue ͑cell͒ inhomogene- tical learning can also be helpful, providing methodologies ity can be registered within the inherent spatial resolution for feature extraction and data reduction. limits of the resultant images.23 Evidence-based medicine ͑EBM͒ has been recently estab- Despite the term, current MI modalities used to image lished as the approach of choice to medical practice. EBM animals and patients do not visualize individual molecules or uses the best current evidence and statistical methods to jus- even cells but rather populations thereof, since there are spe- tify the value of therapeutic decisions in an individual pacific requirements for generating sufficient signal-to-noise tient. What it effectively does is to identify similarities or ratios to render imaging possible. The challenge for remote matches between the specific patient’s patterns of clinical imaging modalities ͑i.e., PET, SPECT, MRI, and optical im- and laboratory data and scientifically valid evidence. The aging͒ is the direct imaging of DNA,24 which is associated availability of integrated data will allow us to describe all the with problems of nonspecific and nontarget binding of imag- relevant variables and their interactions in a deep and struc- ing probes in case of polymorphisms. Direct targeting of tured manner and finally to expose the underlying mecha- mRNA is also challenging, as it requires one to one correla- nisms that give rise to these patterns. We could then obtain tion of mRNA molecules with the imaging probes, whereas better specifications of one’s health status and consequently only 50 to thousands of mRNA molecules are present in aim at personalized treatment or prevention. every cell. These problems are solved in the case of protein

Medical Physics, Vol. 35, No. 8, August 2008 3447 Nikiforidis, Sakellaropoulos, and Kagadis: Molecular imaging and the unification of multilevel mechanisms 3447 imaging since proteins are present in quite higher amounts Instruments based on THz spectrometers with resolution bet- ͑thousands to millions of copies per cell͒, that make their ter than 400 ␮m are expected to complement existing bio- imaging more feasible.25,26 By using carefully designed medical imaging technologies. probes in order to target proteins that act as enzymes MI can Nanoparticles have the potential to change the role of im- provide an indirect measurement of characteristic signals that aging technologies in diagnosis and therapy. They are colloi- arise from the expression of specific DNA parts. While direct dal vesicular systems that vary in size from 10 to 1000 nm measurement seems infeasible, MI takes advantage of the with the drug and/or imaging probe of interest either en- enzymatic amplification of protein function. trapped therein or attached thereon.31 Inherently, when Contrary to the paradigms followed until now, the under- echogenic nanoparticles are bound to surfaces, they can be lying biological question rather than the technology itself modified for compatibility with MR, US, x ray, or nuclear should drive the choice of imaging technique. MI seeks to imaging methodologies.32 There are several examples that identify and evaluate specific molecular signals which in turn prove the advantages of such bimodal agents. For example, induce specific requirements for spatial resolution and sensi- fluorine ͑19F͒ MRI of cells labeled with different types of tivity. PET and SPECT use contrast agents that are synthe- liquid perfluorocarbon nanoparticles produces unique and sized at sufficiently high specific activities and provide the sensitive cell markers distinct from any tissue background required levels of image contrast. MRI, on the other hand, a signal.33 Successful full body microSPECT/CT mouse imag- preferred modality when high spatial resolution is required, ing of Cd125mTe/ZnS NPs linked to either a monoclonal an- suffers from the need for 4–6 orders of magnitude higher tibody against mouse lung thrombomodulin ͑mAb 201B͒,or contrast agent concentration due to the indirect nature of en- a control antibody ͑mAb 33͒, has shown that nanoparticles hancement produced by MRI contrast agents.24 This intro- conjugated to mAb 201B principally target the lungs while duces clinical risks of toxicity as well as the danger of con- the nanoparticles coupled to mAb 33 accumulate in the liver trast agent concentration, perturbing the underlying and spleen.34 Similarly, PET labeled nanoparticles have been molecular signal that is being monitored by MRI. Similar successfully imaged.35 PET and MRI studies are carried out trade-offs are intrinsic to US contrast agents, optical imaging in parallel due to the lack of combined imaging systems.36,37 techniques, and even x-ray contrast agents. It is estimated that simultaneous imaging of bimodal nanoparticles will maximize the benefits from the combination of nuclear medicine and MR information.38 Other magnetic III.A. Future steps in MI technology nanoparticles can be caused to oscillate under the influence Merging PET with optical imaging techniques seems of an incident ultrasonic wave with the advantage of greater technically feasible and there are already published results sensitivity due to the absence of a large background signal.39 toward this direction.27 Such a system ͑OPET͒ is capable of By the use of targeted gold nanoparticles, the combination of detecting both high-energy gamma rays and optical wave- US with contrast enhanced photoacoustic imaging seems length photons and allows the noninvasively and repetitive possible. This is proposed as a visual tool to compound mo- imaging of small animal models in vivo for the presence of lecular and structural information for early stage prostate PET and optical signals. Thus, both technologies’ tracers can cancer detection.40 be combined and provide simultaneous different information. An additional promise of endogenous expression, where The expected improvements in detector technology will contrast reagents are engineered to interrogate endogenously make the construction of simultaneous OSPECT systems expressed proteins or nucleic acids, is the combination of with similar advantages feasible. imaging with therapeutic reagents such that they can both be More exotic technologies, coming from the world of high optimized in an iterative fashion. The effect of therapeutic energy physics, are being investigated for potential medical reagents can give rise to modified signals which in turn can applications. It is obvious that they have to be seen not as be identified with the use of different contrast reagents. The single imaging modalities but in combination with the al- latter can give evidence for new therapeutic pathways, etc. It ready existing ones. For example, x-ray phase-contrast imag- is now recognized that many of the survival attributes of ing reconstructs the projected absorption and refractive index neoplastic cells are determined by proteins involved in distributions of an object and offers dramatically reduced mechanisms of antiapoptosis, cell cycle regulation, and dam- noise levels with greatly enhanced imaging contrast.28 Neu- age repair.41 Therapeutic radiation—following the definition tron imaging can offer alternative tools, since neutrons are of the underlying molecular features of cancer cells by MI— highly penetrating. Therefore, it can image deeply seated can act as focused biology ͑i.e., producing molecular events body structures that cannot be reached by other probes.29 in the irradiated tissue͒ that targets molecular entities other Neutron stimulated emission computed tomography illumi- than DNA, offering new opportunities for therapeutic attacks nates the body with fast neutrons ͑with energies between 1 on cancer cells.42 and 10 MeV͒ and could identify malignancies by the way they change concentrations of chemical elements in tissue, long before cancer has begun to produce macroscopic ana- IV. UNIFICATION tomical changes. Terahertz ͑THz͒ spectroscopy can be used In its course through history research often passes through to image fatty tissue, bone, teeth, and thin slices of nonfatty stages of conformity. In our opinion, we are currently expe- tissue by using electromagnetic waves at THz frequencies.30 riencing such a stage. New research hypotheses are rare—on

Medical Physics, Vol. 35, No. 8, August 2008 3448 Nikiforidis, Sakellaropoulos, and Kagadis: Molecular imaging and the unification of multilevel mechanisms 3448 a global scale—and most research is conducted in deference and later on, in developing dual energy CT modalities and to the mandates of what has been established as a valid re- functional MRI. Research studies in functional imaging mo- search trend at that particular time. Researchers often publish dalities such as in the areas of optimizing data acquisition results originating from repetitions of experiments already ͑time of flight PET͒,47 scatter modeling,48 CT based attenu- performed elsewhere, perhaps responding to an indirect man- ation correction,49 etc., require a strong physics background. date of the peer-review publication procedure. A possible Besides, US is used for both diagnostic evaluation of ero- validation of results is preferred to the statement and pursuit sions or synovitis and therapeutic follow-up,50 whereas me- of new hypotheses. Technology offers an alibi for this atti- tabolizing bone can be observed with the aid of functional tude, shifting our focus to its impressive advances. However, imaging by using PET ͑Ref. 51͒ and SPECT.52 At molecular we are now entering a new era in which technological level, techniques, such as bioluminescence and fluorescence 43,44 progress alone does not suffice. The current challenge for reflectance imaging, allow imaging of the delivery of thera- medical physics is the development of a framework that will peutic agents. To this direction, physicists have worked in lead us from the deepening of our knowledge in the details of many areas like tomographic optical imaging53 and com- specific phenomena to the widening of our scope in under- bined procedures of PET and optical imaging.27 Furthermore, standing the underlying etiologies. From the deductive mode microarrays allow an open-ended survey to comprehensively of reasoning, we must march to the statement of new hypoth- identify the fraction of genes that define each sample’s eses and consequently invent the experiments to test them. unique expression.54 IL-17RA and IL-17RC were found to A new paradigm must be followed in order to reverse this be overexpressed in RA peripheral whole blood,55 while oli- trend of conformity and provide new pathways for research. gonucleotide microarrays have already been used in order to MI can facilitate such a paradigm. Lying between the gene elucidate the molecular effects of antirheumatic drugs on hu- and the cell level, it provides images and measurements of man chondrocyte gene expression.56 Research studies con- populations of molecules, thus incorporating the statistical ducted by physicists have contributed in optimizing the tech- nature of the mechanisms which give rise to the measured niques for better signal acquisition and better microarray quantities. New variables, which emerge through the analysis 57 image segmentation. RT-PCR has been used in order to of this new kind of data, could describe these quantities ef- evaluate the potent effects of vasoactive intestinal peptide in ficiently and offer a connection with modalities pertinent to human RA,58 while the efficacy of a soluble ligand of other levels of complexity of the human organism. It is the CD200R has been evaluated in established collagen-induced potential for broadening the scope of our goals within biol- arthritis in mice.59 Additionally, southern blot,60 northern ogy and medicine that makes MI unique. Apart from aiming blot,61 and western blot62 analyses have been used in mea- at improved diagnostic and prognostic performance, MI can suring the expression of different cell types in RA. Optical become a vehicle for the development of conceptual frame- imaging techniques have also emerged in the field of RA works that transect the entire range of information levels. ͑Ref. 63͒ with the more recent advancement of coupled pho- Clinicians have traditionally treated the various levels of available data in a top-down fashion: they start with clinical toacoustic tomography and image reconstruction in joint in- manifestations of diseases and they attempt to find relations flammatory diseases with high sensitivity and accuracy ͑ ͒ 64 with specific patterns in low-level molecular data. On the Fig. 1 . other hand, biologists take the opposite direction: they per- A model that would efficiently combine these multilevel form research on DNA sequences and gene expression, and fragments of information is still missing. Such a model they try to link them with specific diseases, following a would not only result in the improvement of the diagnostic bottom-up approach inside the multilevel data space. This and therapeutic potential of modern medicine but would also observation does not necessarily exclude sideway move- render the—now hidden—underlying mechanisms of inter- ments inside the same level or even opposite direction steps actions observable and explainable, bridging the gap be- within the main trend. For example, biologists, performing tween the phenotypic and the genotypic level. The concept of gene coexpression experiments with the use of microarray probability as a measure of plausibility constitutes a core technology, might need to go along the top-down direction to notion for the modeling of biological mechanisms. The investigate through sequencing whether a polymorphism Bayesian perspective to probability can assist researchers in causes the apparent behavior. Similarly, clinicians are mov- this task with its main advantage being that it allows reasoning bottom-up when their low-level findings are attributed to ing based on subjective evidence accumulated in a stepwise 65–68 clinical cases similar to the ones they originated from. manner. Bayesian networks constitute a graphical repre- 69 The case of rheumatoid arthritis ͑RA͒ can be used as an sentation of knowledge, explicitly representing complexity, example of a disorder in which various imaging modalities and simultaneously an efficient tool for inference and reason- are used to provide details at different levels of information. ing under uncertainty. They are being extensively used in The tissues within a joint, usually harmed in patients suffer- medicine70–72 and biology.73–77 They are learning from data ing from RA, can be examined with tomographic and their modularity allows the inclusion of fragments of techniques45,46 that depict the phenotypic manifestation of knowledge into larger reasoning systems. Therefore, Baye- the illness and/or inflammation. Physicists have helped in sian networks can effectively capture the various constraints this endeavor by working in the area of CT and MRI for posed by the different disciplines involved in MI. It is our many years, initially in the concept of tomographic imaging belief that Bayesian theory can provide a solid and transpar-

Medical Physics, Vol. 35, No. 8, August 2008 3449 Nikiforidis, Sakellaropoulos, and Kagadis: Molecular imaging and the uniﬁcation of multilevel mechanisms 3449

FIG. 1. The case of RA where various imaging modalities are used to provide details at different levels of information. ent chassis for the conduct of experiments that will justify Physicists have a key role in identifying these sources of the steps toward a uniﬁcation of our theories for the mecha- statistical noise through their comprehension of the physical nisms under study. processes governing the instrumentation used. Joining a team The apparent bottleneck in the exploitation of the cur- consisting of biologists, physicians, and bioinformaticists, rently available data cannot only be attributed to the relative medical physicists will have distinct and important roles in hysteresis in the development of information management estimating the magnitude of this noise, designing improved methodologies as compared to the technological break- measurement apparatus, providing the physical constraints through. What is more signiﬁcant is the ignorance of the bounding the proposed hypotheses, and setting-up novel ex- sources of variance and its magnitude in our measurements. periments to test them.

Medical Physics, Vol. 35, No. 8, August 2008 3450 Nikiforidis, Sakellaropoulos, and Kagadis: Molecular imaging and the uniﬁcation of multilevel mechanisms 3450

The introduction of nanoparticles ͑described previously͒ modality covers efficiently only a narrow region. As technol- may be considered as an example of this procedure. Their ogy advances, each modality becomes increasingly better in use within MI gives rise to a number of considerations rel- terms of precision within this continuum, shedding light to evant to their characteristics. Paramagnetic, radioactive, and new mechanisms and processes. We are thus given the op- chemical properties of nanoparticles and imaging probes portunity to build new theories that link the mechanisms rel- which are bound to them, influence both the way they inter- evant to one level with mechanisms relevant to another. act at the molecular level and the characteristics of their im- The design of new complex experiments will be needed, aging. Medical physicists are studying how these properties involving variables pertinent to many levels of biological affect parameters like spatial resolution, sensitivity, acquisi- organization. Obviously, MI is an interdisciplinary approach tion time, and dose and provide optimization guidelines spe- where end-user needs and challenges have to be well defined cific to the particular task. and clearly understood; clinicians define the diagnostic or The emergence of MI offers the opportunity for studying therapeutic needs; biologists can define the biological phe- mechanisms acting on different biologic organization levels. nomena that can be targeted; and physicists will have to in- Medical physicists will be asked to provide support to the vestigate the appropriate physical processes and suggest im- pursuit of a future unification theory incorporating the entire aging concepts. These will lead to the advancement of both array of mechanisms underlying the phenotypic manifesta- science and technology. New theories will be developed and tions. Toward this end, a reorientation of medical physics is new conceptual frameworks will be established to include needed. Currently, most medical physicists dedicate a large them. We thus have the opportunity to build genuine inter- part of their education and work in becoming specialists in a disciplinary collaborations within which the ideas originating particular diagnostic modality or therapeutic apparatus. In from different disciplines will fuse and create a new core of this way, medical physicists acquire not only deep knowl- thinking. edge of the physical principles underlying the specific mo- This is expected to affect the field of medical physics in dality but work to optimize its applications. This leads to the its theoretical foundations. It is unlikely that its current struc- rapid development of the modality with impressive results. ture can accommodate the increasing interactions with biol- Unfortunately, this overspecialization is not sufficient to ad- ogy and medicine; new ways of thinking will be needed to dress the issues that will be raised in the immediate future. meet new scientific challenges. We now have the possibility The new scientific and working environment, which the of performing a step into revolutionary science,78 exploring medical physicist is going to be part of in the years to come, alternatives to long-held, obvious-seeming assumptions. calls for developing a broader view of the scientific questions From an epistemological viewpoint, there are many similari- raised and the methodologies at hand within both medical ties with the situation in physics at the dawn of the 20th physics education and research activities. century. Experimental data that could not be explained with The education of medical physicists should aim at devel- the physical theories available at that time were partially ac- oping scientists with enhanced capabilities for synthesis. The syllabi of future medical physics courses will require sub- commodated by the Bohr atomic model and later with refine- stantial augmentation with carefully selected and intercon- ments made by Sommerfeld. However, only when the connected topics from molecular and computational biology. cept of the wave function and the Schrödinger equation These types of courses will familiarize physicists with con- appeared did quantum theory manage to describe and explain cepts and methodologies they can use in their collaboration the mechanisms giving rise to the phenomena. The growth of with scientists from other disciplines. MI can acquire a the quantum theory offered a unifying framework for con- dominant position in these courses not only as an exposition cepts initially bound to either the microscopic or macro- of a new technology but mainly as a new means for under- scopic level and gave birth to electronics as a new discipline. standing the mechanisms governing the function of the hu- Medical physics might follow the same route. Its theoretical man organism at various levels of organizational complexity. expansion may develop as a result of our attempt to provide Apart from research in the traditional fields of medical phys- a unifying view of the biological processes from the mol- ics, additional research activities will then naturally unfold ecule to the entire organism. MI may become both a technol- toward theoretical aspects of a unified conceptual ogy that produces experimental data not yet accounted for by framework. current theories and a bridge through which fragments of knowledge will be assembled into a unified theory. The role that medical physicists will play in this endeavor V. DISCUSSION/CONCLUSION cannot be predicted precisely. It will be the result of a num- From a DNA strand anomaly to a clinical symptom or ber of factors ranging from the reorientation of medical sign, there are many different levels at which technology physics courses’ syllabi to the self-motivation and degree of offers means for inspection. But since they have emerged at engagement of each individual medical physicist. Medical different points in our perpetual attempt to comprehend the physicists should closely collaborate with biologists, bio- structure and function of the human organism, imaging tech- chemists, physicians, and bioinformaticists. They should take nologies constitute instruments of fragmentary value. In the a strategic position due to their diverse role in both providing continuum of interactions among the various entities that new results in the imaging research as well as giving feed- modern medicine and biology have revealed, each imaging back to the research of other disciplines.

Medical Physics, Vol. 35, No. 8, August 2008 3451 Nikiforidis, Sakellaropoulos, and Kagadis: Molecular imaging and the uniﬁcation of multilevel mechanisms 3451

͒ a Author to whom correspondence should be addressed. Telephone: tide,” J. Nucl. Med. 38, 105–111 ͑1997͒. ϩ30 2610 969144; Fax: ϩ30 2610 969166. Electronic mail: 27D. L. Prout, R. W. Silverman, and A. Chatziioannou, “Detector concept [email protected] for OPET-A combined PET and optical imaging system,” IEEE Trans. ͒ b Electronic mail: [email protected] Nucl. Sci. 51, 752–756 ͑2004͒. ͒ c Electronic mail: [email protected] 28C.-Y. Chou, Y. Huang, D. Shi, and M. A. Anastasio, “Image reconstruc- 1R. F. Wagner, “From medical images to multiple-biomarker microarrays,” tion in quantitative x-ray phase-contrast imaging employing multiple Med. Phys. 34, 4944–4951 ͑2007͒. measurements,” Opt. Express 15, 10002 ͑2007͒. 2A. D. Chesler, Symposium on Tomographic Imaging in Nuclear Medi- 29J. E. Bender, A. J. Kapadia, A. C. Sharma, G. D. Tourassi, B. P. Harra- cine, New York, 1972. wood, and C. E. Floyd, Jr., “Breast cancer detection using neutron stimu- 3D. E. Kuhl, R. Q. Edwards, A. R. Ricci, and M. Reivich, “Quantitative lated emission computed tomography: Prominent elements and dose resection scanning using orthogonal tangent correction,” J. Nucl. Med. 14, quirements,” Med. Phys. 34, 3866–3871 ͑2007͒. 196–200 ͑1973͒. 30M. C. Beard, G. M. Turner, and C. A. Schmuttenmaer, “Progress towards 4H. W. Strauss, B. L. Zaret, N. D. Martin, H. P. Wells, Jr., and M. D. two-dimensional biomedical imaging with THz spectroscopy,” Phys. Flamm, Jr., “Noninvasive evaluation of regional myocardial perfusion Med. Biol. 47, 3841–3846 ͑2002͒. with potassium 43. Technique in patients with exercise-induced transient 31Y. W. Cho, S. A. Park, T. H. Han, D. H. Son, J. S. Park, S. J. Oh, D. H. myocardial ischemia,” Radiology 108, 85–90 ͑1973͒. Moon, K. J. Cho, C. H. Ahn, Y. Byun, I. S. Kim, I. C. Kwon, and S. Y. 5H. N. Wagner, A Personal History of Nuclear Medicine ͑Springer, Lon- Kim, “In vivo tumor targeting and radionuclide imaging with self- don, 2006͒. assembled nanoparticles: Mechanisms, key factors, and their implica- 6T. Beyer, D. W. Townsend, T. Brun, P. E. Kinahan, M. Charron, R. tions,” Biomaterials 28, 1236–1247 ͑2007͒. Roddy, J. Jerin, J. Young, L. Byars, and R. Nutt, “A combined PET/CT 32T. Cyrus, D. R. Abendschein, S. D. Caruthers, T. D. Harris, V. Glattauer, scanner for clinical oncology,” J. Nucl. Med. 41, 1369–1379 ͑2000͒. J. A. Werkmeister, J. A. Ramshaw, S. A. Wickline, and G. M. Lanza, 7S. C. Blankespoor, X. Xu, K. Kaiki, J. K. Brown, H. R. Tang, C. E. Cann, “MR three-dimensional molecular imaging of intramural biomarkers with and B. H. Hasegawa, “Attenuation correction of SPECT using x-ray CT targeted nanoparticles,” J. Cardiovasc. Magn. Reson. 8, 535–541 ͑2006͒. on an emission-transmission CT system: Myocardial perfusion assess- 33K. C. Partlow, J. Chen, J. A. Brant, A. M. Neubauer, T. E. Meyerrose, M. ment,” IEEE Trans. Nucl. Sci. 43, 2263–2274 ͑1996͒. H. Creer, J. A. Nolta, S. D. Caruthers, G. M. Lanza, and S. A. Wickline, 8D. W. Townsend, “Multimodality imaging of structure and function,” “19F magnetic resonance imaging for stem/progenitor cell tracking with Phys. Med. Biol. 53, R1–R39 ͑2008͒. multiple unique perfluorocarbon nanobeacons,” FASEB J. 21, 1647–1654 9Disruptive technology: The conflict over PET/CT, http:// ͑2007͒. www.imagingeconomics.com/issues/articles/2005-06_02.asp accessed 34J. D. Woodward, S. J. Kennel, S. Mirzadeh, S. Dai, J. S. Wall, T. Richey, February 9, 2008. J. Avenell, and A. J. Rondinone, “In vivo SPECT/CT imaging and bio- 10A. Alavi, A. Mavi, S. Basu, and A. Fischman, “Is PET-CT the only distribution using radioactive Cd125mTe/ZnS nanoparticles,” Nanotech- option?,” Eur. J. Nucl. Med. Mol. Imaging 34, 819–821 ͑2007͒. nology 18, 175103–175108 ͑2007͒. 11H. Zaidi, “The quest for the ideal anato-molecular imaging fusion tool,” 35E. D. Pressly, R. Rossin, A. Hagooly, K. Fukukawa, B. W. Messmore, M. Biomed. Imaging Interv. J. 2, e47 ͑2006͒. J. Welch, K. L. Wooley, M. S. Lamm, R. A. Hule, D. J. Pochan, and C. J. 12B. Wessels, “The value of PET/CT is being over-sold as a clinical tool in Hawker, “Structural effects on the biodistribution and positron emission radiation oncology. Against the proposition,” Med. Phys. 32, 1458–1459 tomography ͑PET͒ imaging of well-defined ͑64͒Cu-labeled nanoparticles ͑2005͒. comprised of amphiphilic block graft copolymers,” Biomacromolecules 13L. Xing, “The value of PET/CT is being over-sold as a clinical tool in 8, 3126–3134 ͑2007͒. radiation oncology. For the proposition,” Med. Phys. 32, 1457–1458 36Z. Burbar, R. Grazioso, and J. Corbeil, “PET performance of MR/PET ͑2005͒. brain insert tomograph ͓abstr͔,” IEEE Nuclear Science Symposium and 14E. H. Shortliffe and J. J. Cimino, in Health Informatics, edited by K. J. Medical Imaging Conference, San Diego, California, 2006. Hannah and M. J. Ball ͑Springer, New York, 2006͒. 37M. S. Judenhofer, C. Catana, B. K. Swann, S. B. Siegel, W. I. Jung, R. E. 15G. C. Kagadis, P. Nagy, S. Langer, M. Flynn, and G. Starkschall, “Anni- Nutt, S. R. Cherry, C. D. Claussen, and B. J. Pichler, “PET/MR images versary paper: Roles of medical physicists and health care applications of acquired with a compact MR-compatible PET detector in a 7-T magnet,” informatics,” Med. Phys. 35, 119–127 ͑2008͒. Radiology 244, 807–814 ͑2007͒. 16Omics-Omics.org, http://omics.org/index.php/Main_Page, accessed Feb- 38H. Zaidi, O. Mawlawi, and C. G. Orton, “Point/counterpoint. Simulta- ruary 9, 2008. neous PET/MR will replace PET/CT as the molecular multimodality im- 17W. Sujansky, “Heterogeneous database integration in biomedicine,” J. aging platform of choice,” Med. Phys. 34, 1525–1528 ͑2007͒. Biomed. Inform. 34, 285–298 ͑2001͒. 39S. J. Norton and T. Vo-Dinh, “Imaging the distribution of magnetic nano- 18D. S. Wang, M. D. Dake, J. M. Park, and M. D. Kuo, “Molecular imag- particles with ultrasound,” IEEE Trans. Med. Imaging 26, 660–665 ing: A primer for interventionalists and imagers,” J. Vasc. Interv. Radiol. ͑2007͒. 17, 1405–1423 ͑2006͒. 40A. Uedono, K. Ito, T. Narumi, M. Sometani, K. Yamabe, Y. Miyagawa, T. 19B. Louie, P. Mork, F. Martin-Sanchez, A. Halevy, and P. Tarczy-Hornoch, Murata, K. Honda, N. Hattori, M. Matsuura, K. Asai, T. Ohdaira, and R. “Data integration and genomic medicine,” J. Biomed. Inform. 40, 5–16 Suzuki, “Annealing properties of open volumes in strained SiN films ͑2007͒. studied by monoenergetic positron beams,” J. Appl. Phys. 102, 064513 20R. J. Gillies, “In vivo molecular imaging,” J. Cell. Biochem. Suppl. 39, ͑2007͒. 231–238 ͑2002͒. 41R. K. Schmidt-Ullrich, “Molecular targets in radiation oncology,” Onco- 21R. Weissleder and U. Mahmood, “Molecular imaging,” Radiology 219, gene 22, 5730–5733 ͑2003͒. 316–333 ͑2001͒. 42C. N. Coleman, “Linking radiation oncology and imaging through mo- 22G. D. Luker, “Special conference of the American Association for Cancer lecular biology ͑or now that therapy and diagnosis have separated, it’s Research on molecular imaging in cancer: Linking biology, function, and time to get together again!͒,” Radiology 228, 29–35 ͑2003͒. clinical applications in vivo,” Cancer Res. 62, 2195–2198 ͑2002͒. 43G. D. Fullerton, “The development of technologies for molecular imaging 23R. Blasberg, “PET imaging of gene expression,” Eur. J. Cancer 38, 2137– should be driven principally by biological questions to be addressed 2146 ͑2002͒. rather than by simply modifying existing imaging technologies. For the 24V. Sharma, G. D. Luker, and D. Piwnica-Worms, “Molecular imaging of proposition,” Med. Phys. 32, 1231–1232 ͑2005͒. gene expression and protein function in vivo with PET and SPECT,” J. 44J. D. Hazle, “The development of technologies for molecular imaging Magn. Reson. Imaging 16, 336–351 ͑2002͒. should be driven principally by biological questions to be addressed 25E. P. Krenning et al., “Somatostatin receptor scintigraphy with ͓111In- rather than by simply modifying existing imaging technologies. Against DTPA-D-Phe1͔- and ͓123I-Tyr3͔-octreotide: The Rotterdam experience the proposition,” Med. Phys. 32, 1232–1233 ͑2005͒. with more than 1000 patients,” Eur. J. Nucl. Med. 20, 716–731 ͑1993͒. 45U. M. Dohn, B. J. Ejbjerg, M. Hasselquist, E. Narvestad, J. Moller, H. S. 26J. Lister-James, S. Vallabhajosula, B. R. Moyer, D. A. Pearson, B. J. Thomsen, and M. Ostergaard, “Detection of bone erosions in rheumatoid McBride, M. A. De Rosch, L. R. Bush, J. Machac, and R. T. Dean, arthritis wrist joints with magnetic resonance imaging, computed tomog- “Pre-clinical evaluation of technetium-99m platelet receptor-binding pep- raphy and radiography,” Arthritis Res. Ther. 10, R25 ͑2008͒.

Medical Physics, Vol. 35, No. 8, August 2008 3452 Nikiforidis, Sakellaropoulos, and Kagadis: Molecular imaging and the uniﬁcation of multilevel mechanisms 3452

46M. Knupp, A. Skoog, H. Tornkvist, and S. Ponzer, “Triple arthrodesis in 315–318 ͑2008͒. rheumatoid arthritis,” Foot Ankle Int. 29, 293–297 ͑2008͒. 61J. K. Jackson, T. Higo, W. L. Hunter, and H. M. Burt, “Topoisomerase 47W. W. Moses, “Time of flight in PET revisited,” IEEE Trans. Nucl. Sci. inhibitors as anti-arthritic agents,” Inflamm. Res. 57, 126–134 ͑2008͒. 50, 1325–1330 ͑2003͒. 62H. Okamoto, Y. Katagiri, A. Kiire, S. Momohara, and N. Kamatani, “Se- 48H. Zaidi, “Scatter modelling and correction strategies in fully 3-D PET,” rum amyloid A activates nuclear factor-kappaB in rheumatoid synovial Nucl. Med. Commun. 22, 1181–1184 ͑2001͒. fibroblasts through binding to receptor of advanced glycation end- 49J. P. Carney, D. W. Townsend, V. Rappoport, and B. Bendriem, “Method products,” J. Rheumatol. 35, 752–756 ͑2008͒. for transforming CT images for attenuation correction in PET/CT imag- 63U. J. Netz, J. Beuthan, and A. H. Hielscher, “Multipixel system for giga- ing,” Med. Phys. 33, 976–983 ͑2006͒. hertz frequency-domain optical imaging of finger joints,” Rev. Sci. In- 50S. Ozgocmen, H. Ozdemir, A. Kiris, Z. Bozgeyik, and O. Ardicoglu, strum. 79, 034301 ͑2008͒. “Clinical evaluation and power Doppler sonography in rheumatoid arthri- 64X. Wang, D. L. Chamberland, P. L. Carson, J. B. Fowlkes, R. O. Bude, D. tis: Evidence for ongoing synovial inflammation in clinical remission,” A. Jamadar, and B. J. Roessler, “Imaging of joints with laser-based pho- South. Med. J. 101, 240–245 ͑2008͒. toacoustic tomography: an animal study,” Med. Phys. 33, 2691–2697 51E. H. Elzinga, C. J. van der Laken, E. F. Comans, A. A. Lammertsma, B. ͑2006͒. A. Dijkmans, and A. E. Voskuyl, “2-Deoxy-2-͓F-18͔fluoro-D-glucose 65R. G. Cowell, A. P. Dawid, and S. L. Lauritzen, Probabilistic Networks joint uptake on positron emission tomography images: Rheumatoid arthri- and Expert Systems ͑Springer, Berlin, 1999͒. tis versus osteoarthritis,” Mol. Imaging Biol. 9, 357–360 ͑2007͒. 66F. V. Jensen and T. D. Nielsen, Bayesian Networks and Decision Graphs, 52F. M. McQueen and M. Ostergaard, “Established rheumatoid arthritis— 2nd ed. ͑Springer, New York, 2007͒. New imaging modalities,” Best Pract. Res. Clin. Rheumatol. 21, 841–856 67R. E. Neapolitan, Learning Bayesian Networks ͑Pearson Prentice-Hall, ͑2007͒. Englewood Cliffs, NJ, 2004͒. 53G. Alexandrakis, F. R. Rannou, and A. F. Chatziioannou, “Tomographic 68J. Pearl, Probabilistic Reasoning in Intelligent Systems ͑Morgan Kauf- bioluminescence imaging by use of a combined optical-PET ͑OPET͒ sys- mann, San Francisco, CA, 1988͒. tem: A computer simulation feasibility study,” Phys. Med. Biol. 50, 69D. Poole, “Logic, knowledge representation, and Bayesian decision 4225–4241 ͑2005͒. theory,” in Computational Logic—CL 2000 ͑Springer, Berlin/Heidelberg, 54T. C. van der Pouw Kraan, L. G. van Baarsen, F. Rustenburg, B. Baltus, 2000͒, Vol. 1861/2000, pp. 70–86. M. Fero, and C. L. Verweij, “Gene expression profiling in rheumatology,” 70N. Cruz-Ramirez, H. G. Acosta-Mesa, H. Carrillo-Calvet, L. A. Nava- Methods Mol. Med. 136, 305–327 ͑2007͒. Fernandez, and R. E. Barrientos-Martinez, “Diagnosis of breast cancer 55S. Zrioual, M. L. Toh, A. Tournadre, Y. Zhou, M. A. Cazalis, A. Pachot, using Bayesian networks: A case study,” Comput. Biol. Med. 37, 1553– V. Miossec, and P. Miossec, “IL-17RA and IL-17RC receptors are essen- 1564 ͑2007͒. tial for IL-17A-induced ELR+ CXC chemokine expression in synovio- 71J. P. Sacha, L. S. Goodenday, and K. J. Cios, “Bayesian learning for cytes and are overexpressed in rheumatoid blood,” J. Immunol. 180, 655– cardiac SPECT image interpretation,” Artif. Intell. Med. 26, 109–143 663 ͑2008͒. ͑2002͒. 56K. Andreas, C. Lubke, T. Haupl, T. Dehne, L. Morawietz, J. Ringe, C. 72G. C. Sakellaropoulos and G. C. Nikiforidis, “Development of a Bayesian Kaps, and M. Sittinger, “Key regulatory molecules of cartilage destruc- network for the prognosis of head injuries using graphical model selection tion in rheumatoid arthritis: An in vitro study,” Arthritis Res. Ther. 10,R9 techniques,” Methods Inf. Med. 38, 37–42 ͑1999͒. ͑2008͒. 73Bayesian Networks for Expression References, http://www.stat.wisc.edu/ 57A. Daskalakis, D. Cavouras, P. Bougioukos, S. Kostopoulos, D. Glotsos, ~yandell/statgen/reference/network.html, accessed January 31, 2008. I. Kalatzis, G. C. Kagadis, C. Argyropoulos, and G. Nikiforidis, “Improv- 74R. Jansen, H. Yu, D. Greenbaum, Y. Kluger, N. J. Krogan, S. Chung, A. ing gene quantification by adjustable spot-image restoration,” Bioinfor- Emili, M. Snyder, J. F. Greenblatt, and M. Gerstein, “A Bayesian net- matics 23, 2265–2272 ͑2007͒. works approach for predicting protein-protein interactions from genomic 58Y. Juarranz, I. Gutierrez-Canas, B. Santiago, M. Carrion, J. L. Pablos, and data,” Science 302, 449–453 ͑2003͒. R. P. Gomariz, “Differential expression of vasoactive intestinal peptide 75S. M. McMahon, “Quantifying the community: Using Bayesian learning and its functional receptors in human osteoarthritic and rheumatoid syn- networks to find structure and conduct inference in invasions biology,” ovial fibroblasts,” Arthritis Rheum. 58, 1086–1095 ͑2008͒. Biol. Invasions 7, 833–844 ͑2005͒. 59E. Simelyte, G. Criado, D. Essex, R. A. Uger, M. Feldmann, and R. O. 76C. J. Needham, J. R. Bradford, A. J. Bulpitt, and D. R. Westhead, “A Williams, “CD200-FC, a novel antiarthritic biologic agent that targets primer on learning in Bayesian networks for computational biology,” proinflammatory cytokine expression in the joints of mice with collagen- PLOS Comput. Biol. 3, e129 ͑2007͒. induced arthritis,” Arthritis Rheum. 58, 1038–1043 ͑2008͒. 77S.Y. Kim, in Computational Methods in Systems Biology ͑Springer, Ber- 60A. Komatsuda, H. Wakui, T. Nimura, and K. I. Sawada, “Reversible lin, 2003͒, Vol. 2602, pp. 104–113. infliximab-related lymphoproliferative disorder associated with Epstein- 78T. S. Kuhn, The Structure of Scientific Revolutions ͑The University of Barr virus in a patient with rheumatoid arthritis,” Mod. Rheumatol. 18, Chicago Press, Chicago, 1962͒.

Medical Physics, Vol. 35, No. 8, August 2008 Towards new functional nanostructures for medical imaging ͒ Naomi Matsuuraa and J. A. Rowlands Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada ͑Received 2 March 2008; revised 10 July 2008; accepted for publication 10 July 2008; published 16 September 2008͒ Nanostructures represent a promising new type of contrast agent for clinical medical imaging modalities, including magnetic resonance imaging, x-ray computed tomography, ultrasound, and nuclear imaging. Currently, most nanostructures are simple, single-purpose imaging agents based on spherical constructs ͑e.g., liposomes, micelles, nanoemulsions, macromolecules, dendrimers, and solid nanoparticle structures͒. In the next decade, new clinical imaging nanostructures will be designed as multi-functional constructs, to both amplify imaging signals at disease sites and deliver localized therapy. Proposals for nanostructures to fulfill these new functions will be outlined. New functional nanostructures are expected to develop in five main directions: Modular nanostructures with additive functionality; cooperative nanostructures with synergistic functionality; nanostructures activated by their in vivo environment; nanostructures activated by sources outside the patient; and novel, nonspherical nanostructures and components. The development and clinical translation of next-generation nanostructures will be facilitated by a combination of improved clarity of the in vivo imaging and biological challenges and the requirements to successfully overcome them; development of standardized characterization and validation systems tailored for the preclinical assessment of nanostructure agents; and development of streamlined commercialization strategies and pipelines tailored for nanostructure-based agents for their efficient translation to the clinic. © 2008 American Association of Physicists in Medicine. ͓DOI: 10.1118/1.2966595͔

Key words: medical imaging, nanostructures, nanotechnology, contrast agents

I. INTRODUCTION newed academic and commercial interest in the creation of new nanostructures for all imaging modalities has been due Imaging is a fundamental tool in the practice of modern to the convergence of several factors: The recent capability medicine. In parallel with the development of more sensitive to easily synthesize, image, and characterize such nanostruc- detectors and imaging systems, there is increasing interest in tures using inexpensive, standard laboratory tools; improved designing new types of contrast agents for all modalities, to insights into the biology of diseases to create a demand for sensitively and successfully diagnose specific disease pa- specialized, targeted contrast agents; advances in imaging thologies. Exogenous contrast agents are designed to differ- technologies that allow preclinical contrast agents to be eas- entially scatter, absorb, or emit radiation such that upon in- ily tested, particularly in animal models; and growing public troduction into a patient, the contrast agent’s location may be curiosity in nanotechnology combined with greater patient distinguished from its surrounding tissue or background awareness and strong market demand for new and improved noise. This may greatly increase the utility of imaging, as medical treatment options. All these factors have resulted in normal and diseased tissues typically exhibit minimal native increased funding and investment in basic nanotechnology contrast. Since the in vivo distribution of the contrast agent research. depends on the patient’s physiology and the properties of the Exogenous contrast agents have long been used in medi- agent, the radiologist can use contrast agents to reveal struc- cal imaging. The first radiographic iodinated contrast media tural, functional, and/or molecular information about the pa- was demonstrated in 1929 followed by its introduction into tient to assist in disease diagnosis. At the forefront of new general clinical use in the 1950s4. Since then, thousands of contrast agent development are nanometer-scale structures, new contrast agents for all imaging modalities have been or “nanostructures,” that can act as, or carry, contrast agents. proposed in the research literature. These agents are typically Nanostructures are constructs with physical dimensions designed for a specific imaging modality and/or the diagno- between a few nanometers to hundreds of nanometers in size. sis of particular disease/organ-dependent pathologies, which Although simple nanostructures have been utilized for de- has led to a natural and convenient end-user-based classifi- cades in clinical medicine ͑e.g., colloidal and particulate car- cation scheme for contrast agents based on modality or riers for pharmaceutical applications,1,2 and radiocolloids for disease/organ type. Imaging modality-dependent classifica- imaging and therapy3͒, there has been a recent revival in tion is based upon the specific contrast mechanism upon developing new nanostructures of different materials, sizes, which the imaging modality is based, independent of the and properties for biotechnological and medical applications size, composition, or function of the particular contrast and, in particular, for medical imaging. Much of this re- agent. Similarly, contrast agents can be classified to image

4474 Med. Phys. 35 „10…, October 2008 0094-2405/2008/35„10…/4474/14/$23.00 © 2008 Am. Assoc. Phys. Med. 4474 4475 N. Matsuura and J. A. Rowlands: Functional nanostructures 4475 particular characteristics of specific diseases and disease II. NANOSTRUCTURES FOR CLINICAL MEDICAL sites, for example, cancer, angiogenesis, atherothrombosis, IMAGING: CURRENT STATUS and musculoskeletal, neurological, and cardiovascular dis- Current nanostructures under investigation as contrast eases. agents for magnetic resonance imaging ͑MRI͒, x-ray com- Contrast agents may also be classified by size, indepen- puted tomography ͑CT͒, ultrasound ͑US͒, and nuclear imag- dently of imaging modality. The general subdivisions are ing ͓i.e., positron emission tomography ͑PET͒, and single small molecule contrast agents on the order of ϳ1nm͑gen- photon emission computed tomography ͑SPECT͔͒ include erally ഛ1000 Da͒; micron-scale contrast agents larger than assemblies of molecules ͑e.g., liposomes, micelles, na- ϳ1000 nm; and nanoscale contrast agents between ϳ1 and noemulsions͒, large macromolecules and dendrimers, or ϳ1000 nm in size. This size-based subdivision is convenient solid structures ͑e.g., metal, ceramic, or polymer nanopar- for both agent end-users and designers, because the in vivo ticles͒. The contrast agent may be a major component of the properties of nanoscale constructs are generally distinct from nanostructure, or it may be a high sensitivity, secondary those of small molecules ͑typically purely extracellular component attached to it. Despite significant differences be- agents͒ and micron-scale structures ͑typically purely intra- tween imaging modalities and nanostructures types, there are vascular blood pool agents͒, and because the synthesis for some commonalities and interrelationships between nano- different sizes/types of agents tend to be similar. Since nanostructure design and use in vivo. This section will briefly ͑ ͒ structures are one to three orders of magnitude smaller than summarize a the general features of nanoscale contrast ͑ ͒ cells, they can be used to obtain structural and functional agents and b factors to be considered for the successful information and to interface with molecular targets on or design of nanoscale contrast agents for the clinic. within cells, making them very promising for applications in molecular imaging.5–11 By definition, nanoscale contrast agents are always classified by size, irrespective of modality II.A. General features of nanoscale contrast agents or function for which they were designed. One reason why nanostructures are of interest in medical The use and properties of different types of nanostructures imaging is because their size imparts them with physiologi- as contrast agents have been extensively reviewed in the cal properties in vivo that are beneficial for imaging specific literature.12–21 Thus, this review will not catalog all current pathologies, compared to their smaller molecular ͑ϳ1nm͒ nanoscale contrast agents, but will rather provide a general or larger vascular ͑Ͼ1000 nm͒ counterparts. Since normal context for the existing literature for the nonspecialist, inde- vascular endothelia are permeable to agents less than ϳ2nm pendent of imaging modality, disease, and/or nanostructure in size, small molecule contrast agents commonly used in type, as well as speculate on future developments. We will MRI, CT, and nuclear imaging circulate systemically. Fol- introduce the underlying principles and challenges of nano- lowing injection into the intravascular space, they are rapidly scale contrast agent development, with the aim of providing diluted in the circulating plasma volume, and then rapidly researchers a condensed blueprint upon which innovative leak out of this space into the extra-vascular extra-cellular ͑ ͒ 22 new contrast agents can be rationally designed for clinical space interstitium . This results in short circulation times ͑i.e., minutes͒ due to their rapid metabolism and practice. 14,16,22 We begin in Sec. II by briefly summarizing the general excretion. This short half-life of small molecule con- features of nanostructures and factors that must be consid- trast agents can limit delivery and accumulation of the agent ered for their use as clinical nanoscale imaging contrast to the disease site and thus affect the ability to image diseased tissue above background levels. On the other hand, agents. Section III will expand on our premise that future larger, micron-scale contrast agents ͑e.g., microbubble con- development of new functional constructs will not only am- trast agents ϳ1000 to 8000 nm in size used in US plify imaging signals at disease sites for various imaging imaging23͒ cannot escape the vasculature and are conse- modalities, but also deliver localized therapy. We propose quently limited to blood vessels, which are typically that new functional nanostructures will develop in five basic 10 000 to 50 000 nm in diameter. ͑ ͒ directions: a Cooperative nanostructures with added func- Comparatively, medical nanostructures, with their inter- ͑ ͒ tionality, b modular nanostructures with synergistic func- mediate size, can “passively” extravasate to and accumulate ͑ ͒ tionality, c “smart” nanostructures that can be activated by in various diseased sites that have certain characteristic ͑ ͒ the in vivo environment, d cross-modal nanostructures that “leaky” pathological vasculature compared to normal healthy ͑ ͒ may be activated by means external to the patient, and e tissue. This leaky pathological vasculature occurs at tumor novel, nonspherical, nanostructure components. Section IV sites or in inflamed tissue, and can facilitate nanostructure highlights current issues preventing the rapid translation of accumulation to these sites via the “enhanced permeability preclinical nanostructures into the clinic, including ͑a͒ the and retention ͑EPR͒ effect.”24 This property, in combination wide knowledge gap between highly specialized and dispar- with the fact that nanostructures can be designed to have a ate fields, ͑b͒ the lack of specialized, early-stage validation prolonged circulatory half-life necessary to reach their target, tools, and ͑c͒ the lack of streamlined commercialization has resulted in extensive interest in using nanostructures for pipelines for the efficient translation of promising new the detection and treatment of diseases with leaky pathologi- agents into the clinic. In Section V are our conclusions. cal vasculature, such as cancer.13,16,21,25–27

Medical Physics, Vol. 35, No. 10, October 2008 4476 N. Matsuura and J. A. Rowlands: Functional nanostructures 4476

Another key feature of medical nanostructures is their potential to carry significant payloads of small molecular or particulate imaging agents within them or on their surface. For example, a nanostructure ϳ100 nm in diameter has a volume equivalent to ϳ100 000 small imaging molecules and a surface area equivalent to the cross-sectional area of ϳ10 000 small molecules. The localization of high concentrations of imaging agents within or on the surface of nanostructures combined with their preferential accumulation in target sites can enhance the image signal-to-noise ratio, reduce dosage, and limit toxicity by decreasing distribution of the imaging nanostructure in normal tissue.28 In addition to the EPR effect, nanostructures can potentially be designed to “actively” segregate to diseased tissue ͑or indicators of disease͒, through their conjugation to targeting moieties ͑e.g., peptides, aptamers, or antibodies͒ that specifically bind to surface epitopes or receptors preferentially 29–32 FIG. 1. The rational design of new nanostructures for clinical imaging ͑gray͒ overexpressed at disease sites. This type of active target- must holistically consider the imaging modality ͑blue͒, the imaging target ing may enhance the accumulation of nanostructures to dis- ͑yellow͒, and the in vivo properties ͑pink͒. This differs from the design of ease sites, which is the reason behind the proposed use of contrast agents for nonhuman subjects ͑green͒, nonspecific agents ͑purple͒, nanostructures for future molecular imaging applications. or targeted drug delivery vehicles ͑orange͒ that typically only have to consider two of these three factors. Nanostructures may also be used to revive small molecule agents that were previously limited by their innate nonideal in vivo properties. For example, the incorporation of imaging agents within nanostructures may increase the stability of in vivo properties ͑i.e., its pharmacokinetics, pharmacody- existing small molecule agents with short half-lives and namics, and biodistribution͒.36–39 There are also specific im- rapid clearance12,14,16,28 and allow molecular agents previ- aging modality-related accessibility issues that must be con- ously limited by their poor aqueous solubility to be used in sidered, e.g., the critical condition that relaxation-enhancing imaging and therapy applications.12,16,28,33–35 MRI contrast agents have access to water. Target accessibility must not only consider spatial accessibility, but how long the agent can circulate in the patient to II.B. Rational design of nanoscale contrast agents reach its target before being cleared from the system. The Much of the recent focus in nanostructure development is nanostructures need to be stable enough to circulate in the the rational design of new contrast agents for clinical imag- blood long enough to localize to disease sites while retaining ing. In general, a rational design must consider three interre- their payload/targeting ligands ͑e.g., at least ϳ2 to 3 h are lated factors: The imaging modality proposed to detect the required for all blood to complete passage through a remote contrast agent, the characteristics of the disease pathology to vascular bed40͒. Additionally, the nanostructures must be de- be imaged, and the behavior of the contrast agent in vivo. signed to take into account possible elimination by the This is contrary to the design of nanostructures for pharma- mononuclear phagocytic system ͑MPS͒. This can happen ceutical drug delivery, nonspecific imaging probes, or imag- within a few minutes and minimizes the quantity of nano- ing agents for nonhuman use, which typically require only structures passing by the target site and, if actively labeled, two of the three interrelated factors in their design ͑Fig. 1͒. significantly decreases their interactions with target antigens. For imaging, since the nanostructure must provide suffi- To avoid MPS elimination the nanostructure surface is typi- cient signal to identify disease pathologies and address a spe- cally cloaked, frequently with a hydrophilic polymer ͓e.g., cific biological question, the contrast agent is typically de- polyethylene glycol ͑PEG͒38,39,41,42͔ with low immunogenic- signed to maximize its imaging efficacy for a particular ity and antigenicity. imaging modality. The imaging modality ͑and thus contrast In opposition to the strategy of avoiding MPS elimination, mechanism͒ is selected based on the spatial and temporal nanostructures can be designed for maximal uptake by mac- resolution desired; the location, distribution, orientation, and rophages in vivo to track their fate for direct and indirect concentration of the target ͑i.e., the diseased tissue͒; the imaging of disease. For example, certain dextran-coated, specificity and sensitivity that can be achieved; the source long-circulating, superparamagnetic iron oxide ͑SPIO͒ nano- and locations of background and nonspecific signal; and the particles are preferentially taken up by macrophage cells, and requirement for target quantification. these cell-encapsulated long-lived entities can thus “pas- In parallel, the nanostructure design must take into con- sively” target pathological inflammatory processes for MR sideration the accessibility of the target and microscopic lo- imaging of atherosclerotic plaques.43 However, for effective cations of the epitopes ͑e.g., vascular, interstitial, membrane, in vivo use, the degree to which only target macrophages are or intracellular͒, and its ability to reach the disease site by labeled must be established for their use in this capacity. overcoming biological delivery barriers as determined by its Alternatively, “cell tracking” ͑the passive ex vivo labeling

Medical Physics, Vol. 35, No. 10, October 2008 4477 N. Matsuura and J. A. Rowlands: Functional nanostructures 4477 of cells with nanoscale imaging nanostructures followed by clinical utility. This motivates researchers to either synthe- reinjection into the patient͒ may be another way to counter size “new” agents with only incremental modifications to issues related to MPS elimination while achieving labeling clinically accepted technologies or to partially “develop” of specific cells without issues related to active, in vivo tar- high-risk/high-reward-type agents without rigorous testing or geting. This concept is in the early stages of being used to specific optimization for clinical use. This current paradigm track labeled stem cells and cancer cells,44,45 and to image for agent development is inefficient, expensive, leads to du- retransplanted cell populations ͑e.g., islets of Langerhans46͒ plication of effort, and has a disproportionate reliance on in animal models. Such ex vivo labeling methods will not luck and/or an ab initio, perfectly defined imaging/biology only require validation that the labeled cells will survive re- problem. This suggests that new, more general approaches to injection, but that they will retain their cellular functions as the design of functional nanostructures are needed. compared to healthy, unlabeled cells. Active targeting applications for nanoscale contrast agents III. TOWARDS NEW FUNCTIONAL require the appropriate selection of a suitable biomarker, the NANOSTRUCTURES development of a suitable conjugation strategy for the effec- In our opinion, the next decade will see the rational de- tive binding of the targeting ligand to the nanostructure sur- sign of a new generation of nanostructures for medical im- face, and the affinity of the selected targeting ligand to the aging progressing towards the inclusion of added functional- biological target of interest. It is also critical to consider the ity, with a focus on effective treatment and improved patient immunogenicity of the targeting ligands and proposed strat- outcome resulting from more sensitive and specific detection egies for conjugation to the nanostructure in their selection. of disease. Already, the role of nanostructures in medical For example, a common conjugation strategy in in vitro bio- imaging is expanding toward this goal, from simple detection diagnostic applications is the avidin-biotinylated ligand ͑pep- of disease to characterization/diagnosis of disease, local ap- tide or antibody͒ linkage system, which is rapidly cleared by plication of therapy, real-time assessment of response to the liver47 and is thus not feasible for in vivo clinical imag- therapy, and as a tool in the drug discovery and development ing. process.11,49–52 The continuing evolution of current nano- For translation of research-level nanostructures to clinical structures towards multifunctional, nanoscale medical de- imaging, the nanostructures’ biocompatibility ͑i.e., the poten- vices has been explicitly and implicitly anticipated in the tial short-term and long-term toxicity to the patient͒ is argu- recent literature.11,16,18,26,27,29,53–58 ably their biggest hurdle. This aspect differentiates We propose that new functional nanostructure designs nanostructures for use in humans from those used for will move away from the current paradigm of relatively ex vivo/in vitro cell studies, biodiagnostics, and/or in vivo simple, spherical nanostructures encapsulating imaging animal studies where such probes have found significant util- agents and/or targeting diseased tissues by size-specific or ity and success. The nanoscale quantum dot ͑QD͒ particle, a mono-ligand attachment. In this section, concepts that can successful optical probe for nonhuman applications, is an facilitate the development of novel, multifunctional nano- example of one such clinically limited imaging agent due to structures will be briefly described, along with proposals on its toxicity.14,27,35 In addition to not affecting cellular func- how new nanostructures could fulfill these functions. These tion, for potential clinical utility, the nanoscale imaging concepts are classified into five main directions, which are nanostructure must be formulated with either completely outlined below: ͑a͒ Modular nanostructures with additive nontoxic components, and/or must biodegrade to clearable functionality, ͑b͒ cooperative nanostructures with synergistic components, and/or must be small enough ͑i.e., with a hy- functionality, ͑c͒ nanostructures activated by their in vivo drodynamic diameter Յ5.5 nm͒ to permit complete elimina- environment, ͑d͒ nanostructures activated by sources outside tion from the body.48 These toxicity and elimination studies the patient, and ͑e͒ novel, nonspherical nanostructures and must be evaluated in both healthy and unhealthy patients. components. Such constraints drastically limit the choice of materials and types of nanostructures that can be used for the development of new nanoscale imaging agents for clinical applications. III.A. Evolution of modular nanostructures with additive functionality To a large extent, these three interrelated factors of imaging modality, imaging target, and in vivo properties will ͑1͒ The most obvious tactic for the evolution of multifunc- restrict the type of construct ͑e.g., liposomes, micelles, emul- tional nanostructures that will permit multiple imaging sions, polymers, dendrimers, and solid nanoparticles͒ that and/or therapy applications is a linear “add-on” approach, can be used, ͑2͒ determine its parameters ͑i.e., its where individual components ͑i.e., imaging agents and/or composition/structure, size, size distribution, surface proper- therapy agents͒ are combined to form a single multifunc- ties, and stability͒, and ͑3͒ dictate its in vivo properties. The tional construct.10,59,60 particular design challenges and constraints of new nano- This add-on approach has been explored in preclinical, structures for clinical medical imaging have resulted in an multimodal imaging applications. Numerous multimodal individualized approach to optimizing unifunctional, imag- nanostructures have been proposed, including many dual- ing constructs tailored for a single modality and specific dis- modal nanostructures ͑e.g., MRI/SPECT,15,61 MRI/PET,61 ease sites. Such an individualized approach forces an early, MRI/optical,20,62–64 and CT/MRI65͒, and a few tri-modal re- preclinical “stop-go” decision on the new agent’s potential porters ͑e.g., for PET, MRI, and fluorescence imaging,66 and

Medical Physics, Vol. 35, No. 10, October 2008 4478 N. Matsuura and J. A. Rowlands: Functional nanostructures 4478 for MR, CT, and US imaging67͒. It is worth noting that nanostructures can carry contrast agents for virtually all mo- complementary advances in multi-modal imaging systems dalities based on this principle.15,17 Also, the structure of have occurred, which are, in turn, expected to help drive the nanoscale constructs may accommodate payloads of mixed rapid development and implementation of new, correspond- molecular or particulate agents within their volumes or on ing multi-modal imaging nanostructures into the clinic. For their surfaces. example, dual-modality technologies are in various stages of Multifunctional nanostructures comprised of truly modu- development. PET/CT and SPECT/CT imaging systems are lar components will require significant technical advance- commonplace in the clinic as they can provide functional or ments, particularly in the area of “coatings” to integrate dif- molecular information using PET/SPECT molecular contrast ferent modular components. However, technical progress agents in the context of human anatomy using CT imaging.68 may be fast because this approach has already proved to be a Other dual-modality imaging systems include PET/MRI, valuable tool for the early, preclinical characterization of optical/PET,61 optical/SPECT,61 MRI/US, and MRI/CT sys- new nanostructures. Not only will this lead to faster assess- tems. The introduction of new technological systems into the ment and iteration of clinically useful nanostructures at an clinic may pave the way for new niche nanoscale agents to early stage of development, new common platform technolo- gain a foothold in the clinical environment. gies and strategies can thus be developed for the future ef- Similar to this multimodal concept of combining imaging fective integration of disparate modular components for probes into the same construct, extra nanostructure function- clinical imaging. For example, many new imaging nano- ality may be added by combining imaging and therapy structures are being designed to contain an optical marker for agents. For many decades, FDA-approved nanostructures preclinical cross-validation.20,62–64 The high sensitivity and have been used for the delivery of cancer therapeutics ͑e.g., subcellular spatial resolution of optical agents can be used to liposomes, albumin-based particles, nanoparticles͒, in clini- assess different targeting strategies in vitro, without altering cal trials ͑e.g., using polymeric micelles or polymer-based the overall properties of the nanostructure. Useful informa- particles͒, and in preclinical development ͑e.g., with den- tion about the agent may then be obtained prior to moving on drimers, inorganic or other solid particles͒.13,25,69,70 Since the to in vivo models. In the same manner, other validation mol- nanostructure is already optimized to localize to its target, ecules ͑e.g., those for histopathology60͒ may be integrated the integration of imaging agents to existing therapy agents into early-stage nanostructures to confirm the behavior and in the same construct, and vice versa, can allow for localized pharmacokinetics of preclinical agents for faster translation imaging as well as treatment.16,18,26,27,58,71,72 Furthermore, into the clinic. the addition of imaging agents to a therapeutic nanoscale In general, designing multimodal and multifunctional construct may alter the acceptable toxicity profile compared nanostructures will remain challenging compared to design- to an imaging agent alone. Since both imaging and therapeu- ing unimodal or unifunctional nanostructures. The integra- tic nanostructures have been independently used in tion of two or more different agents within the nanostructure humans,12 combining imaging and therapy agents is expected will add a level of complexity to their synthesis, will de- to be the most likely path for future functional nanostructures crease the loading capability of each individual agent, and to be translated to clinical use. may change the overall nanostructure’s pharmacokinetics One of the more intriguing subconcepts to this add-on and stability. To counter this, nanostructures that provide in- approach is the potential to make “designer” agents via trinsic contrast in more than one imaging modality can be “modular” nanoscale construct assembly. By decoupling the exploited. For example, Gd-chelates can provide contrast in nanostructure components from each other, independently both MR and CT.73 Perfluorocarbon droplets and their de- assessing and optimizing these components, and reassem- rivatives have been used to provide contrast in CT,74–76 US,77 bling them into nanostructures using optimized components, and/or MR78–80 imaging, and have also been demonstrated as constructs tailored for specific imaging modalities and dis- drug delivery vehicles81 and as radiosensitizers.82 ease pathologies may be easily designed. These new composite nanostructures may be rapidly translated to the clinic. Although the properties of the overall construct may be III.B. Evolution of cooperative nanostructures systems with synergistic functionality somewhat modified using this approach, this differs greatly from molecular conjugates, whose behaviors in vivo are so The development of new functional nanostructures may particular to their specific molecular structures that indi- also occur through the evolution of nanostructures designed vidual characterization of even slightly different agents is a to have an increased and predictable ability to interact with necessity. their targets and/or other nanostructures. Instead of changing Tailoring the components of the nanostructure in a the components of a single nanostructure to increase its func- pseudo-modular fashion may be accomplished because many tionality in an additive function, it may be possible to design imaging nanostructures already are comprised of an intrinsic nanostructures such that their cooperative interaction be- bi-component, core-shell-type structure, which may facilitate tween multiple constructs and/or their intended target allows similar types of molecules or components replacing one an- them to increase their utility as an imaging and/or therapeutic other. Such replacements can drastically change its function agent. as an imaging and/or therapy agent, but minimally change its Modifications of the constructs’ size or surface properties in vivo properties. For example, liposomal and micelle-based may lead to changes in their interactions with the target rela-

Medical Physics, Vol. 35, No. 10, October 2008 4479 N. Matsuura and J. A. Rowlands: Functional nanostructures 4479 tive to normal tissue such that the contrast agents can accu- from the system before introduction of the next, which may mulate disproportionately ͑i.e., nonlinearly͒ in the disease be feasible if each nanostructure’s surface ligands require site, or result in a spatial distribution of individual nanoscale multivalent binding for attachment. constructs that will otherwise provide signal amplification. Other cooperative effects between nanostructures can be Such signal amplification is significant in imaging applica- used to help diagnose disease, e.g., through exploitation of tions where increasing signal to noise can decrease the lower the expected spatial distribution of targeted nanostructures at limit for detection ͑currently on the order of hundreds of disease sites. Since agglomerated iron oxide nanostructures millions of cells͒, as well as in pharmaceutical delivery result in a significantly larger MR signal than the same mass where any advantage in therapeutic ratio may play a role in of material dispersed into multiple, smaller units,89 targeted improved patient outcome. iron oxide nanoparticles accumulated at a disease site may The simplest example of nonlinear, preferential accumu- cooperatively result in an “amplified” signal. Other preclini- lation of nanostructures is the localization that occurs via the cal examples of nanostructures that may result in amplified EPR effect at disease sites with leaky pathologies. In addi- imaging signals after accumulation compared to their dis- tion to size-dependent accumulation, further nonlinear accu- persed forms include perfluorocarbon droplets, which give mulation may occur by modifications to the nanostructure’s an enhanced backscatter signal in US imaging,90 and aggre- surface. This is the underlying concept behind enhancing gated gold nanostructures, which result in enhanced size-dependent nanostructure localization in diseased tissue photothermal-based imaging and therapy in live cells.54 Also, through active targeting, or the simple attachment of target- as the relaxation properties in Gd-based MRI contrast agents ing molecules to the nanostructure’s surface for further im- are dependent on their attached ligands and/or surrounding aging or therapeutic amplification.13,16,21,25–27 In opposition environment,91 and size and surface effects have been shown to the concept of preferential accumulation at disease sites, to affect the properties of iron-based nanostructures,92 their the nanostructure’s surface may be tailored to assist its clear- aggregation and/or successful attachment to their target may ance and/or elimination from nontarget tissue to reduce back- significantly increase their signal such that they could be ground noise and toxicity.83–85 distinguished from background noise. More complex strategies for nonlinear accumulation are There are significant challenges in designing new agents possible. This concept is particularly beneficial for the pref- using these proposed cooperative and synergistic approaches. erential discrimination of disease sites from normal tissues These challenges lie in the effective and controlled conjuga- that express the same biomarkers of disease but at different tion of different targeting molecules to the surfaces of nano- levels. The large surface area of the nanostructure compared scale structures, and the effective synthesis of new agents to targeting ligands ͑which range from ϳ1toϳ20 nm in with such nonlinear properties, which will, by definition, be size͒ potentially allows the attachment of multiple targeting very sensitive to these factors. The determination of effective ligands. This may facilitate multivalent binding to cell sur- amplification strategies for nanostructure imaging will result face receptors such that collections of low-affinity ligands from the development of highly nonlinear contrast agent can have very high “effective” affinities.86–88 This not only configurations, and correlations with disease parameters, can greatly expand the range of useful, active targeting such as biomarker/target distribution in vivo. Appropriate ligands, but may allow nanostructures to be conjugated to combinations of various low-affinity targeting ligands, multiple weak-binding ligands for disease-specific biomark- and/or their disease-dependent distribution, must also be well ers such that they would bind only to sites expressing abnor- understood in order to detect disease sites compared to normally high levels of the biomarker, but not at normal, lower mal tissue. levels. Further enhancement of preferential targeting may be accomplished by using several sets of nanostructures, each labeled with weak-binding ligands for different biomarkers III.C. Evolution of “smart” multifunctional nanostructures that may be activated by the in vivo expressed by a disease. A similar strategy, but more techni- environment cally challenging, would be to use several different biomarkers on the same nanostructure such that disease targets that Recently, new types of “smart” contrast agents, designed express relative proportions of a series of agents will result in to activate exclusively in the presence of their intended tar- preferential nanostructure accumulation. get, have been proposed.6,7,49,51 Due to the absence of a The accumulation of nanostructures at a disease site may background signal, these agents have a significant signal ad- be augmented through the use of a series of different sets of vantage over simple targeted agents. Most of the more so- targeted nanostructures. After saturating the disease site with phisticated examples of these sensor-type, activatable con- a first set of targeted nanostructures, it may be possible to trast agents in the research literature are small molecule add a second, labeled nanostructure that could attach only to agents in the early stages of development, including MR multiple nanostructures of the first kind, and so on, such that agents that exhibit an enhancement in contrast in the pres- imaging and/or therapeutic nanostructures could preferen- ence of ␤-galactosidase,93 and optical imaging probes acti- tially, and controllably, accumulate at the disease site. In or- vatable by enzymes.6,49,51,94,95 The development of activat- der to prevent nonspecific, uncontrolled accumulation, which able nanostructures ͑rather than activatable molecular agents͒ could lead to thrombosis and/or high background imaging may potentially result in even higher signal to noise ratios, signals, each type of nanostructure must be fully cleared because the activation may be magnified by the larger size/

Medical Physics, Vol. 35, No. 10, October 2008 4480 N. Matsuura and J. A. Rowlands: Functional nanostructures 4480 volume of the nanostructure. They can also have a signifi- The challenges associated with making complex, environ- cantly longer half-life to accumulate and localize in greater mentally activatable contrast nanostructures are that such numbers in diseased tissue. nanostructures ͑and their molecular components͒ are cur- The most straightforward type of environmentally activat- rently difficult to synthesize and design, and significant bar- able nanostructures simply dissolve and/or aggregate in cer- riers in the complex biological environment of the human tain in vivo environments. In fact, the controlled, environ- body must be overcome before reaching the target site. One mentally dependent degradation of nanostructures into their possible approach to shielding the nanoscale components molecular components in vivo has been the basis for pharma- from the biological environment is to use a biological entity ceutical delivery of drugs for decades.96,97 More recently, as a delivery vehicle. Already, modified lipoproteins120 and pH- and temperature-responsive polymeric nanostructures cells have been used as carriers for contrast nanostructures, for potential imaging and drug delivery applications have and the tracking of stem cells, cancer cells, and macrophages been reported in the preclinical research literature.98–103 have been demonstrated in vivo.43–45 Simple nanostructures can also aggregate in certain in vivo For environmentally activatable nanostructures to be de- environments resulting in a significant change in imaging signed and utilized, and for the considerable technical chal- signal. For example, preclinical iron oxide-based nanostruc- lenges of synthesizing the agents themselves to be overcome, tures for MRI have been shown to undergo reversible clus- it is critical to understand how the contrast signal correlates tering in the presence of enzymes, chemical compounds,104 to the physical changes in the nanostructure ͑i.e., its degra- or analytes ͑e.g., glucose105 or calcium106͒. dation and/or self-assembly͒, how these structural changes One intriguing concept that has not been extensively ex- are related to environmental conditions ͑e.g., hypoxia/ plored in medical imaging is the controlled in vivo assembly oxygenation, pH, and temperature͒, and how these changes of nanostructures at the target site. Many nanostructures are correlate to disease pathologies. composed of atoms or molecules that assemble together via intermolecular bonding using “weak” chemical bonds. Since nanostructures have large surface-area to mass ratios, surface III.D. Evolution of multifunctional cross-modal nanostructures that may be activated by devices effects ͑e.g., intermolecular bonding͒ and surface-dominated external to the patient reactions ͑e.g., surface oxidation, saturation of dangling surface bonds͒ are strongly enhanced in nanoscale constructs. New types of nanostructures that can be remotely acti- For example, the weak noncovalent forces between molecu- vated by an energy source external to the patient are also lar components that dominant at the nanoscale ͑i.e., the con- under investigation. External triggering from energy sources struct’s stability͒ are highly sensitive to slight changes in using different imaging modalities may localize the agent to their surrounding environmental conditions ͑e.g., tempera- its target site, excite the agent to emit a detectable signal ture, pH͒107–109. above background noise, and/or produce a local therapeutic These environmentally sensitive surface properties can be effect. utilized to modify and/or assemble/disassemble structures Externally applied US energy can push contrast nano- under appropriate conditions in situ, as a function of their structures in the vasculature towards the target site using environmental surroundings in a simplified mimicry of bio- radiation force, to increase local binding121 or to cause indi- logical self-assembly processes ͑i.e., “biomimetics”͒.40,110–115 vidual particles to attract each other and coalesce.122 This Transient, metastable nanostructures can be constructed from same concept may allow US to be used to improve the lo- biological or exogenous molecules that will self-assemble calization of other ͑i.e., non-US͒ imaging and therapy nano- in vivo for short periods of time, depending on the local structures. This type of controlled localization of selected environment or external application of energy. This concept structures external to the patient may also eventually facili- could be expanded further such that nanoscale reaction tate the directed self-assembly of larger constructs in vivo at vessels116–118 for the fabrication of contrast nanostructures a target site. could be assembled within the biological system. The use of In another example of localization, externally applied smaller molecular components in vivo that can assemble di- magnetic fields have been used to control and track magnetic rectly at the target site may allow larger nanostructures to be beads using magnetic field gradients to increase localization/ built at the target without prior elimination by the MPS. binding to target sites in preclinical systems.123–126 The con- A simple example of in vivo “assembly” of a larger struc- cept of enhanced localization of drugs using this method may ture from smaller nanostructure components can be found in be envisioned, as magnetic particles have been coupled with the preclinical literature, where nanostructures ͑i.e., perfluo- pharmaceutical agents124 and therapeutic radiolabeled rocarbon nanodroplets and drug-loaded micelles͒ were in- molecules.126 jected into an animal model. After injection, the nanostruc- Imaging modalities have been used to activate an exog- tures underwent temperature-induced coalescence and enous contrast nanostructure in vivo from outside the body. conversion to form micron-scale gas-filled microbubbles.119 For example, US can convert contrast nanostructures ͑e.g., Further, it was reported that microbubbles “created” in vivo perfluorocarbon emulsions͒ to gas bubbles, thereby signifi- not only acted as effective acoustic scatterers for US imag- cantly increasing their acoustic contrast127 and signal to noise ing, they could also be disrupted by US to enhance the de- such that single bubbles may be imaged in vivo. The energy livery of their encapusulated therapeutic cargo.119 of the imaging system can also be applied to nanostructures

Medical Physics, Vol. 35, No. 10, October 2008 4481 N. Matsuura and J. A. Rowlands: Functional nanostructures 4481 to directly induce a therapeutic effect and/or to trigger the modifications.101,139,140 The main focus in medicine has been release of their encapsulated therapeutic payload in vivo. For on finding unique medical applications for traditional nano- example, in MR, there has been considerable effort in heat- structures instead of designing new types of unique struc- ing iron oxide nanostructures using RF to cause local tures tailored for medicine. In reality, advanced synthesis hyperthermia.126,128,129 techniques developed for the fabrication of intricate 3D We predict a surge of interest in the development of cross- nanoscale architectures remain largely unexplored and un- functional nanostructures, in which the full suite of clinical derutilized in medical imaging compared to other fields ͑e.g., medical imaging technologies will be harnessed for com- optoelectronics͒. bined imaging and therapy. For example, it is possible to use Currently, there are methods to synthesize 1D ͑wire-type͒, the energy from one imaging modality to activate a contrast 2D ͑sheet-type͒, and complex 3D hierarchical nanostructures agent, and another imaging modality for its detection. Some ͑e.g., carbon nanotubes and fullerenes141͒, as well as nano- preclinical examples include a demonstration that the absorp- structures of different shapes including rods, cubes, tetra- tion of light into nanostructures can result in the formation of pods, and coils.142–145 New nanostructures developed to gas bubbles at their surfaces which may be detected by US.54 maximize contrast phenomena can be fabricated, e.g., nano- In another example, light was used to induce the release of scale magnetic coils may be synthesized to label cells or be MR contrast agents from nanostructure micelles in vitro.130 targeted to disease sites for tracking and imaging using MRI. For cross-modal imaging and/or therapy, it is feasible to use Recent advances in the biomolecular-assisted assembly of metal-based nanostructures as both CT contrast agents131,132 nanostructures using biological components such as DNA, and to enhance the RF-based thermal destruction of cancer antibodies, viruses, and proteins, as well as the development cells.133 Magnetic nanostructures have also been combined of various hybrid materials based on proteins that bind spe- with light-activated chemotherapy drugs ͓i.e., photodynamic cifically to inorganic materials,111–115 may allow unique, fully cancer therapy ͑PDT͔͒ for enhanced cell death.53,134 biocompatible, in vivo self-assembly of complex functional US agents have been used to enhance drug delivery from devices to take place. the vasculature into tissue across the blood-brain barrier by These nanostructures may in turn be used as building causing localized release from a carrier vehicle or by increas- blocks or components for new 2D/3D hierarchical “super- ing cell membrane permeability by mechanical or thermal structures” by their controlled aggregation using non- action.135,136 The enhanced delivery of secondary imaging covalent interactions between them. Novel nanoscale compo- and/or therapy agents ͑e.g., therapeutic nents may allow nonspherical hierarchical structures to radiopharmaceuticals,137 therapeutic gold compounds138͒ by assemble in situ to form new devices at length scales that can such external means can be easily envisaged. Expanding on be adaptable according to their in vivo environment, and this concept, it may be possible for nanostructures to carry thereby potentially result in contrast agents with tunable targeting ligands or other components of self-assembly, properties. For example, nanoscale cantilevers26 could be as- which may be externally triggered to release their contents sembled in vivo such that one end could be attached to the near their intended targeting site to form a larger construct disease site while the other end is free. The formation of such with higher signaling capabilities. structures could be binary, dependent on the initial deposi- There are several key issues that must be considered in tion of a minimal number of “priming” ligands deposited at the development of agents that may be controllably activated the disease site. If such cantilever-type nanostructures can be by energy sources external to the patient. The nanostructures assembled at disease sites and are sensitive to US frequen- must be activatable using a minimum amount of energy such cies, they could be used as an adjunct to traditional spherical that normal tissue is undamaged; the energy used must result gas or fluid-filled contrast agents for US imaging, but with in a high enough signal to detect small numbers of agents completely different, and tailored, material properties ͑e.g., and/or induce a significant therapeutic response; and the dy- composition, size, surfaces, and stability͒. This means that namic in vivo environment must be considered in the devel- traditional limitations as determined by the imaging modal- opment, validation, and characterization of the more com- ity, biological target site, and/or in vivo properties may be plex, externally activatable agents. circumvented through the synthesis of, effectively, a new designer material that does not pre-exist in nature. The forces acting on nonspherical nanostructures will be III.E. Evolution of novel, nonspherical, nanostructure orientationally and environmentally dependent, which could components be utilized in different hydrodynamic environments.26,146,147 Most nanostructures designed for medical imaging are For example, nanorods, with different functionalization at simple, spherical, so-called “zero-dimensional ͑0D͒” con- the tips than on the lengths,144 may be designed to self- structs. 0D nanostructures are easy to synthesize by methods assemble into different structures depending on the disease- that can be directly adopted from simple, decades-old, syn- dependent hydrodynamic and biological environment ͑e.g., thesis technologies. Although such nanostructures can have within tumors compared to in normal vasculature͒. The un- simple functionality ͑e.g., agent loadability, ligand attach- derstanding of the properties of particular disease patholo- ment for targeting, and controlled dissolution͒ they have gies may be exploited in the development of new shape/size/ been largely adopted from other fields ͑e.g., optoelectronic or surface-specific nanostructures to further differentiate slight drug delivery͒ without any major structural pathological differences, much in the same way that the EPR

Medical Physics, Vol. 35, No. 10, October 2008 4482 N. Matsuura and J. A. Rowlands: Functional nanostructures 4482 effect has been the key to developing imaging and pharma- imaging modality also depends on the expected target distri- ceutical nanostructures for cancer detection and therapy. bution within the patient—e.g., whole body ͑tomographic͒ The emergence of new imaging modalities should play a imaging can be done with CT, MRI, and nuclear imaging, role in propelling the development of new complementary but is not commonly undertaken with US or optical imaging. contrast agents and increase the functionality of existing For combined detection and therapy, the imaging properties nanostructures. One example gaining in popularity is trans- must be weighed with the desired effect of the therapeutic cutaneous optical imaging, which has led to the development agent, as determined by its degradation rate, concentration, 148 of biocompatible molecular near-infrared probes. In addi- and effective target delivery. All these factors must be con- tion to current fluorescence and luminescence methods, other sidered for the efficient development of new nanostructures aspects of optical technology ͑including absorption, emis- for medical imaging, and will facilitate the design of new sion, and scattering techniques͒ will require the optimization contrast agents and imaging techniques to allow not only the of new contrast agents to complement these different contrast agents’ detection but also their quantification, allowing spe- mechanisms. cific information about the changes in expression levels of The main challenge in developing new types of nano- the target to be obtained. structures for functional imaging is that they must truly be The wide knowledge gap between the disparate fields in- rationally designed for them to be successful. A thorough volved in the design of new functional nanostructures must understanding of the imaging and disease parameters is nec- be addressed. Critical bottlenecks in nanostructure agent de- essary, and the dependence on variations in size, composi- velopment are often not elucidated preventing progress in tion, and morphology should be established beforehand. The creating suitable nanostructures for medical imaging. Re- design of new nanostructure must be balanced with practical cently, many institutes and government agencies have recog- issues of cost and yield, which will depend greatly on the nized the importance of communication within this interdis- synthesis method. ciplinary ensemble of highly specialized fields and have implemented interdisciplinary teams to increase the effi- IV. STRATEGIES FOR MOVING FORWARD ciency of their interactions.57,149,150 Despite the innumerable nanostructures outlined in the Another simple way to link the scientific community is to preclinical research literature, the translation of new nano- utilize the massive information sharing capability of the in- structures into humans is in the early stages. For example, in ternet to develop a database of core parameters that identify 2006, the only marketed nanoscale contrast agents were three different types of imaging and therapeutic nanostructures, superparamagnetic iron oxide nanoparticle contrast agents their correlative compositions, and their imaging and in vivo for MRI.69 To facilitate the rapid progression of new, func- properties. Recently, the National Center for Biotechnology tional nanostructures into the clinic, we must address three Information ͑NCBI͒ at the National Institutes of Health main challenges: ͑a͒ Improving the clarity of both the desired ͑NIH͒ implemented such a freely accessible online database nanostructure properties and the challenges needed to be ͑MICAD͒151 to provide the scientific community working overcome for their successful implementation, ͑b͒ determin- with in vivo molecular imaging and contrast agents with in- ing better methods to test and validate the new nanostruc- formation aimed to foster research and development. A simi- tures early in their development, and ͑c͒ developing accepted lar database focusing on nanoscale agents should be devel- and established strategies for the efficient translation of new oped, supplemented by correlative databases that identify the nanostructures from the lab bench into the clinic. parameters desired from an imaging perspective ͑e.g., ideal type/number/distribution of molecular or atomic units re- IV.A. Improved clarity of desired properties and quired per unit, size range, amount of agent required, special existing challenges considerations/parameters͒, a biological perspective ͑e.g., The development of new functional contrast agents re- ideal disease targets, targeting ligands/biomarkers, delivery quires the convergence of highly specialized and disparate paths, safety data͒, and a commercial/market perspective fields. In addition to overcoming the biological issues ͑effec- ͑e.g., the desired yield, purity and final application/market tive delivery to the target, biocompatibility, toxicity͒ and fab- demand and size͒. In addition to being freely accessible, rication issues ͑synthesis, yield, quality assurance͒ as out- these databases should be linked, cross-searchable, and able lined earlier in this review, it is also necessary to overcome to accommodate dynamic adaptation by the users. Although medical imaging issues ͑to obtain sufficient contrast for im- some specific fabrication protocols may be restricted due to aging͒. patenting and commercialization concerns, the protocols and Through collaboration with physicians, biologists, and procedures employed for characterization of the agents as chemists, medical physicists must determine the appropriate well as their properties should be listed, which will assist in design parameters, such as minimum required loading, and establishing baseline standards for development of new ideal agent and imaging timepoints, in parallel with the spa- nanostructure agents. This massive collaborative effort tial resolution required for disease diagnosis. For contrast should help differentiate which nanostructures are in the agent design and determination of minimum detection limits, early, mid, and late stages of development; identify major the expected number, location, and distribution of the target knowledge gaps and the likelihood of the successful transla- should be known. The overall suitability of the particular tion of various agents to the clinic; and help scientists to

Medical Physics, Vol. 35, No. 10, October 2008 4483 N. Matsuura and J. A. Rowlands: Functional nanostructures 4483 converge toward the most optimal nanostructure design pa- IV.C. Development of commercialization pipelines, rameters to yield the greatest patient beneﬁt. scale-up strategies, and regulatory process negotiation for efﬁcient clinical translation

IV.B. Development of early-stage validation and The move from laboratory-based probes to clinical agents characterization tools specific for nanostructure is long, arduous, and extremely costly. Since nanoscale imaging and therapy applications agents use macroscopic amounts of material, a full drug toxicity study must be conducted, and this realistically requires First, the development of common standards and valida- a market/application that can support these costs. The fact tion tools for functional nanostructure assessment will be that IP protection must typically be obtained for clinical necessary to streamline and adequately evaluate the thou- translation of new agents is another issue that must be ad- sands of nanostructures under investigation for imaging and dressed. This is not unique to imaging probes, but is an issue therapy applications reported in the literature. Currently, spanning the biotechnology and drug sectors. Suitable mod- even agreement on what constitutes agent size has not been els to overcome considerable commercialization, scale-up, ͑ standardized e.g., hydrodynamic radius versus “dry” ra- and regulatory hurdles are necessary for this ͒ 26,40,69,150,152–154 dius , and something as simple as the adoption of common translation. units to quantify size would help alleviate the confusion be- Stringent regulatory approval issues will limit the transla- ͑ 26 tween chemists who measure size using atomic mass Dal- tion of most new nanostructures to the clinic. In addition to ͒ ͑ tons and physicists who measure linear dimension nanom- the assessment of their biocompatibility, biodistribution, and ͒ eters . Also, it would be beneficial to establish “gold- production protocols, nanostructures could fall under the standard” protocols for the assessment of toxicity/safety and drugs, medical devices, and biological agents branches of the bioconjugation, and for allowing different agents and numer- Food and Drug Adminstration ͑FDA͒,26 further complicating ͑ ͒ ous and occasionally contradictory protocols in the litera- an already unpredictable process. The time and cost required ture to be compared, while reducing the abundance of re- to translate a new agent for clinical use is considerable— search nanostructures to those that have met a known, although estimates vary, the translation of a single agent accepted standard. In addition, the development of validation from bench to bedside requires a commitment of 35–61 mil- tools specifically for nanostructure imaging agents would be lion dollars and 2 to 4 years.153 In general, countries outside useful. Currently, most researchers cannot image nanostruc- the United States have a less stringent approval process, with tures on a subcellular scale without an integrated optical biomedical products typically marketed in Europe and/or marker. The development of a suite of subcellular and other Canada for 2–3 years before they receive US regulatory high-resolution imaging tools that mimic clinical systems approval,40 which often provides an opportunity to gain extra may allow early assessment of nanostructures, which could clinical experience with a product prior to FDA review.40 lead to faster iteration of nanostructure design in the early The transfer of knowledge into practice requires a stream- developmental stage. lined approach and the identification and negotiation of Second, it would be very useful if common platform tech- bottlenecks in the technology transfer pipeline. Piggybacking nologies could be developed such that the targeting ligands, off of prevalidated or semi-validated imaging or pharmaceu- bioconjugation strategies, surface, interfacial, and capping tical agents to develop new products, prior working knowl- layers could be tested independently of the imaging con- edge of the intricacies of the approval process, and strong struct. In this way, it may be possible to develop a consistent assessment of the nanostructures prior to clinical trials may description of the behavior of nanostructures in biological be a few ways to increase the chances of translation to the systems as a function of nanostructure size, structure, and clinic. The faster establishment of safe regulatory approval material composition. The ability to tune the surfaces to be protocols would ameliorate concerns about the length of time efficiently “capped” by various targeting/shielding ligands it takes for agents to be assessed by the FDA.26 would also assist in differentiating the properties of the nanostructure from the properties of their surfaces ͑e.g., structure vs. charge͒. Current challenges such as hydrodynamic size V. CONCLUSIONS effects, pH stability of the composite structures, and repro- Researchers are on the path towards designing functional ducibility ͑biological versus structural͒ issues may be ad- nanostructures through the increased sensitivity of imaging dressed using universal nanoscale constructs. This can lead modalities, the advancement of nanoscale fabrication and to predictive models of nanostructure systems, and further to characterization technologies, and a better understanding of the engineering of specific nanostructures tailored to biologi- the biology of disease, including the sequencing of the ge- cal applications. nome that has identified new potential disease targets.6,155 Already, the concept of using standardized, validated Future nanostructures will be designed to have added func- nano-based imaging agents for the real-time assessment of tionality through assembly of prevalidated, modular compo- the efficacy of therapeutic regimens as a complement to, or a nents, or will be designed with amplified functionality substitute for, conventional end point analysis has been through synergistic effects. Such nanostructures can be acti- proposed.26 This application can assist in the design and ad- vated for imaging and/or therapy applications either by their vancement of standardized, nanostructure-based validation in vivo disease environment or through activation external to tools. the patient. Also, the development of novel nanostructures

Medical Physics, Vol. 35, No. 10, October 2008 4484 N. Matsuura and J. A. Rowlands: Functional nanostructures 4484 will facilitate the design of entirely new nanoscale agents for 19S. A. Wickline, A. M. Neubauer, P. M. Winter, S. D. Caruthers, and G. M. imaging and therapy applications. The development and Lanza, “Molecular imaging and therapy of atherosclerosis with targeted nanoparticles,” J. Magn. Reson Imaging 25͑4͒, 667–680 ͑2007͒. clinical translation of next-generation nanostructures will be 20W. J. Mulder, G. J. Strijkers, G. A. van Tilborg, A. W. Griffioen, and K. facilitated by a combination of improved clarity of the in Nicolay, “Lipid-based nanoparticles for contrast-enhanced MRI and mo- vivo imaging challenges and the requirements to successfully lecular imaging,” NMR Biomed. 19͑1͒, 142–164 ͑2006͒. 21 overcome them; development of standardized characteriza- I. Brigger, C. Dubernet, and P. Couvreur, “Nanoparticles in cancer therapy and diagnosis,” Adv. Drug Delivery Rev. 54͑5͒, 631–651 ͑2002͒. tion and validation systems tailored for the preclinical as- 22P. Dawson, “Functional imaging in CT,” Eur. J. Radiol. 60͑3͒, 331–340 sessment of nanostructure agents; and development of ͑2006͒. streamlined commercialization strategies and pipelines tai- 23D. Cosgrove, “Ultrasound contrast agents: An overview,” Eur. J. Radiol. ͑ ͒ ͑ ͒ lored for nanostructure-based agents for their efficient trans- 60 3 , 324–330 2006 . 24H. Maeda, T. Sawa, and T. Konno, “Mechanism of tumor-targeted deliv- lation to the clinic. ery of macromolecular drugs, including the EPR effect in solid tumor and clinical overview of the prototype polymeric drug SMANCS,” J. Con- ACKNOWLEDGMENTS trolled Release 74͑1–3͒, 47–61 ͑2001͒. 25N. G. Portney and M. Ozkan, “Nano-oncology: Drug delivery, imaging, The authors would like to acknowledge Dr. Elizabeth Gil- and sensing,” Anal. Bioanal. Chem. 384͑3͒, 620–630 ͑2006͒. lies ͑University of Western Ontario͒, Dr. Greg Stanisz ͑Sun- 26M. Ferrari, “Cancer nanotechnology: Opportunities and challenges,” Nat. ͒ ͑ Rev. Cancer 5͑3͒, 161–171 ͑2005͒. nybrook Health Science Centre , and Dr. John Valliant Mc- 27 ͒ K. Y. Kim, “Nanotechnology platforms and physiological challenges for Master University for critical review of the manuscript. This cancer therapeutics,” Nanomedicine 3͑2͒, 103–110 ͑2007͒. work was supported by the CIHR Excellence in Radiation 28H. Devalapally, A. Chakilam, and M. M. Amiji, “Role of nanotechnology Research for the 21st century ͑EIRR21st͒ Research Training in pharmaceutical product development,” J. Pharm. Sci. 96͑10͒, 2547– ͑ ͒ Program, and the Ontario Institute for Cancer Research Net- 2565 2007 . 29R. Sinha, G. J. Kim, S. Nie, and D. M. Shin, “Nanotechnology in cancer work through funding provided by the Province of Ontario. therapeutics: Bioconjugated nanoparticles for drug delivery,” Mol. Can- cer Ther. 5͑8͒, 1909–1917 ͑2006͒. ͒ a Author to whom correspondence should be addressed. Electronic mail: 30T. M. Allen, “Ligand-targeted therapeutics in anticancer therapy,” Nat. [email protected] Rev. Cancer 2͑10͒, 750–763 ͑2002͒. 1T. M. Allen and P. R. Cullis, “Drug delivery systems: Entering the main- 31L. Nobs, F. Buchegger, R. Gurny, and E. Allemann, “Current methods for stream,” Sciences ͑N.Y.͒ 303͑5665͒, 1818–1822 ͑2004͒. attaching targeting ligands to liposomes and nanoparticles,” J. Pharm. Sci. 2R. H. Muller and C. M. Keck, “Challenges and solutions for the delivery 93͑8͒, 1980–1992 ͑2004͒. of biotech drugs—a review of drug nanocrystal technology and lipid 32B. Stella, S. Arpicco, M. T. Peracchia, D. Desmaele, J. Hoebeke, M. nanoparticles,” J. Biotechnol., 113͑1–3͒, 151–170 ͑2004͒. Renoir, J. D’Angelo, L. Cattel, and P. Couvreur, “Design of folic acid- 3R. M. Kniseley, “Marrow studies with radiocolloids,” Semin Nucl. Med. conjugated nanoparticles for drug targeting,” J. Pharm. Sci. 89͑11͒, 1452– 2͑1͒, 71–85 ͑1972͒. 1464 ͑2000͒. 4P. Dawson, D. O. Cosgrove, and R. G. Grainger, ͑eds.͒, Textbook of 33D. Horn and J. Rieger, “Organic nanoparticles in the aqueous phase- Contrast Media. ͑Isis Medical Media, Oxford, 1999͒. theory, experiment, and use,” Angew. Chem., Int. Ed. 40͑23͒, 4330–4361 5R. Weissleder, “Molecular imaging: Exploring the next frontier,” Radiol- ͑2001͒. ogy 212͑3͒, 609–614 ͑1999͒. 34B. E. Rabinow, “Nanosuspensions in drug delivery,” Nat. Rev. Drug Dis- 6S. R. Cherry, “In vivo molecular and genomic imaging: New challenges covery 3͑9͒, 785–796 ͑2004͒. for imaging physics,” Phys. Med. Biol. 49͑3͒, R13–R48 ͑2004͒. 35S. Nie, Y. Xing, G. J. Kim, and J. W. Simons, “Nanotechnology applica- 7A. S. Dzik-Jurasz, “Molecular imaging in vivo: An introduction,” Br. J. tions in cancer,” Annu. Rev. Biomed. Eng. 9, 257–288 ͑2007͒. Radiol. 76͑Spec. No. 2͒, S98–S109 ͑2003͒. 36R. K. Jain, “Transport of molecules in the tumor interstitium: A review,” 8R. J. Gillies, “In vivo molecular imaging,” J. Cell Biochem. Suppl. 39, Cancer Res. 47͑12͒, 3039–3051 ͑1987͒. 231–238 ͑2002͒. 37R. K. Jain, “Delivery of molecular and cellular medicine to solid tumors,” 9H. R. Herschman, “Molecular imaging: Looking at problems, seeing so- Adv. Drug Delivery Rev. 46͑1–3͒, 149–168 ͑2001͒. lutions,” Sciences ͑N.Y.͒ 302 ͑5645͒, 605–608 ͑2003͒. 38S. M. Moghimi and J. Szebeni, “Stealth liposomes and long circulating 10A. Hengerer, A. Wunder, D. J. Wagenaar, A. H. Vija, M. Shah, and J. nanoparticles: Critical issues in pharmacokinetics, opsonization and Grimm, “From genomics to clinical molecular imaging,” Proc. IEEE protein-binding properties,” Prog. Lipid Res. 42͑6͒, 463–478 ͑2003͒. 93͑4͒, 819–828 ͑2005͒. 39S. M. Moghimi, A. C. Hunter, and J. C. Murray, “Long-circulating and 11K. C. Li, S. D. Pandit, S. Guccione, and M. D. Bednarski, “Molecular target-specific nanoparticles: Theory to practice,” Pharmacol. Rev. 53͑2͒, imaging applications in nanomedicine,” Biomed. Microdevices 6͑2͒, 113– 283–318 ͑2001͒. 116 ͑2004͒. 40C. S. S. R. Kumar, J. Hormes, and C. Leuschner, Nanofabrication To- 12O. M. Koo, I. Rubinstein, and H. Onyuksel, “Role of nanotechnology in wards Biomedical Applications: Techniques, Tools, Applications, and Im- targeted drug delivery and imaging: A concise review,” Nanomedicine pact ͑Wiley-VCH, Weinheim, 2005͒. 1͑3͒, 193–212 ͑2005͒. 41A. L. Klibanov, K. Maruyama, V. P. Torchilin, and L. Huang, “Amphip- 13J. R. Heath and M. E. Davis, “Nanotechnology and cancer,” Annu. Rev. athic polyethyleneglycols effectively prolong the circulation time of lipo- Med. 59, 251–265 ͑2008͒. somes,” FEBS Lett. 268͑1͒, 235–237 ͑1990͒. 14S. K. Sahoo, S. Parveen, and J. J. Panda, “The present and future of 42J. M. Harris and R. B. Chess, “Effect of pegylation on pharmaceuticals,” nanotechnology in human health care,” Nanomedicine 3͑1͒, 20–31 Nat. Rev. Drug Discovery 2͑3͒, 214–221 ͑2003͒. ͑2007͒. 43S. A. Schmitz, M. Taupitz, S. Wagner, K. J. Wolf, D. Beyersdorff, and B. 15V. P. Torchilin, “PEG-based micelles as carriers of contrast agents for Hamm, “Magnetic resonance imaging of atherosclerotic plaques using different imaging modalities,” Adv. Drug Delivery Rev. 54͑2͒, 235–252 superparamagnetic iron oxide particles,” J. Magn. Reson Imaging 14͑4͒, ͑2002͒. 355–361 ͑2001͒. 16V. P. Torchilin, “Targeted pharmaceutical nanocarriers for cancer therapy 44W. J. Rogers, C. H. Meyer, and C. M. Kramer, “Technology insight: In and imaging,” AAPS J. 9͑2͒, E128–E147 ͑2007͒. vivo cell tracking by use of MRI,” Nat. Clin. Pract. Cardiovasc. Med. 17C. Tilcock, “Delivery of contrast agents for magnetic resonance imaging, 3͑10͒, 554–562 ͑2006͒. computed tomography, nuclear medicine and ultrasound,” Adv. Drug De- 45E. Sykova and P. Jendelova, “Migration, fate and in vivo imaging of adult livery Rev. 37͑1–3͒, 33–51 ͑1999͒. stem cells in the CNS,” Cell Death Differ 14͑7͒, 1336–1342 ͑2007͒. 18S. A. Wickline and G. M. Lanza, “Molecular imaging, targeted therapeu- 46N. V. Evgenov, Z. Medarova, G. Dai, S. Bonner-Weir, and A. Moore, “In tics, and nanoscience,” J. Cell Biochem. Suppl. 39, 90–97 ͑2002͒. vivo imaging of islet transplantation,” Nat. Med. 12͑1͒, 144–148 ͑2006͒.

Medical Physics, Vol. 35, No. 10, October 2008 4485 N. Matsuura and J. A. Rowlands: Functional nanostructures 4485

47N. C. Phillips, L. Gagne, C. Tsoukas, and J. Dahman, “Immunoliposome 4729–4749 ͑2006͒. targeting to murine CD4+ leucocytes is dependent on immune status,” J. 73S. B. Yu and A. D. Watson, “Metal-based x-ray contrast media,” Chem. Immunol. 152͑6͒, 3168–3174 ͑1994͒. Rev. ͑Washington, D.C.͒ 99͑9͒, 2353–2378 ͑1999͒. 48H. Soo Choi, W. Liu, P. Misra, E. Tanaka, J. P. Zimmer, B. Itty Ipe, M. G. 74R. F. Mattrey, D. M. Long, F. Multer, R. Mitten, and C. B. Higgins, Bawendi, and J. V. Frangioni, “Renal clearance of quantum dots,” Nat. “Perfluoroctylbromide: A reticuloendothelial-specific and tumor-imaging Biotechnol. 25͑10͒, 1165–1170 ͑2007͒. agent for computed tomography,” Radiology 145͑3͒, 755–758 ͑1982͒. 49R. Weissleder, “Scaling down imaging: Molecular mapping of cancer in 75D. M. Long, Jr., E. C. Lasser, C. M. Sharts, F. K. Multer, and M. Nielsen, mice,” Nat. Rev. Cancer 2͑1͒, 11–18 ͑2002͒. “Experiments with radiopaque perfluorocarbon emulsions for selective 50M. Rudin and R. Weissleder, “Molecular imaging in drug discovery and opacification of organs and total body angiography,” Invest. Radiol. development,” Nat. Rev. Drug Discovery 2͑2͒, 123–131 ͑2003͒. 15͑3͒, 242–247 ͑1980͒. 51T. F. Massoud and S. S. Gambhir, “Molecular imaging in living subjects: 76D. M. Long, F. K. Multer, A. G. Greenburg, G. W. Peskin, E. C. Lasser, Seeing fundamental biological processes in a new light,” Genes Dev. W. G. Wickham, and C. M. Sharts, “Tumor imaging with x-rays using 17͑5͒, 545–580 ͑2003͒. macrophage uptake of radiopaque fluorocarbon emulsions,” Surgery ͑St. 52S. K. Lyons, “Advances in imaging mouse tumour models in vivo,” J. Louis͒ 84͑1͒, 104–112 ͑1978͒. Pathol. 205͑2͒, 194–205 ͑2005͒. 77C. W. Hughes, R. W. Williams, M. Bradley, and G. H. Irvine, “Ultrasound 53B. Ross, A. Rehemtulla, Y.-E. L. Koo, R. Reddy, G. Kim, C. Behrend, S. monitoring of distraction osteogenesis,” Br. J. Oral Maxillofac Surg. Buck, R. J. Schneider, M. A. Philbert, R. Weissleder, and R. Kopelman, 41͑4͒, 256–258 ͑2003͒. “Photonic and magnetic nanoexplorers for biomedical use: from subcel- 78A. M. Morawski, G. A. Lanza, and S. A. Wickline, “Targeted contrast lular imaging to cancer diagnosis and therapy,” Proc. SPIE 5331, 76–83 agents for magnetic resonance imaging and ultrasound,” Curr. Opin. Bio- ͑2004. technol. 16͑1͒, 89–92 ͑2005͒. 54V. P. Zharov, J. W. Kim, D. T. Curiel, and M. Everts, “Self-assembling 79G. M. Lanza, R. Lamerichs, S. Caruthers, and S. A. Wickline, “Molecular nanoclusters in living systems: Application for integrated photothermal Imaging in MR with targeted paramagnetic nanoparticles,” Med. Mundi nanodiagnostics and nanotherapy,” Nanomedicine 1͑4͒, 326–345 ͑2005͒. 47͑1͒, 34–39 ͑2003͒. 55O. Salata, “Applications of nanoparticles in biology and medicine,” 80S. D. Caruthers, A. M. Neubauer, F. D. Hockett, R. Lamerichs, P. M. Nanobiotechnol. 2͑1͒͑2004͒. Winter, M. J. Scott, P. J. Gaffney, S. A. Wickline, and G. M. Lanza, “In 56T. W. Prow, J. H. Salazar, W. A. Rose, J. N. Smith, L. Reece, A. A. vitro demonstration using 19F magnetic resonance to augment molecular Fontenot, N. A. Wang, R. S. Lloyd, and J. F. Leary, “Nanomedicine: imaging with paramagnetic perfluorocarbon nanoparticles at 1.5 Tesla,” Nanoparticles, molecular biosensors, and targeted gene/drug delivery for Invest. Radiol. 41͑3͒, 305–312 ͑2006͒. combined single-cell diagnostics and therapeutics,” Proc. SPIE 5318, 81Y. B. Yu, “Fluorocarbon nanoparticles as multifunctional drug delivery 1–11 ͑2004͒. vehicles,” J. Drug Target. 14͑10͒, 663–669 ͑2006͒. 57M. C. Roco, “Nanotechnology: Convergence with modern biology and 82S. Rockwell, M. Kelley, C. G. Irvin, C. S. Hughes, E. Porter, H. Yabuki, medicine,” Curr. Opin. Biotechnol. 14͑3͒, 337–346 ͑2003͒. and J. J. Fischer, “Modulation of tumor oxygenation and radiosensitivity 58T. M. Fahmy, P. M. Fong, J. Park, T. Constable, and W. M. Saltzman, by a perfluorooctylbromide emulsion,” Radiother. Oncol. 22͑2͒, 92–98 “Nanosystems for simultaneous imaging and drug delivery to T cells,” ͑1991͒. AAPS J. 9͑2͒, E171–E180 ͑2007͒. 83C. Wilhelm, C. Billotey, J. Roger, J. N. Pons, J. C. Bacri, and F. Gazeau, 59T. Ishida, D. L. Iden, and T. M. Allen, “A combinatorial approach to “Intracellular uptake of anionic superparamagnetic nanoparticles as a producing sterically stabilized ͑Stealth͒ immunoliposomal drugs,” FEBS function of their surface coating,” Biomaterials 24͑6͒, 1001–1011 ͑2003͒. Lett. 460͑1͒, 129–133 ͑1999͒. 84J. Kreuter, “The influence of coatings with surfactants on the body distri- 60V. P. Torchilin, “Recent advances with liposomes as pharmaceutical car- bution of nanoparticles after intravenous injection to rats,” Clini. Materi. riers,” Nat. Rev. Drug Discovery 4͑2͒, 145–160 ͑2005͒. 13͑1–4͒, 131–134 ͑1993͒. 61R. G. Blasberg, “In vivo molecular-genetic imaging: Multi-modality 85V. Labhasetwar, C. Song, W. Humphrey, R. Shebuski, and R. J. Levy, nuclear and optical combinations,” Nucl. Med. Biol. 30͑8͒, 879–888 “Arterial uptake of biodegradable nanoparticles: Effect of surface modi- ͑2003͒. fications,” J. Pharm. Sci. 87͑10͒, 1229–1234 ͑1998͒. 62E. A. Schellenberger, D. Sosnovik, R. Weissleder, and L. Josephson, 86C. B. Carlson, P. Mowery, R. M. Owen, E. C. Dykhuizen, and L. L. “Magneto/optical annexin V, a multimodal protein,” Bioconjugate Chem. Kiessling, “Selective tumor cell targeting using low-affinity, multivalent 15͑5͒, 1062–1067 ͑2004͒. interactions,” ACS Chem. Biol. 2͑2͒, 119–127 ͑2007͒. 63L. Josephson, M. F. Kircher, U. Mahmood, Y. Tang, and R. Weissleder, 87S. Hong, P. R. Leroueil, I. J. Majoros, B. G. Orr, J. R. Baker, Jr., and M. “Near-infrared fluorescent nanoparticles as combined MR/optical imaging M. Banaszak Holl, “The binding avidity of a nanoparticle-based multiva- probes,” Bioconjugate Chem. 13͑3͒, 554–560 ͑2002͒. lent targeted drug delivery platform,” Chem. Biol. 14͑1͒, 107–115 ͑2007͒. 64V. S. Talanov, C. A. Regino, H. Kobayashi, M. Bernardo, P. L. Choyke, 88X. Montet, M. Funovics, K. Montet-Abou, R. Weissleder, and L. Joseph- and M. W. Brechbiel, “Dendrimer-based nanoprobe for dual modality son, “Multivalent effects of RGD peptides obtained by nanoparticle dis- magnetic resonance and fluorescence imaging,” Nano Lett. 6͑7͒, 1459– play,” J. Med. Chem. 49͑20͒, 6087–6093 ͑2006͒. 1463 ͑2006͒. 89A. Tanimoto, K. Oshio, M. Suematsu, D. Pouliquen, and D. D. Stark, 65J. Zheng, G. Perkins, A. Kirilova, C. Allen, and D. A. Jaffray, “Multimo- “Relaxation effects of clustered particles,” J. Magn. Reson Imaging 14͑1͒, dal contrast agent for combined computed tomography and magnetic 72–77 ͑2001͒. resonance imaging applications,” Invest. Radiol. 41͑3͒, 339–348 ͑2006͒. 90O. Couture, P. D. Bevan, E. Cherin, K. Cheung, P. N. Burns, and F. S. 66M. Nahrendorf, H. Zhang, S. Hembrador, P. Panizzi, D. E. Sosnovik, E. Foster, “Investigating perfluorohexane particles with high-frequency ul- Aikawa, P. Libby, F. K. Swirski, and R. Weissleder, “Nanoparticle trasound,” Ultrasound Med. Biol. 32͑1͒, 73–82 ͑2006͒. PET-CT imaging of macrophages in inflammatory atherosclerosis,” Cir- 91P. Caravan, “Strategies for increasing the sensitivity of gadolinium based culation 117͑3͒, 379–387 ͑2008͒. MRI contrast agents,” Chem. Soc. Rev. 35͑6͒, 512–523 ͑2006͒. 67M. A. McDonald and K. L. Watkin, “Small particulate gadolinium oxide 92U. I. Tromsdorf, N. C. Bigall, M. G. Kaul, O. T. Bruns, M. S. Nikolic, B. and gadolinium oxide albumin microspheres as multimodal contrast and Mollwitz, R. A. Sperling, R. Reimer, H. Hohenberg, W. J. Parak, S. therapeutic agents,” Invest. Radiol. 38͑6͒, 305–310 ͑2003͒. Forster, U. Beisiegel, G. Adam, and H. Weller, “Size and surface effects 68S. R. Cherry, “Multimodality in vivo imaging systems: Twice the power on the MRI relaxivity of manganese ferrite nanoparticle contrast agents,” or double the trouble?” Annu. Rev. Biomed. Eng. 8,35–62͑2006͒. Nano Lett. 7͑8͒, 2422–2427 ͑2007͒. 69V. Wagner, A. Dullaart, A. K. Bock, and A. Zweck, “The emerging na- 93A. Y. Louie, M. M. Huber, E. T. Ahrens, U. Rothbacher, R. Moats, R. E. nomedicine landscape,” Nat. Biotechnol. 24͑10͒, 1211–1217 ͑2006͒. Jacobs, S. E. Fraser, and T. J. Meade, “In vivo visualization of gene 70R. Duncan, “The dawning era of polymer therapeutics,” Nat. Rev. Drug expression using magnetic resonance imaging,” Nat. Biotechnol. 18͑3͒, Discovery 2͑5͒, 347–360 ͑2003͒. 321–325 ͑2000͒. 71N. Oku, “Delivery of contrast agents for positron emission tomography 94J. Rao, A. Dragulescu-Andrasi, and H. Yao, “Fluorescence imaging in imaging by liposomes,” Adv. Drug Delivery Rev. 37͑1–3͒, 53–61 ͑1999͒. vivo: Recent advances,” Curr. Opin. Biotechnol. 18͑1͒, 17–25 ͑2007͒. 72A. Mitra, A. Nan, B. R. Line, and H. Ghandehari, “Nanocarriers for 95S. Kumar and R. Richards-Kortum, “Optical molecular imaging agents nuclear imaging and radiotherapy of cancer,” Curr. Pharm. Des. 12͑36͒, for cancer diagnostics and therapeutics,” Small 1͑1͒, 23–30 ͑2006͒.

Medical Physics, Vol. 35, No. 10, October 2008 4486 N. Matsuura and J. A. Rowlands: Functional nanostructures 4486

96R. H. Muller, K. Mader, and S. Gohla, “Solid lipid nanoparticles ͑SLN͒ ultrasound to selectively localize nanodroplets for targeted imaging and for controlled drug delivery—a review of the state of the art,” Eur. J. therapy,” Mol. Imaging 5͑3͒, 160–174 ͑2006͒. Pharm. Biopharm. 50͑1͒, 161–177 ͑2000͒. 122P. A. Dayton, K. E. Morgan, A. L. Klibanov, G. Brandenburger, K. R. 97D. A. Wood, “Biodegradable drug delivery systems,” Int. J. Pharm. 7͑1͒, Nightingale, and K. W. Ferrara, “A preliminary evaluation of the effects 1–18 ͑1980͒. of primary and secondary radiation forces on acoustic contrast agents,” 98Y. Bae, S. Fukushima, A. Harada, and K. Kataoka, “Design of IEEE Trans. Ultrason. Ferroelectr. Freq. Control 44͑6͒, 1264–1277 environment-sensitive supramolecular assemblies for intracellular drug ͑1997͒. delivery: Polymeric micelles that are responsive to intracellular pH 123S. Martel, J. B. Mathieu, O. Felfoul, A. Chanu, E. Aboussouan, S. Tamaz, change,” Angew. Chem., Int. Ed. 42͑38͒, 4640–4643 ͑2003͒. P. Pouponneau, L. Yahia, G. Beaudoin, G. Soulez, and M. Mankiewicz, 99R. Haag, “Supramolecular drug-delivery systems based on polymeric “Medical and technical protocol for automatic navigation of a wireless core-shell architectures,” Angew. Chem., Int. Ed. 43͑3͒, 278–282 ͑2004͒. device in the carotid artery of a living swine using a standard clinical 100E. R. Gillies and J. M. Frechet, “A new approach towards acid sensitive MRI system,” Med. Image Comput. Comput. Assist. Interv. 10͑Pt 1͒, copolymer micelles for drug delivery,” Chem. Commun. ͑Cambridge͒ 144–152 ͑2007͒. 2003͑14͒, 1640–1641 ͑2003͒. 124R. Jurgons, C. Seliger, A. Hilpert, L. Trahms, S. Odenbach, and C. Al- 101R. Haag and F. Kratz, “Polymer therapeutics: Concepts and applications,” exiou, “Drug loaded magnetic particles for cancer therapy,” J. Phys.: Angew. Chem., Int. Ed. 45͑8͒, 1198–1215 ͑2006͒. Condens. Matter 18, S2893–S2902 ͑2006͒. 102R. Duncan, “The dawning era of polymer therapeutics,” Nat. Rev. Drug 125N. Gaponik, I. L. Radtchenko, G. B. Sukhorukov, and A. L. Rogach, Discovery 2͑5͒, 347–360 ͑2003͒. “Luminescent polymer microcapsules addressable by a magnetic field,” 103G. B. Sukhorukov, A. L. Rogach, B. Zebli, T. Liedl, A. G. Skirtach, K. Langmuir 20͑4͒, 1449–1452 ͑2004͒. Kohler, A. A. Antipov, N. Gaponik, A. S. Susha, M. Winterhalter, and W. 126Q. A. Pankhurst, J. Connolly, S. K. Jones, and J. Dobson, “Applications J. Parak, “Nanoengineered polymer capsules: Tools for detection, con- of magnetic nanoparticles in biomedicine,” J. Phys. D: Appl. Phys. trolled delivery, and site-specific manipulation,” Small 1͑2͒, 194–200 36͑13͒, R167–R181 ͑2003͒. ͑2005͒. 127O. D. Kripfgans, J. B. Fowlkes, D. L. Miller, O. P. Eldevik, and P. L. 104D. E. Sosnovik and R. Weissleder, “Emerging concepts in molecular Carson, “Acoustic droplet vaporization for therapeutic and diagnostic ap- MRI,” Curr. Opin. Biotechnol. 18͑1͒, 4–10 ͑2007͒. plications,” Ultrasound Med. Biol. 26͑7͒, 1177–1189 ͑2000͒. 105E. Y. Sun, L. Josephson, K. A. Kelly, and R. Weissleder, “Development 128I. Hilger, R. Hiergeist, R. Hergt, K. Winnefeld, H. Schubert, and W. A. of nanoparticle libraries for biosensing,” Bioconjugate Chem. 17͑1͒, 109– Kaiser, “Thermal ablation of tumors using magnetic nanoparticles: An in 113 ͑2006͒. vivo feasibility study,” Invest. Radiol. 37͑10͒, 580–586 ͑2002͒. 106T. Atanasijevic, M. Shusteff, P. Fam, and A. Jasanoff, “Calcium-sensitive 129R. Ivkov, S. J. DeNardo, W. Daum, A. R. Foreman, R. C. Goldstein, V. S. MRI contrast agents based on superparamagnetic iron oxide nanoparticles Nemkov, and G. L. DeNardo, “Application of high amplitude alternating and calmodulin,” Proc. Natl. Acad. Sci. U.S.A. 103͑40͒, 14707–14712 magnetic fields for heat induction of nanoparticles localized in cancer,” ͑2006͒. Clin. Cancer Res. 11͑19 Pt 2͒, 7093s–7103s ͑2005͒. 107S. Forster and T. Plantenberg, “From self-organizing polymers to nano- 130M. Lepage, J. Jiang, J. Babin, B. Qi, L. Tremblay, and Y. Zhao, “MRI hybrid and biomaterials,” Angew. Chem., Int. Ed. 41͑5͒, 689–714 ͑2002͒. observation of the light-induced release of a contrast agent from photo- 108G. M. Whitesides and B. Grzybowski, “Self-assembly at all scales,” Sci- controllable polymer micelles,” Phys. Med. Biol. 52͑10͒, N249–N255 ences ͑N.Y.͒ 295͑5564͒, 2418–2421 ͑2002͒. ͑2007͒. 109I. W. Hamley, “Nanotechnology with soft materials,” Angew. Chem., Int. 131Q. Y. Cai, S. H. Kim, K. S. Choi, S. Y. Kim, S. J. Byun, K. W. Kim, S. H. Ed. 42͑15͒, 1692–1712 ͑2003͒. Park, S. K. Juhng, and K. H. Yoon, “Colloidal gold nanoparticles as a 110S. E. Sakiyama-Elbert and J. A. Hubbell, “Functional biomaterials: De- blood-pool contrast agent for X-ray computed tomography in mice,” In- sign of novel biomaterials,” Annu. Rev. Mater. Res. 31, 183–201 ͑2001͒. vest. Radiol. 42͑12͒, 797–806 ͑2007͒. 111M. Sarikaya, C. Tamerler, A. K. Jen, K. Schulten, and F. Baneyx, “Mo- 132J. F. Hainfeld, D. N. Slatkin, T. M. Focella, and H. M. Smilowitz, “Gold lecular biomimetics: Nanotechnology through biology,” Nat. Mater. 2͑9͒, nanoparticles: A new X-ray contrast agent,” Br. J. Radiol. 79͑939͒, 248– 577–585 ͑2003͒. 253 ͑2006͒. 112M. Sarikaya, C. Tamerler, D. T. Schwartz, and F. Baneyx, “Materials 133C. J. Gannon, C. R. Patra, R. Bhattacharya, P. Mukherjee, and S. A. assembly and formation using engineered polypeptides,” Annu. Rev. Curley, “Intracellular gold nanoparticles enhance non-invasive radiofre- Mater. Res. 34, 373–408 ͑2004͒. quency thermal destruction of human gastrointestinal cancer cells,” Nano- 113S. Zhang, D. M. Marini, W. Hwang, and S. Santoso, “Design of nanobiotechnol. 6͑2͒͑2008͒. structured biological materials through self-assembly of peptides and pro- 134J. R. McCarthy, F. A. Jaffer, and R. Weissleder, “A macrophage-targeted teins,” Curr. Opin. Chem. Biol. 6͑6͒, 865–871 ͑2002͒. theranostic nanoparticle for biomedical applications,” Small 2͑8–9͒, 983– 114G. F. Payne, “Biopolymer-based materials: The nanoscale components 987 ͑2006͒. and their hierarchical assembly,” Curr. Opin. Chem. Biol. 11͑2͒, 214–219 135R. Deckers, C. Rome, and C. T. Moonen, “The role of ultrasound and ͑2007͒. magnetic resonance in local drug delivery,” J. Magn. Reson Imaging 115D. W. Wendell, J. Patti, and C. D. Montemagno, “Using biological inspi- 27͑2͒, 400–409 ͑2008͒. ration to engineer functional nanostructured materials,” Small 2͑11͒, 136N. Y. Rapoport, D. A. Christensen, H. D. Fain, L. Barrows, and Z. Gao, 1324–1329 ͑2006͒. “Ultrasound-triggered drug targeting of tumors in vitro and in vivo,” Ul- 116M. Karlsson, M. Davidson, R. Karlsson, A. Karlsson, J. Bergenholtz, Z. trasonics 42͑1–9͒, 943–950 ͑2004͒. Konkoli, A. Jesorka, T. Lobovkina, J. Hurtig, M. Voinova, and O. Orwar, 137W. A. Volkert and T. J. Hoffman, “Therapeutic radiopharmaceuticals,” “Biomimetic nanoscale reactors and networks,” Annu. Rev. Phys. Chem. Chem. Rev. ͑Washington, D.C.͒ 99͑9͒, 2269–2292 ͑1999͒. 55, 613–649 ͑2004͒. 138C. F. Shaw III, “Gold-based therapeutic agents,” Chem. Rev. ͑Washing- 117A. Kawamura, A. Harada, K. Kono, and K. Kataoka, “Self-assembled ton, D.C.͒ 99͑9͒, 2589–2600 ͑1999͒. nano-bioreactor from block ionomers with elevated and stabilized enzy- 139J. Kreuter, “Nanoparticles—a historical perspective,” Int. J. Pharm. matic function,” Bioconjugate Chem. 18͑5͒, 1555–1559 ͑2007͒. 331͑1͒, 1–10 ͑2007͒. 118D. M. Vriezema, M. Comellas Aragones, J. A. Elemans, J. J. Cornelissen, 140R. C. Oppenheim, “Solid colloidal drug delivery systems: Nanoparticles,” A. E. Rowan, and R. J. Nolte, “Self-assembled nanoreactors,” Chem. Rev. Int. J. Pharm. 8͑3͒, 217–234 ͑1981͒. ͑Washington, D.C.͒ 105͑4͒, 1445–1489 ͑2005͒. 141R. H. Baughman, A. A. Zakhidov, and W. A. de Heer, “Carbon 119N. Rapoport, Z. Gao, and A. Kennedy, “Multifunctional nanoparticles for nanotubes—the route toward applications,” Sciences ͑N.Y.͒ 297 ͑5582͒, combining ultrasonic tumor imaging and targeted chemotherapy,” J. Natl. 787–792 ͑2002͒. Cancer Inst. 99͑14͒, 1095–1106 ͑2007͒. 142C. Burda, X. Chen, R. Narayanan, and M. A. El-Sayed, “Chemistry and 120J. C. Frias, M. J. Lipinski, S. E. Lipinski, and M. T. Albelda, “Modified properties of nanocrystals of different shapes,” Chem. Rev. ͑Washington, lipoproteins as contrast agents for imaging of atherosclerosis,” Contrast D.C.͒ 105͑4͒, 1025–1102 ͑2005͒. Media Mol. Imaging 2͑1͒, 16–23 ͑2007͒. 143Y. Chen and A. Pepin, “Nanofabrication: Conventional and nonconven- 121P. A. Dayton, S. Zhao, S. H. Bloch, P. Schumann, K. Penrose, T. O. tional methods,” Electrophoresis 22͑2͒, 187–207 ͑2001͒. Matsunaga, R. Zutshi, A. Doinikov, and K. W. Ferrara, “Application of 144P. D. Cozzoli, T. Pellegrino, and L. Manna, “Synthesis, properties and

Medical Physics, Vol. 35, No. 10, October 2008 4487 N. Matsuura and J. A. Rowlands: Functional nanostructures 4487

perspectives of hybrid nanocrystal structures,” Chem. Soc. Rev. 35͑11͒, perspective from the London Centre for Nanotechnology,” Nanomedicine 1195–1208 ͑2006͒. 2͑1͒, 42–48 ͑2006͒. 145S. Yang, X. Chen, S. Motojima, and M. Ichihara, “Morphology and mi- 150L. Mazzola, “Commercializing nanotechnology,” Nat. Biotechnol. crostructure of spring-like carbon micro-coils/nano-coils prepared by 21͑10͒, 1137–1143 ͑2003͒. catalytic pyrolysis of acetylene using Fe-containing alloy catalysts,” Car- 151Molecular Imaging and Contrast Agent Database ͑MICAD͓͒database on- bon 43͑4͒, 827–834 ͑2005͒. line͔, National Library of Medicine ͑US͒, Bethesda MD: NCBI; 2004– 146P. Decuzzi, S. Lee, B. Bhushan, and M. Ferrari, “A theoretical model for 2008. Available from http://micad.nih.gov. the margination of particles within blood vessels,” Ann. Biomed. Eng. 152R. H. Glassman and A. Y. Sun, “Biotechnology: Identifying advances 33͑2͒, 179–190 ͑2005͒. from the hype,” Nat. Rev. Drug Discovery 3͑2͒, 177–183 ͑2004͒. 147P. Decuzzi, S. Lee, M. Decuzzi, and M. Ferrari, “Adhesion of microfab- 153J. V. Frangioni, “Translating in vivo diagnostics into clinical reality,” Nat. ricated particles on vascular endothelium: A parametric analysis,” Ann. Biotechnol. 24͑8͒, 909–913 ͑2006͒. Biomed. Eng. 32͑6͒, 793–802 ͑2004͒. 154V. M. Runge, “Changes in the approval process for contrast media,” J. 148J. V. Frangioni, “In vivo near-infrared ﬂuorescence imaging,” Curr. Opin. Magn. Reson Imaging 10͑3͒, 485–488 ͑1999͒. Chem. Biol. 7͑5͒, 626–634 ͑2003͒. 155D. A. Benaron, “The future of cancer imaging,” Cancer Metastasis Rev. 149M. A. Horton and A. Khan, “Medical nanotechnology in the UK: A 21͑1͒, 45–78 ͑2002͒.

Medical Physics, Vol. 35, No. 10, October 2008 Magnetic resonance spectroscopy ͒ Robert W. Prosta Department of Radiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226 ͑Received 27 October 2007; revised 29 July 2008; accepted for publication 29 July 2008; published 17 September 2008͒ The nuclear magnetic resonance phenomenon has given rise to both magnetic resonance imaging, which yields morphologic data, and magnetic resonance spectroscopy ͑MRS͒, which yields chemical data. In humans these data are derived principally from the resonances of the hydrogen nucleus in the low molecular weight compounds in the body. Hydrogen MRS has become a routinely used clinical tool in the brain, prostate, and breast. Other nuclei also demonstrate this phenomenon but each of these comes with additional difﬁculties, including low abundance, low sensitivity, and/or low chemical concentrations. The future of MRS includes a drive to higher main magnetic ﬁeld strengths and new methods to create 4–5 orders of magnitude greater signal. The future of MRS is bright, but in the United States it is endangered by overuse and misuse driven by the advent of reimbursement. © 2008 American Association of Physicists in Medicine. ͓DOI: 10.1118/1.2975225͔

I. INTRODUCTION shift imparted by the local bonding environment is given the symbol ␴ and is called the chemical shift. The chemical shift I.A. Comparing magnetic resonance imaging and magnetic resonance spectroscopy is a very small fraction of the resonance frequency of the nucleus, ranging in magnitude from 10−5 for hydrogen ͑1H͒ −3 ͑19 ͒ In Fig. 1, axial magnetic resonance ͑MR͒ images and spectra to 10 for fluorine F . Unlike the case where resonance ␴ are shown from the brain of a volunteer in a repeatability frequency is shifted by gradients for MRI, is a linear func- study. On the morning of the second ͑rightmost͒ session, the tion of the strength of the main magnetic field. For instance, subject was profoundly different. After a late night of drink- the difference in resonance frequency between the hydrogen ing, the subject was still inebriated that morning. The ethanol nuclei in water and the hydrogen nuclei in the methylene groups of fat is 210 Hz at 1.5 T and 420 Hz at 3 T. While ͑ETOH͒ was easily detected in her brain as shown from the the chemical shift of MRS and resonance shift of MRI arise resonances in the MR spectra, while the T1-weighted MR from different sources, and are typically of significantly dif- images were unchanged. To understand why the information ferent magnitudes, the chemical shift can interfere with im- in the magnetic resonance imaging ͑MRI͒ and magnetic aging. The combination of imaging shifts and chemical shifts resonance spectroscopy ͑MRS͒ differed, we must understand causes fat containing tissues to appear displaced from their how the two methods, imaging and spectroscopy, relate. real locations ͑Fig. 2͒. This displacement in MRI worsens MRS and MRI arise from the same principle, nuclear mag- with increasing field strength. netic resonance ͑NMR͒, first observed by Bloch and Purcell In MRS, the resonance offset is normalized to the operat- in 1946.1 In Bloch’s classical description of the phenomenon, ing frequency of the magnet and referenced to a standard polarized nuclei precess about the direction of the main mag- resonance to minimize confusion when comparing results netic field with a frequency that is a product of the gyromag- from laboratories that use different magnetic field strengths. netic ratio of the nucleus, ␥, and the strength of the magnetic Resonance positions are then reported in parts per million field at the nucleus, B . The origin of MRS dates to 1951 0 ͑ppm͒. For 1H spectroscopy, the standard is the methyl pro- when Albert described small changes in resonant frequency ton resonance of tetramethyl silane which was chosen to be due to the bonding positions of two hydrogen nuclei in dif- 0 ppm. Based on this standard, protons in water resonate at ferent locations on a molecule.2 Changes in the resonant fre- 4.8 ppm regardless of magnetic field strength. The resonance quency of populations of nuclei give rise to the information of the methylene protons in adipose tissue is 1.3 ppm. The content of both MRI and MRS. In MRI, the resonant fre- shift between water and fat remains 3.5 ppm regardless of quency of a spin is modified by gradients imposed on the field strength, although the frequency difference in hertz main magnetic field. The frequency of the spin thus becomes changes. a function of the position of that spin relative to the gradient where f =␥͓B +g͑r͒ r͔, g͑r͒ is the magnetic field gradient, 0 * I.B. A truly small signal: NMR and r is the distance from system isocenter along that gradient. In this way, spatial information is extracted and images The NMR effect is exceedingly small. Of all of the hy- created. MR spectroscopy, however, detects the modification drogen nuclei in the human body, only 1 in 105 is polarized of the magnetic field at the postion of the spin created by the when immersed in a field of 1.5 T. The signal which can be local chemical bonding environment. The frequency of reso- derived from any NMR experiment ͑MRI or MRS͒ is first ␥ ͑ ␴͒ nance of a spin in a molecule is given by f = B0 1− . The dependent on this polarization. In all but the most recent

1 FIG. 1. Localizing MRI and accompanying H MRS spectrum from a 0.56 cm3 voxel in the left putamen. Data acquired at 0.5 T with short echo time elliptical excitation chemical shift imaging. Acquired as part of a repeatability study. Data shown in ͑b͒ was from the second session when the volunteer was inebriated. Triplet resonance of ethanol marked ETOH. experiments, the magnitude of the polarization is directly overlap. In humans, all of the 1H resonances of interest lie proportional to magnetic field strength. The minuscule size within an approximately 4 ppm range, resulting in the com- of the NMR signal causes the effect to be highly susceptible plete or partial obscuration of otherwise detectable reso- to imperfections in the system. Thus, one of the factors nances. which has driven the evolution of NMR is the quest for stronger magnets which increase polarization. The advent of I.C. Technical considerations in MRS: Signal to noise superconducting magnets has allowed the creation of fields ratio and overlap in excess of 23 T. These very large magnets have tiny bore sizes that make them suitable only for conducting experi- Improving MRS data is usually accomplished by improv- ments on small samples. Designing high field strength mag- ing the signal to noise ratio of the data and by increasing the nets which can accommodate human subjects is constrained separation between resonances. Signal to noise ratio in MR by the tremendous mechanical forces created by large fields spectroscopy is a linear function of field strength and is 5 and the critical current of the superconducting wire. Magnets given by large enough for human use are now available with field B0KNͱNEX͑e−Te/T2͒͑1−e−Tr/T1͒ strengths up to 7 T, and one 9.4 T system has been built.3,4 SNR = ͱ , Higher field strength magnets should allow one to detect lw bw moieties at lower concentrations and to minimize resonance where B0 is the strength of the main magnetic field, NEX is the number of averages, T1 and T2 are longitudinal and transverse relaxation times, lw is the linewidth of the resonance, N is the number of spins, bw is the receiver bandwidth, and K is a constant that accounts for other device- specific factors. For all other equal factors, signal to noise ratio ͑SNR͒ will increase linearly with B0. With increasing B0, the dispersion ͑difference in resonance frequency in hertz͒ between singlet resonances also increases linearly. Therefore, closely spaced singlet resonances become more distinct and quantifiable as field strength increases. This occurs despite the fact that the difference as measured in ppm remains the same ͑Fig. 3͒. One other complication arises in considering these resonances. Many of these resonances are 1 FIG.2. H spectrum from a leg showing water and lipid resonances in ͑a͒. not singlets ͑a single resonance line͒. Nuclei with different ͑ ͒ This frequency difference manifests itself in routine imaging b as a spatial chemical shifts may exchange energy through the bonding shift in the readout gradient direction. Thick black arrow is muscle, predominantly water containing physically shifted from the surrounding adi- electron clouds in the molecule. Coupling can occur between pose tissue. nuclei of the same element or a nucleus with a different ␥

Medical Physics, Vol. 35, No. 10, October 2008 4532 Robert William Prost: Magnetic resonance spectroscopy 4532

1 FIG. 3. Ethanol phantom H spectra demonstrating change of chemical shift with main magnetic ﬁeld ͑B0͒ strength. In ͑a͒ and ͑c͒, spectra are displayed with chemical shift in hertz with water resonance set to 0 Hz. In ͑b͒ and ͑d͒, spectra are displayed in ppm showing that the centers of each multiplet are at the same offset in ppm. Frequency splitting of the multiplets in ͑d͒ appears larger than in ͑b͒ because J coupling is invariant to change in ﬁeld strength, whereas chemical shift is linear with B0.

These effects are referred to as homo- and heteronuclear cou- tected. Intermediate field strengths can cause problems where pling, respectively. Also known as J coupling, it causes the the phase of the individual resonances in the multiplet de- resonance to split into two or more resonances, depending on structively interfere. Figure 5 demonstrates this effect in the the number of other nuclei involved in the coupling and the methylene protons of glutamate. Even at very high field magnitude of the coupling, as shown in Fig. 4. The total strengths, resonances may still overlap.8 The resonance of amount of energy in the resonance is split between the indi- the two methylene groups in taurine is shown to collapse into vidual resonances with an energy distribution which is de- a singlet at 0.5 T. Establishing the identity of an unknown pendent on the quantum states of the spins in the coupled coupled resonance may be accomplished by sampling in an- nuclei.6 Two coupled spins form a doublet with two reso- other dimension, allowing the J couplings to evolve in time.9 nances of equal amplitude ͑1:1͒ and three coupled spins form Spectra of J-coupled spins evolve with echo time as shown a 1:2:1 pattern, while four create a 1:3:3:1 pattern. The mag- in Fig. 6 for the doublet of lactate in a phantom. The J nitude of the coupling is independent of field strength, and is coupling, under some circumstances, may be removed by measured in hertz, not ppm. The appearance of coupled reso- irradiating the spin to which the observed spin is coupled. In nances is a function of the ratio of ␴/J, which is a function doing so, the J coupling disappears and the resulting reso- of field strength. As B0 approaches zero, the coupled resonance area is the sum of all the areas in the multiplet, as nances degenerate into a singlet as the ratio ␴/J approaches shown in Fig. 4͑b͒. In addition to the effects noted above, the 7 zero. At very high values of B0, the individual resonances in spins also experience the same types of relaxation parameters the multiplet may separate sufficiently to be individually de- well known in MR imaging. These include T1, T2, and T2*

Medical Physics, Vol. 35, No. 10, October 2008 4533 Robert William Prost: Magnetic resonance spectroscopy 4533

FIG. 4. Homonuclear and heteronuclear spin ͑J͒ coupling in ͑a͒ and ͑b͒, respectively, showing the paths of coupling. Note that the coupling is much smaller for the homonuclear case. Removal of heteronuclear splittings by proton decoupling shown in top spectrum on the right in ͑b͒. The area and amplitude of the resulting resonance after decoupling is greater than the coupled case as energy split between resonances in the multiplet are summed when the J coupling is removed. relaxation. Each resonance has its own relaxation parameters dient pulses.10 Until the late 1980s, gradient slew-rate and which are usually different than the water in the same voxel. magnetic field homogeneity were both insufficiently con- As a result, the choice of echo time ͑TE͒ and repetition time trolled in whole-body MRI systems to support echo planar ͑TR͒, have an impact on the absolute and relative intensity of imaging. Additionally, gradient eddy currents swamped the each resonance. The effect of changing echo time in a brain effects of the localizing gradients. Once the engineering 1 mimicking phantom can be appreciated in Fig. 6 where a H challenges had been met ͑shielded gradient coils, stronger spectrum was repeatedly acquired at different echo times. gradient amplifiers, and rapid shimming methods͒, Mans- The resonances of some moieties, such as glutamate and field’s original concept became an integral part of the routine myoinositol vanish at the longer echo times as the T2of MRI exam. Another physical phenomenon, the diffusion of these are short. water, first demonstrated in the laboratory in the 1960s, became practical in humans, but only after the same problems I.D. MRI and MRS: Past is prolog preventing the application of echo planar imaging had been 11 New techniques in clinical MRI or MRS are first devel- solved. MR spectroscopy has developed along a similar oped using phantom and animal models in preclinical, small trajectory. Localized spectroscopy within organs, and lesions bore systems, followed by evolution of whole-body magnet within those organs, required that gradient eddy currents and technology and proof of safety and efficacy through human magnetic field homogeneity problems in whole-body MRI clinical trials. One of the first methods proposed for MR systems be resolved. Localization is accomplished with imaging by Mansfield in 1977 was echo planar imaging shaped radio frequency pulses ͑e.g., slice selective sinc- where the spin system is excited and the entire k-space plane shaped pulses͒ combined with gradients to modify the mag- is acquired by a string of phase and frequency encoding gra- netic field so as to allow only the spins close to the resonance

Medical Physics, Vol. 35, No. 10, October 2008 4534 Robert William Prost: Magnetic resonance spectroscopy 4534

FIG. 5. Phantom study of the change of resonance appearance with ﬁeld strength. The creatine resonances are singlets which do not change appearance with ﬁeld strength while coupled resonances of glutamate and taurine are strongly affected. Phantom composed of 20 mM each creatine, glutamate, and taurine in water, titrated to physiologic pH. frequency to be excited.12 These methods, now common, the future of MR spectroscopy, one should examine those were previously impractical due to the effect of gradient applications presently in the analytical and small-bore MR eddy currents. Early MRS studies therefore accomplished lo- systems. While the concept of MRS was described in 1951, calization by placing a surface radio frequency ͑RF͒ coil four decades would elapse before this effect was reliably over the area of interest.13 Many of these early studies were reproduced in human subjects. In 1991, Frahm showed that of phosphorus and took place in skeletal muscle. To predict alterations in the area of resonances observed in the brain

FIG. 6. Data acquired at 1.5 T in a brain mimicking phantom at constant repetition time ͑TR͒ and multiple echo times ͑TE͒. Note that the phase of the doublet of lactate at 1.3 ppm changes phase with echo time. This forms the basis of J-coupled spectroscopy. Also it can be seen that each of the metabolites changes amplitude with TE based on the T2 of that resonance. Therefore, observation of some metabolites such as glutamate requires short TE times.

Medical Physics, Vol. 35, No. 10, October 2008 4535 Robert William Prost: Magnetic resonance spectroscopy 4535 lesions in patients were due to histological changes associ- two 180° RF pulses to form a right rectangular prism of ated with those lesions14 Since that time, 1H MRS has moved excited tissue.16 The second most used sequence is stimu- into routine use in patients. lated echo acquisition mode ͑STEAM͒, which consists of three successive 90° pulses which create the same right rect- 14 II. THE STATE OF THE ART angular prism of excited tissue. The virtue of STEAM is that the magnetization is stored along –Z between the second II.A. 1H MR Spectroscopy and third RF pulses. This time does not count against the Spectroscopy methods fall roughly into two categories. echo time of the sequence. Shorter echo times can be The first are hydrogen based ͑1H͒ and the second are all achieved by STEAM for the identical gradient and RF capa- other nuclei ͑sometimes referred to as “X” nuclei͒. The pre- bilities of the scanner, but at the cost of half of the SNR of ponderant clinical application is 1H MRS, which dominates PRESS. The difference in signal is due to the fact that only in part because additional additional hardware is not re- half of the magnetization in the transverse plane is rotated 17 quired. All of the same RF coils transmit and receive systems down to −Z by the second of the three RF pulses. All sig- used for MRI are applicable to 1H MRS. In fact, the reso- nals arising from spins in the voxel sum together to create nances of all hydrogen-bearing moieties other than water and the received signal. Unless further steps are taken to produce the methyl/methelene groups are contained within the signals spatial encoding within the voxel, the data from the voxel received during a MRI image acquisition. However, these yield only one spectrum. resonances are not detectable for two reasons. The first is that the concentrations of the molecules which give rise to II.C. Multiple voxel acquisition methods: Chemical these resonances are far below that of water. For example, shift imaging water in brain parenchyma is approximately 72 Molar in hydrogen, while the methyl resonance of the most abundant Spatial encoding when applied across the voxel can create ͑ ͒ of the metabolites of interest, n-acetyl aspartate ͑NAA͒,is chemical shift imaging CSI data where each voxel has as- 15 1 1 sociated with it a spectrum.18 The method of encoding is 30 mM. The concentration ratio, Hwater: HNAA is 2400:1. In a typical MRI brain image with an SNR of 100, the voxel usually performed using a phase-encoding gradient pulse volume is on the order of 5 mm3. The theoretical signal to along each encoded dimension and a much larger excited noise ratio for NAA in this same acquisition is 0.042. As a volume. The resultant data set from a two-dimensional CSI ͑ ͒ result, MRS acquisitions utilize much larger voxels to pro- acquisition is shown in Fig. 7 b for the case of a patient with vide a useful SNR. The volume of the MRS voxel must be a brain tumor. The duration of the acquisition is extended by 2400 times greater than that of MRI, for an equivalent signal a factor which is a product of the number of phase encodings to noise ratio. This translates into a cube 13.4 times larger on in each direction. In the conventional CSI imaging method, an edge than the MRI voxel. The smallest currently practical one or more dimensions must be orthogonally encoded with MRS voxel in a conventional head RF coil is about 1 cm3. its own individual value of phase encoding. Therefore, the Imaging gradients also broaden the resonance, lowering its acquisition time for a CSI dataset with a resolution of 16 in SNR and further rendering it undetectable. The second major each of the possible three dimensions is at a minimum 4096 problem of 1H MRS is water suppression. The dispersion of times as long as a single voxel acquisition. MR imaging the 1H spectrum is small, with all the resonances of interest enjoys a greater efficiency because phase and frequency en- in the human within 5 ppm of the water resonance coding can be simultaneously applied without loss of infor- ͑0–4.8 ppm͒. The line shape of the water resonance in vivo mation. In MRS, applying a frequency encoding gradient yields a large base line signal in the 0–4.8 ppm range, over- causes a phase twist along the chemical shift dimension whelming the resonances of interest. The method developed which cannot be removed except by incrementing the echo to ameliorate this problem is water suppression, nominally time and acquiring data at multiple echo times. This tech- ͓ implemented by a series of RF pulses that selectively excite nique phase encoded echo planar spectroscopic imaging ͑ ͔͒ 19 just the water resonance with crusher gradients to eliminate PEPSI has been applied using echo planar imaging. the residual signal. Large signals also arise from lipid in the However, numerous artifacts are generated as a result of skull marrow and the scalp. These resonances, predomi- eddy currents and resolution in the chemical shift dimension nantly at 1.3 ppm can hide resonances arising in adjacent is inversely dependent on the size of the echo time incre- parenchyma. Eliminating lipid signal is accomplished by ment. In elliptical polarization illumination-based methods avoiding excitation of the scalp and skull marrow and/or by demonstrated to date, the acquisition times are the same as placing spatial saturation pulses over the scalp and marrow that used in conventional encoding for equivalent SNR. spaces. Data acquired with CSI can be displayed as a grid of spectra, or a pseudocolor image where the color is a function of the fitted or integrated area of a particular resonance. The II.B. Pulse sequences for acquisition slow nature of CSI limits the number of voxels which can be Two principle pulse sequences are used for 1H MRS. Both sampled over the field of view. This in turn leads to under- use three orthogonal slice selective RF pulses. Of these, the sampling errors and broadens the point spread function most commonly used sequence is point resolved spectros- which describes the shape of each voxel.20 The rectangular copy ͑PRESS͒, which consists of a 90° RF pulse followed by nature of the sampling matrix means that the voxel will have

Medical Physics, Vol. 35, No. 10, October 2008 4536 Robert William Prost: Magnetic resonance spectroscopy 4536

FIG. 7. Sum of spectra in ͑a͒, from a single slice CSI acquisition in a patient with a newly appearing lesion shows a characteristic pattern for neoplasm increased choline and decreased NAA. Plotting several spectra as shown in ͑b͒ demonstrates the necrotic core of the lesion with changing neoplastic features. The use of this spatial data provides the actual tissue diagnosis, glioblastoma. Data acquired at 0.5 T using a short echo time CSI sequence.

Medical Physics, Vol. 35, No. 10, October 2008 4537 Robert William Prost: Magnetic resonance spectroscopy 4537

FIG. 8. Coronal T2-weighted image of a patient with a brainstem lesion. Ac- quired voxel is illustrated by the rect- angle on the image. Accompanying 1H spectrum demonstrates elevated choline, decreased to absent NAA and strongly elevated methyl and methylene resonances. Lesion diagnosed as a high-grade neoplasm.

a sinc ͑sin x/x͒ shape with positive and negative sidelobes. voxel method is that the entire acquisition may be completed These sidelobes, if they fall in the area of incompletely sup- in less time than required by CSI for patients who are mar- pressed lipid, can generate a significant contribution to the ginally cooperative. signal arising from the central lobe of the point spread function. II.E. X nucleus methods The SNR efficiency of conventionally encoded CSI 1 makes it the most used method.21 Figure 7 demonstrates the In contrast to H MRS, relatively few clinical applications utility of CSI. In Fig. 7͑a͒, a single large voxel has been exist for X nucleus MRS. While the X nuclei do not suffer 1 acquired in the brain of a patient with a lesion in the right from the water and lipid suppression problems of H MRS, frontal lobe. The voxel covers not only the frontal lobe but there are two other significant issues that determine which other areas as well. The spectrum does not appear normal acquisition methods can be used. The first of these issues is when compared to a spectrum from a healthy control subject. the lower sensitivity per nucleus. The smaller magnetic mo- However, no information is available about the difference in ment of any of the X nuclei produces less signal per nucleus tissue between what is very clearly, by MRS, abnormal, and than in the case of hydrogen. The second issue is that the what is by MRI, apparently normal tissue. The same large required gradient amplitudes for slice selection, phase encod- voxel, with phase encoding applied in dimensions transverse ing, and readout all scale inversely with ␥. The ␥ of phos- to the slice ͓Fig. 7͑b͔͒, yields spectra which demonstrate ne- phorus is 2.5 times smaller than that of hydrogen. Gradients crosis within the lesion ͑elevated lipid and lactate reso- for localizing or encoding phosphorus signal must therefore nances͒, while voxels adjacent become progressively less be 2.5 times greater. This represents a significant limitation neoplastic appearing with distance from the lesion, with the for most whole-body gradient systems. Single voxel excita- choline eventually returning to normal levels in the voxels tion methods such as PRESS or STEAM are generally not furthest away from the lesion. The spatially encoded data used for X nucleus work due both to gradient limitations and allow the lesion to be diagnosed as glioblastoma multiforme the short T2 of many of the X nucleus moieties. Surface coil for which this spectroscopic change with position is pathog- localization combined with pulse and acquire methods or nomonic of this tumor. Judged only by the single spectrum as slice selective methods with CSI phase encoding are among 22 shown in Fig. 7͑a͒, the lesion would have been diagnosed as the principal localization methods used. The smallest prac- a glioma of lower grade. tical voxel volumes at 3 T are 8 cm3 or greater. An additional problem which further limits the utilization of X nucleus methods is the need for additional MR system hardware. Present generation MRI systems have all been de- II.D. Single voxel MRS signed to operate only at the resonant frequency of hydrogen. Despite the ability of CSI to acquire data from many vox- Resonant frequencies of the X nuclei are all far enough from els simultaneously, single voxel MRS methods retain signifi- that of hydrogen so as to require additional hardware. The X cant diagnostic utility. Some smaller lesions in areas of the nuclei acquisitions require separate RF coils, preamplifiers, brain which may be surrounded by air, bone, or adipose tis- power amplifiers, and transceiver hardware. Such hardware, sue are not amenable to exploration by CSI methods due to especially RF coils and preamplifiers are not typically sup- contamination from adjacent voxels which may sample tis- ported by MRI manufacturers, requiring the user to acquire sue outside of parenchyma. For example, the lesion shown in custom built hardware from third party vendors. The cost of Fig. 8 could only be sampled with a single voxel technique. the X-nucleus capable hardware is a significant fraction of Another compelling reason to acquire data by the single cost of the entire system.

Medical Physics, Vol. 35, No. 10, October 2008 4538 Robert William Prost: Magnetic resonance spectroscopy 4538

II.F. Present usual and customary acquisition and analysis techniques Hydrogen MRS voxel sizes range from 0.5 to 8 cm2 or more. The acquisition times are typically 5–30 min. The upper limits of acquisition time are set by patient tolerance. Data are acquired using both PRESS and STEAM excitation methods, although PRESS is predominant due to its factor of 2 advantage in SNR over STEAM. Single voxel methods are the most used for human brain, while CSI methods, which can range from one-dimensional to three-dimensional encoding, tend to be two-dimensional, single slice methods. This is primarily due to time constraints. Acquisitions in prostate are often 3D CSI to map the choline distribution. Single voxel studies of isolated lesions are used in breast. Echo times in brain range from 20 to 290 ms and in prostate or breast, 138 to 290 ms. These longer echo times are used to minimize the artifact from lipid moieties which are not nominally a problem in brain parenchyma. Spectra may be interpreted in several different ways. Qualitative interpretation of resonance amplitudes is common in the clinical setting. Most of this interpretation is done 1 by radiologists and consists of comparing the relative ampli- FIG. 9. Images from two patients with similar lesions referred for H MRS of newly appearing lesions. Images on the right have a false color overlay of tude, presence, or absence of resonances in the frequency the ratio of choline to NAA. Lesion in the upper patient clearly demonstrates domain spectra. Qualitative assessment of spectra is prone to neoplasm ͑Cho/NAAϾ1͒ while the image below shows that the lesion is two important errors. The first is that the entire spectrum is not neoplastic. reduced in amplitude due to partial volume averaging with inert material. The second is that the changes in TR, TE, or 27 magnetic field strength changes relative amplitudes as a re- lesion. Choline is a precursor or breakdown product of the sult of differential T1, T2 relaxation or the change in T1 and phosphocholines which are a constituent of the cell mem- T2 with field strength. Quantitative analysis of spectra, either brane. Figure 9 demonstrates two patients with similar ap- in the time domain or in the frequency domain will become pearing lesions by MRI. The patient with the neoplastic lesion is easily identified by the elevated choline ͑Cho͒ more broadly utilized in the future as the analyses become 1 more robust.23 resonance in the H MRS. Similar results have been obtained in the breast and prostate.28 The X nucleus localization methods can be more varied at 29 least in part due to the fact that no water suppression is Therapy planning has advanced furthest in prostate. Us- required. The localization method used is more a function of ing an inserted endorectal RF coil, 3D CSI data sets are now the target organ or disease process studied than in the case of generated to delineate regions of neoplasm. As in the brain 1H.24 Localization by RF coil sensitivity profile methods are and breast, choline is elevated. Healthy prostate tissue pro- more common in X nucleus studies of skeletal muscle. Radio duces citrate and the diminution of this resonance is used in frequency coils for X-nucleus spectroscopy will have some conjunction with the elevation of choline to create maps of manner of transmit capability and may be volume or surface neoplasm. Treatment planning using MRS in brain tumors is coils. Some of these coils will also have a second mode of beginning to see some utilization. As is shown in Fig. 10, 1 treatment plans which do not include neoplastic tissue which operation which allows operation at H frequencies. This 30 feature is important for localization imaging and shimming remains occult by MRI, should fail sooner. ͑ ͒ 1 Therapy monitoring by MRS is an increasingly important B0 homogeneity adjustment , both of which require H 31 operation.25 The 1H channel of these dual coils can be used aid in decision making in brain tumor patients. Radiation induced necrosis and recurrent neoplasm are difficult to dis- for decoupling, but with the requirement of yet more hard- 1 ware over and above that required for X nucleus acquisition. tinguish by MRI. With some caveats, H MRS detects recurrence by the elevation of choline. One such caveat is that some temporal phases of radiation recovery in brain may III. CLINICAL APPLICATIONS transiently show elevations in choline that are not due to Clinical spectroscopy applications are almost all 1H ac- neoplastic activity.32 quisitions. Target organs include the brain, prostate, and Studies of metabolic dysfunction, while less common than breast. In the brain, 1H MRS is used to differentiate neoplas- tumor studies, have demonstrated clinical utility. One of the tic from non-neoplastic etiologies of lesions detected by very first clinical applications was the detection of elevated MRI.26 While MRI is exquisitely sensitive to the presence of NAA in Canavan’s disease.33 Canavan’s is an inborn defect lesions, it is less specific as to etiology. Neoplastic processes in the production of aspartoacylase, which catabolizes cause an up-regulation in the amount of free choline in the NAA.34 Other diseases of deranged metabolism detectable

Medical Physics, Vol. 35, No. 10, October 2008 4539 Robert William Prost: Magnetic resonance spectroscopy 4539

is decoupling. It requires yet more hardware and is exquisitely sensitive to artifact. Proton decoupling of the 13C spectrum of ethanol is shown in Fig. 4͑b͒. Phosphorus spectroscopy detects adenosine triphosphate ͑ATP͒, phosphocreatine ͑PCr͒, inorganic phosphate ͑Pi͒, the phosphomono- ͑PME͒, and phosphodiesters. Studies of brain have shown alterations of phospholipid metabolism in psy- chiatric disorders.39 Cardiac function can also be studied by 31P spectroscopy.40 Dynamic studies of muscle are presently being used to assess muscle recovery during isometric or dynamic exercise as shown in Fig. 11. Glycogen in muscle has been studied in humans with the use of the 13C.41 Glucose metabolism and its interaction with neuronal function has been studied in brain using 13C labeled 42 FIG. 10. Chemical shift image of glutamate combined with the postcontrast glucose. Similar studies are giving insight into neuron- T1-weighted image of a patient with a glioblastoma. Also on this image is astrocyte trafficking in glutamate and glutamine and the dis- the 98% dose contour line of the radiation therapy plan shown as the thin 43 red line. The site of eventual recurrence of this tumor was posterior to this eases associated with the dysregulation of this process. lesion and is predicted by the red ͑elevated glutamate͒ area ͑Ref. 63͒. Other nuclei which are not otherwise present in appreciable abundance in the body have been the subject of MRS studies. These include lithium in the brains of bipolar patients and fluorine in antipsychotic drugs in brain and che- by 1H MRS include the adrenoleukodystrophies, MELAS, motherapeutic drugs in liver.44 and phenylketonuria.35 Therapy monitoring by use of MRS Given the additional hardware required and the additional allows the evaluation of the efficacy of treatment strategies X in advance of clinical outcome. Other brain chemistry complications of acquisition, no nucleus exams are in changes which result from disease or trauma include hepatic widespread clinical use. encephalopathy in which glutamine is found to be elevated secondary to hepatic failure and the inability of the brain to clear ammonia.36 In cases of near-death asphyxia, 1H MRS has been shown to be prognosticative of recovery.37 The use of 1H MRS in drug studies has shown great IV. THE IMPERILED FUTURE OF CLINICAL MRS promise. One example of this is the reversal of NAA deple- MR spectroscopy has been shown to have high sensitivity tion as a marker of neuronal recovery in Alzheimers patients and specificity in distinguishing neoplastic from non- receiving an acetocholinesterase inhibitor. These elevations neoplastic etiologies in brain lesions.45 This work has been of NAA correlate well with recovery in minimental status 38 completed in a well controlled setting by MR physicists us- scores. Not all in vivo MRS studies are conducted using hydro- ing methods which required manual adjustment for acquisition and postprocessing. Based on this result and others like gen. Other endogenous candidate nuclei are phosphorus 46 ͑31P͒, and carbon ͑13C͒. These nuclei present several prob- it, spectroscopy became a reimbursable procedure. Concur- lems, among which are resonance frequency, abundance, de- rent with the advent of reimbursement, manufacturers auto- tectability, chemical shift, and resonance overlap. Carbon mated MRS acquisition and postprocessing, eventually offer- presents an additional complication. While a highly abundant ing packages which allowed the scanner operator to acquire nucleus in living systems, 98.9% of the spins are of the iso- data independent of the site physicist. Usage and billing fol- tope carbon-12, which has zero magnetic moment and is un- lowed the ability to bill for the procedure. Unfortunately for detectable. Only 1.1% of carbon is carbon-13. Phosphorus MRS, data quality and the specificity of the results have moieties in the body are spread over a chemical shift range suffered. Recently, Medicare has ruled that MRS is an ex- of approximately 25 ppm and carbon-13 over roughly perimental procedure and will no longer be billable within its 47 200 ppm. This range causes problems in localization se- system. Many private insurers have quickly followed to quences where the chemical shift of a moiety causes the deny reimbursement. Yet, the technique is not worse than it location of the excited tissue to be shifted relative to other once was, instead, it has been used with less than sufficient moieties. The resulting spectrum does not originate from a care for data quality. Thus, many radiology departments have single spatial location. This effect is similar to the spatial abandoned the clinical use of MRS. This state of affairs is displacement of Fig. 2͑b͒. An additional problem is reso- unfortunate because MRI system manufacturers lose interest nance overlap, especially in phosphorus studies. These over- in supporting hardware for procedures which are not reim- laps can be partially resolved while improving the SNR of bursed. Historically, much of the scientific progress in MRI the spectrum by removing the J coupling between the ob- and MRS depends on the diligence with which manufactur- served nucleus and hydrogens to which these are bonded. ers attend to the technological as well as operational prob- This method, well known to the analytical NMR community, lems of the MR system.

Medical Physics, Vol. 35, No. 10, October 2008 4540 Robert William Prost: Magnetic resonance spectroscopy 4540

31 FIG.11. P MRS spectrum from the gastrocnemious muscle of a patient in an isometric contraction apparatus. 15 s contraction demonstrates the decrease of PCr ͑heavy arrow͒ and the increase of Pi ͑thin arrow͒.

V. FUTURE DEVELOPMENTS IN MR tion͒ or spectral-spatial pulses may be applied.50 A greater SPECTROSCOPY chemical shift between water and the aliphatic metabolites of The brain will continue to be one of the most studied interest means that shorter duration saturation pulses can be organs by MRS. The ability to extract functional data nonin- used. Therefore, more of the time in the pulse sequence can vasively continues to be the driving force behind MRS. This be used to sample the signal. High speed echo-planar based is likely to remain so in the future. Several benefits accrue to MRSI sequences, such as PEPSI, also benefit as fewer incre- 1H MRS from increasing field strength. These include the ments in echo time need to be collected to distinguish adja- ability to separate resonances that are too closely spaced at cent resonances. These future developments do not require lower field strengths, most notably 1.5 T. The increased sig- additional hardware, as the same hardware used for high field 1 nal to noise and chemical shift dispersion of increased field MRI is also suitable for H MRS. 1 strength also improves metabolite editing sequences. An ex- It should be noted that not all aspects of H MRS are ample is the detection of the inhibitory neurotransmitter beneficiaries of the quest for higher field strength. There are GABA which nominally is obscured by the creatine practical problems in clinical MRS studies which do not im- resonance.48 Increased SNR from operation at high field and prove with field strength. The first is that human tissues are the use of phased array surface coils allow data acquisition intrinsically magnetically inhomogeneous. Numerous struc- with either shorter total scan times or with higher spatial tures of interest in the brain, such as the basal ganglia, accu- resolution. Similar phase undersampling strategies used by mulate iron with age and disease.51 The deleterious effect of MRI for scan time reduction can also be applied to MRS.49 the iron upon resonance linewidth increases with increasing One further benefit of increased chemical shift dispersion is field strength. The second is the effect of other perturbations the ease with which chemical shift saturation ͑water satura- of the magnetic field, such as the effect of the air/tissue in-

Medical Physics, Vol. 35, No. 10, October 2008 4541 Robert William Prost: Magnetic resonance spectroscopy 4541

FIG. 12. Spectra from a 3.4 cm3 voxel acquired in the occipital lobe of a healthy volunteer acquired under identical conditions at three different magnetic ﬁeld strengths. Note the increased amplitude of the glutamate/glutamine resonance ͑Glx͒ at 0.5 T relative to 1.5 T. While the individual resonances in the multiplet start to become visible at 3 T, they are still clearly overlapped. The prominence of the myoinositol resonance also decreases with increasing ﬁeld strength.

terface above the sinuses and the imperfections of field ho- low 1.5 T have also shown utility in performing clinical mogeneity, both of which increase with field strength, cause MRS.53 It must be remembered that MRS is detecting surro- losses in the SNR. Third, many of the resonances which gate markers of disease, not the disease itself. MRS does not overlap at lower field strengths continue to do so even at detect neoplasm, rather the elevated choline that is a marker field strengths above 7 T. As the MRS field matures, a more of the mitotic process. Knowing exactly which chemical balanced view may become predominant. Many disease moiety is elevated in a disease becomes less important than states will benefit from observation at lower field strengths. the observation that a surrogate marker is reliably altered in Reduced linewidths and the collapse of multiplets into pseu- that disease. Perhaps the most exciting future lies ahead for X dosinglets favor operation at field strengths as low as nucleus applications. Other nuclei which have a nonzero gy- 0.5 T.52 Figure 12 illustrates the change of spectral appear- romagnetic ratio and have been used in human MR studies ance with field strength in the same voxel of a volunteer are 13C, 31P, 19F, 23Na, 7Li, 129Xe, and 3He. Naturally abun- acquired at three different field strengths. Note that the me- dant nuclei in the body are 13C, 31P, and 23Na. Exogenous thylene resonances of glutamate and glutamine at 2.3 ppm contrast agents include 13C, 129Xe, and 3He. Other nuclei that increase in amplitude at 0.5 T. A similar effect is shown in can be detected by MRS in vivo include lithium and fluorine. the myoinositol resonance at 3.56 ppm. Even taurine ben- Lithium is used to treat bipolar disease and fluorine is efits, as was shown in Fig. 5. Magnet designs intended for present in a number of psychoactive drugs and some chemo- obese and/or claustrophobic patients with field strengths be- therapeutic agents. Sodium, like lithium, is only detectable in

Medical Physics, Vol. 35, No. 10, October 2008 4542 Robert William Prost: Magnetic resonance spectroscopy 4542

This extraordinarily long T1 means that the gas can be polarized, stored in a magnetic bottle, and carried to the scanner. Studies of lung function are now being carried out with 3He and 129Xe as shown in Fig. 13. Xenon has been used for cerebral perfusion studies in computed tomography where it changes tissue x-ray attenuation. In MRI, xenon can be used to study cerebral perfusion as it readily dissolves into blood through alveolar exchange. The xenon resonance frequency is sensitive to surrounding tissues. A chemical shift in excess of 200 ppm is created by proximity to the alveolar surface FIG. 13. Hyperpolarized gas images from the lungs of a healthy subject 3 129 and thus can be used to study not just ventilation but lung comparing He to Xe. Images courtesy of Dr. John Mugler, University of 55 Virginia. function as well. The prepolarization of the gas means that a very high field magnet is not needed to yield signal. Smaller, more open and patient-friendly magnets will be suf- 1 the body in ionic form. Having only one moiety, sodium can ficient to create both imaging conditions and the H localiza- be imaged using high speed MRI methods. Phosphorus-31 tion images. has 100% isotopic abundance unlike 13C which is only 1.1% The most exciting new development in spectroscopy is 13 abundant. All of the X nuclei observed with natural polariza- the hyperpolarization of C. Achieved in a different manner tion will benefit from higher field strength magnets. The in- from hyperpolarization of the previously mentioned gases, a creased field strength is needed as the intrinsic signals from a large range of bioavailable chemicals can be created with the 13 normally polarized 13Cor31P nucleus are 0.016 and 0.066 polarized C in their structure. To date, two different meth- that of a hydrogen nucleus. Additional transmit channels can ods for achieving high levels of polarization in carbon-13 be used to eliminate heteronuclear J couplings of the X nu- bearing compounds have been proposed. The first is called 57 clei with 1H as shown in Fig. 4. The signal intensity of the X dynamic nuclear polarization. In this method, the 13C en- nucleus resonance then increases as decoupling removes the riched compound in the solid state undergoes microwave ir- splittings. An additional effect to gain signal, utilizing the radiation in a 3.3 T magnet while the sample is held at 1 K. same hardware, is nuclear Overhauser enhancement ͑NOE͒ Once polarized, the sample is rapidly dissolved in a suitable which can create an increase in the polarization. Decoupling solvent, purified, and injected into the subject who is lying in combined with NOE can provide two to fourfold signal the MRI magnet. The second method is polarization transfer increases.54 Equipping a MRI system with both the addi- from parahydrogen ͑PHIP͒ in which the polarization from tional transmit and receive channels, RF coils, and associated the parahydrogen is transferred to a 13C containing molecule hardware to achieve decoupling can cost a substantial frac- through a rhodium catalyst.58 While naturally polarized tion of the cost of the original MRI system. That is a large carbon-13 labeled glucose has been used to measure the rate investment for what is still a time consuming and difficult of the tricarboxilic acid cycle in brain,59 the technique re- study. There is now a method of increasing the polarization quires long acquisition times and high magnetic field of the nuclei of interest, called hyperpolarization.55 Helium-3 strengths. Hyperpolarization carries the potential to create and xenon-129 can be polarized to 50% or more. This fact is metabolic tracers similar in function to those used in positron quite startling when one realizes that the polarization of 1H emission tomography. Unlike fluorodeoxyglucose ͑FDG͒, the in the body at 1.5 T is 1:100 000. The hyperpolarized gases tracers created using hyperpolarized 13C are chemically iden- have T1 relaxation times ex vivo on the order of 10 min.4,56 tical to those in the body. In postitron emission tomography

1 FIG. 14. Location of the image slab in the rat and the corresponding transversal H-NMR image. The NMR signal distribution obtained simultaneously from pyruvate, lactate, and alanine is calculated, and the color images representing the intensity of each metabolite are projected on the anatomical 1H image. Alanine is most prominent in the skeletal muscle around the spinal cord, whereas the P22 tumor tissue is indicated by the highest signal for lactate. Note the different scale. Images courtesy of Klaes Golman, Rene in’t Zandt, Mathilde Lerche, Rikard Pehrson, and Jan Henrik Ardenkjaer-Larsen, Amersham Health R&D AB ͑Part of GE Healthcare͒, Malmö, Sweden.

Medical Physics, Vol. 35, No. 10, October 2008 4543 Robert William Prost: Magnetic resonance spectroscopy 4543

͑PET͒, FDG does not enter the glucose-hexokinase pathway, a lesion and areas around it more practical. The study of and so the information available from PET using FDG is neurotransmitter-related and other diffuse processes will ben- limited to that of cellular uptake. In brain tumors this creates efit from the increased chemical shift dispersion available at some diagnostic confusion as the elevated metabolic rate of higher field strength as well as the increased ease with which low grade glial tumors is equivalent to that of gray matter. spectral editing for otherwise hidden resonances such as Using hyperpolarized 13C labeled metabolic substrates will GABA may be accomplished. allow direct imaging of neoplastic tissues.60 Also, the 13C Higher field strengths will be of greatest advantage to X label changes chemical shifts as substrate is metabolized into nucleus studies. The inherent low sensitivity and low abun- other moieties. A 13C image of a tumor in an animal model dance of the X nuclei make them perfect candidates for in- which demonstrates the effect of the change in chemical shift vestigation at higher fields. The improved SNR that results of the metabolized substrate is shown in Fig. 14. Two impor- should make it practical to include X nuclei in clinical ex- tant caveats remain. The first is that the lifetime of the po- ams, where previously, acquisition times were far too long. larization state is limited which places constraints on the However, the biggest news in the X nucleus world is the duration of experiments ͑seconds instead of minutes͒ and coming of hyperpolarized nuclei and the 4–5 orders of mag- also constrains the location of the polarizing facility to be nitude in additional signal they create. near the magnet. Like all X-nucleus studies, considerable in- Magnetic resonance spectroscopy is poised to make a vestment in hardware is required, even before the polarizing great leap forward. It is up to us as scientists and clinicians to equipment is acquired. However, the cost of the polarizing use it responsibly, while it is up to the manufacturers to equipment and associated lab may be far less than the cost of continue to support MR spectroscopy by making the MR having one’s own cyclotron for PET isotope production. The system better. To realize the benefit of MR spectroscopy for absence of a radiation dose also means that serial studies all patients, we need to undertake larger, more organized using 13C MRS for screening, therapy monitoring, and dis- studies across platforms and across healthcare ease progression can be done with minimal risk. organizations.62 The time to begin is now.

͒ a Telephone: 414-805-2172; Fax: 414-259-9290. Electronic mail: VI. CONCLUSIONS [email protected] 1 70 ͑ ͒ 1 F. Bloch, Phys. Rev. ,460 1946 ; N. Bloembergen, E. M. Purcell, and In the past 15 years H MR spectroscopy has moved from R. V. Pound, ibid. 73, 679 ͑1948͒. the laboratory into routine use for patient care. MR system 2J. T. Arnold, S. S. Dharmatti, and M. E. Packard, J. Chem. Phys. 19, 507 manufacturers continue to improve their systems to meet the ͑1951͒. 3J. T. Vaughan et al., Magn. Reson. Med. 46,24͑2001͒. stringent demands which MRS places on machine perfor- 4I. C. Atkinson et al., J. Magn. Reson Imaging 26, 1222 ͑2007͒. mance. Higher field strength MR systems will improve many 5C. J. Hardy et al., Magn. Reson. Med. 8, 104 ͑1988͒. facets of spectral data quality, but bring their own complica- 6A. Carrington and A. D. McLachlan, Introduction to Magnetic Resonance ͑ tions, such as a heightened sensitivity to brain iron and a with Applications to Chemistry and Chemical Physics Wiley, New York, 1979͒. change in metabolite ratios. Most clinical spectra are still 7E. Becker, High Resolution NMR, Theory and Chemical Applications qualitatively interpreted by the ratio of resonance ampli- ͑Academic, Orlando, FL, 1980͒. tudes. Changing field strength changes what constitutes nor- 8K. Behar and T. Ogino, Magn. Reson. Med. 17, 285 ͑1991͒. 9 ͑ ͒ mal. These changes need to be measured across patient popu- K. L. Behar et al., Magn. Reson. Med. 32, 294 1994 . 10P. Mansfield, J. Phys. C 10,55͑1977͒. lations and used in patient data analysis. Improvements in 11E. O. Stejskal and J. E. Tanner, J. Chem. Phys. 42, 288 ͑1965͒; R. Turner the analysis and interpretation of spectra, such as time do- et al., Radiology 177, 407 ͑1990͒. main, automated fitting methods in the frequency domain, 12T. H. Mareci and H. R. Brooker, J. Magn. Reson. 92, 229 ͑1991͒. 13J. J. Ackerman et al., Nature ͑London͒ 283, 167 ͑1980͒. and feature-based algorithms to classify tissue types, will 14 J. Frahm et al., Magn. Reson. Med. 9,79͑1989͒. address these field strength questions as well as improve the 15R. Kreis, T. Ernst, and B. D. Ross, J. Magn. Reson., Ser. B 102,9͑1993͒. utility and accessibility of 1H MRS to the clinician. Using 1H 16P. Bottomley, U.S. Patent No. 4 480 228 ͑1987͒. 17 MRS to not only distinguish tissue types but to predict re- J. Frahm et al., J. Magn. Reson. 64,81͑1985͒. 18T. T. Brown, B. M. Kincaid, and K. Ugurbil, Proc. Natl. Acad. Sci. U.S.A. currence or premorphologic tumor spread will secure a place 79 ͑ ͒ 1 , 3523 1982 . in for H MRS in the clinician’s retinue of patient manage- 19S. Posse et al., Magn. Reson. Med. 33,34͑1995͒. ment tools.61 20T. R. Brown, NMR Biomed. 5, 238 ͑1992͒. 21 Future directions in 1H MRS include smaller voxel vol- R. Pohmann, M. von Kienlin, and A. Haase, J. Magn. Reson. 129,145 ͑1997͒. umes which will improve the ability to distinguish healthy 22P. A. Bottomley et al., NMR Biomed. 2, 284 ͑1989͒. from diseased tissue. Decreasing voxel volumes while main- 23S. Mierisova and M. Ala-Korpela, NMR Biomed. 14,247͑2001͒;L. taining clinically useful acquisition times will require higher Vanhamme et al., ibid. 14, 233 ͑2001͒. 24 ͑ ͒ field strength magnets and improved RF coil designs, such as S. F. Keevil, Phys. Med. Biol. 51,21 2006 . 25R. E. Lenkinski et al., Radiology 169, 201 ͑1988͒. phased array head coils. Increased use of multiple voxel ac- 26L. Kwock et al., Laucet Oncol. 7, 859 ͑2006͒. quisition methods such as CSI will make MRS less sensitive 27K. K. Bhakoo et al., Cancer Res. 56, 4630 ͑1996͒. to the skills of the operator and clinician in prescribing a 28C. Mountford et al., J. Magn. Reson Imaging 24, 459 ͑2006͒;P.J.Bolan ͑ ͒ voxel location. A CSI study with small voxels, aided by in- et al., Breast Cancer Res. Treat. 7,149 2005 . 29A. Zapotoczna et al., Neoplasia 9, 455 ͑2007͒. creased SNR from the use of phased array coils and higher 30R. Tarnawski et al., Int. J. Radiat. Oncol., Biol., Phys. 52, 1271 ͑2002͒. field strength magnets will make the retrospective analysis of 31I. Park et al., Int. J. Radiat. Oncol., Biol., Phys. 69,381͑2007͒.

Medical Physics, Vol. 35, No. 10, October 2008 4544 Robert William Prost: Magnetic resonance spectroscopy 4544

32L. L. Wald et al., J. Neurosurg. 87,525͑1997͒. S. Jordan et al., AHQR 2007 ͑2003͒. 33G. Bartalini et al., Childs Nerv. Syst. 8, 468 ͑1992͒. 48G. Bielicki et al., NMR Biomed. 17,60͑2004͒. 34 J. R. Moffett et al., Prog. Neurobiol. 81,89͑2007͒. 49X. Zhao et al., Magn. Reson. Med. 53,30͑2005͒. 35 L. Chang et al., Neurology 48,836͑1997͒. 50C. H. Meyer et al., Magn. Reson. Med. 15, 287 ͑1990͒. 36 ͑ ͒ 51 R. Kreis et al., Radiology 182,19 1992 . J. Vymazal et al., J. Neurol. Sci. 134,19͑1995͒. 37 ͑ ͒ R. Kreis et al., J. Clin. Invest. 97, 1142 1996 . 52R. W. Prost et al., Magn. Reson. Med. 37, 615 ͑1997͒. 38 ͑ ͒ K. R. Krishnan et al., Am. J. Psychiatry 160, 2003 2003 . 53T. G. Perkins et al., ISMRM, Berlin, Germany, 2007 ͑unpublished͒. 39 ͑ ͒ B. K. Puri, Int. Rev. Psychiatry 18, 145 2006 . 54 ͑ ͒ 40 ͑ ͒ D. W. Klomp et al., Magn. Reson. Med. 55, 271 2006 . G. M. Pohost et al., Rays 26,93 2001 . 55 ͑ ͒ ͑ ͒ 41 ͑ ͒ M. S. Albert et al., Nature London 370, 199 1994 . J. J. Prompers et al., NMR Biomed. 19, 927 2006 . 56 ͑ ͒ 42 ͑ ͒ K. Ruppert et al., Magn. Reson. Med. 44, 349 2000 . F. Hyder et al., J. Cereb. Blood Flow Metab. 26, 865 2006 . 57 43C. Zwingmann and D. Leibfritz, NMR Biomed. 16, 370 ͑2003͒. J. H. Ardenkjaer-Larsen et al., Proc. Natl. Acad. Sci. U.S.A. 100, 10158 ͑ ͒ 44R. A. Komoroski, NMR Biomed. 18,67͑2005͒;I.K.LyooandP.F. 2003 . 58 ͑ ͒ Renshaw, Biol. Psychiatry 51, 195 ͑2002͒; R. Martino, M. Malet-Martino, M. Goldman et al., Magn. Reson. Imaging 23,153 2005 . 59 and V. Gilard, Current Drug Metabolism 1, 271 ͑2000͒. G. F. Mason et al., J. Neurochem. 100,73͑2007͒. 60 45S. D. Rand et al., AJNR Am. J. Neuroradiol. 18, 1695 ͑1997͒. K. Golman et al., Cancer Res. 66, 10855 ͑2006͒. 61 46X. Leclerc, T. A. Huisman, and A. G. Sorensen, Curr. Opin. Oncol. 14, E. E. Graves et al., Neurosurgery 46, 319 ͑2000͒. 292 ͑2002͒; J. Butzen et al., AJNR Am. J. Neuroradiol. 21,1213͑1213͒. 62W. Hollingworth et al., AJNR Am. J. Neuroradiol. 27, 1404 ͑1404͒. 47A. P. Lin, T. T. Tran, and B. D. Ross, NMR Biomed. 19, 476 ͑2006͒;H. 63T. Takano et al., Nat. Med. 7, 1010 ͑2001͒.

Medical Physics, Vol. 35, No. 10, October 2008 Breast cancer imaging: A perspective for the next decade ͒ Andrew Karellasa and Srinivasan Vedantham Department of Radiology, University of Massachusetts Medical School, Worcester, MA 01655 ͑Received 9 February 2008; revised 24 June 2008; accepted for publication 26 August 2008; published 14 October 2008͒ Breast imaging is largely indicated for detection, diagnosis, and clinical management of breast cancer and for evaluation of the integrity of breast implants. In this work, a prospective view of techniques for breast cancer detection and diagnosis is provided based on an assessment of current trends. The potential role of emerging techniques that are under various stages of research and development is also addressed. It appears that the primary imaging tool for breast cancer screening in the next decade will be high-resolution, high-contrast, anatomical x-ray imaging with or without depth information. MRI and ultrasonography will have an increasingly important adjunctive role for imaging high-risk patients and women with dense breasts. Pilot studies with dedicated breast CT have demonstrated high-resolution three-dimensional imaging capabilities, but several technological barriers must be overcome before clinical adoption. Radionuclide based imaging techniques and x-ray imaging with intravenously injected contrast offer substantial potential as a diagnostic tools and for evaluation of suspicious lesions. Developing optical and electromagnetic imaging techniques hold signiﬁcant potential for physiologic information and they are likely to be of most value when integrated with or adjunctively used with techniques that provide anatomic information. Experimental studies with breast specimens suggest that phase-sensitive x-ray imaging techniques can provide edge enhancement and contrast improvement but more research is needed to evaluate their potential role in clinical breast imaging. From the technological perspective, in addition to improvements within each modality, there is likely to be a trend towards multi-modality systems that combine anatomic with physiologic information. We are also likely to transition from a standardized screening, where all women undergo the same imaging exam ͑mammography͒, to selection of a screening modality or modalities based an individual-risk or other classiﬁcation. © 2008 American Association of Physicists in Medicine. ͓DOI: 10.1118/1.2986144͔

Key words: breast cancer, mammography, digital mammography, tomosynthesis, CT, ultrasound, MRI, contrast agents, optical imaging

I. INTRODUCTION II. MAMMOGRAPHY

Imaging of the breast is indicated almost exclusively for the Mammography is essentially the only widely used imag- detection, diagnosis, and clinical management of cancer and ing modality for breast cancer screening. Various forms of for the assessment of the integrity of breast implants. Com- radiographic imaging of the breast have been used for nearly monly used imaging modalities include mammography, ul- one hundred years but mammography with dedicated equip- trasonography, magnetic resonance imaging ͑MRI͒, scinti- ment and technique did not emerge as a screening tool until 2 mammography, single photon emission computed the mid-1960s. The importance of physical compression of tomography ͑SPECT͒, and positron emission tomography the breast and the significant association between microcal- ͑PET͒. The goal of this work is to provide a prospective view cifications and breast carcinoma were recognized in the early 1950s by Leborgne.3 While Gershon-Cohen in the United of breast imaging, primarily for detection and diagnosis. States and Gros in Europe were strong advocates for breast In addition to standard recommendations for imaging cancer screening, the development of a low kVp, high mAs based screening, self breast examination ͑SBE͒ has long technique that can be performed in a reproducible manner in been recommended because it is not unusual for women to 1960 by Egan enabled an organized breast cancer screening feel anatomic changes in the breast that turn out to be ma- program.4 In 1966, Compagnie Générale de Radiologie ͑ ͒ lignant. Clinical breast examination CBE is commonly ͑CGR, France͒ in collaboration with Gros developed the first practiced as a part of routine physical examination by health dedicated mammography unit. This unit featured a molybde- providers or when prompted by a concern arising from SBE. num anode with a nominal 0.7-mm focal spot. Subsequently, The scientific evidence is inconclusive on the effectiveness several system manufacturers developed dedicated mam- of SBE and CBE in reducing breast cancer mortality. How- mography units that facilitated its widespread availability. ever, a recent study demonstrated a modest improvement in Several large randomized clinical trials have shown that sensitivity when combined with mammography.1 mammography reduces mortality from breast cancer.5–10

While clinical trials have been essential in establishing the raphy with screen-film mammography in a screening popu- efficacy of mammography as a screening tool, the critical lation demonstrate equivalency for cancer detection,19–21 and role of physics in the evolution of mammography cannot be digital mammography performed significantly better for pre- overemphasized. Key developments in mammography in- and perimenopausal women younger than 50 years with clude the invention of sensitive high-resolution image- dense breasts.22 intensifying screens, improved films, low x-ray absorption Current technological approaches for digital mammogra- cassettes, and dedicated mammography film processors that phy that are in clinical use can be broadly classified into 11 enabled major dose reduction. The development of an x-ray “fixed-detector” and “flexible-detector” installations. In a tube with molybdenum ͑Mo͒ target; molybdenum filter, and “fixed-detector” installation, the dedicated detector is hard- 12 beryllium ͑Be͒ window, and with a small focal spot that wired to the support column of the mammography system was specifically designed for mammography represents an- and is not removable. Examples of such “fixed-detector” in- other major technological breakthrough. The concept of the stallations include indirect conversion hydrogenated amor- projection geometry in which the central ray grazes the chest phous silicon ͑a-Si:H͒ based detectors and direct conversion wall and meets the image receptor close to the chest wall is amorphous selenium ͑a-Se͒ based detectors. In contrast, a unique to mammography, and it represents a crucial design “flexible-detector” installation uses the x-ray cassette holder element that enables maximum inclusion of breast tissue. of a mammography system to house the detector. An ex- The development of low-ratio, high primary transmission ample of such a “flexible-detector” system is computed radi- moving grids and subsequently cellular grids are also impor- ography ͑CR͒ technology. One advantage of the flexible- tant contributors to the high image quality achieved by mod- detector installation is the ease of conversion of an existing ern mammography systems. screen-film mammography system to a digital system. Screen-film mammography has long been considered as a An indirect conversion system uses an intermediary stage, “gold standard” for breast cancer screening. In addition to its typically a scintillator to convert the transmitted x-rays to ability to provide adequate visualization of soft tissue abnor- light photons, followed by detection of the converted light malities, its particular strength is the ability to depict subtle photons using an optical sensor. The scintillator of choice for calcifications. While screen-film mammography is a power- indirect conversion systems is CsI:Tl, which, due to its co- ful tool for initial detection and subsequent follow-up of sus- lumnar structure, suppresses lateral light diffusion and, picious lesions, it has certain inherent limitations which are hence, results in better preservation of spatial resolution. De- difficult to overcome. The most important and widely ac- velopment of a-Si:H arrays was an important contributor for knowledged weaknesses of screen-film mammography are adaptation to large field of view ͑full-field͒ imaging.23 Physi- associated with its limited dynamic range, contrast character- cal characterization indicate a substantial improvement in istics, susceptibility to suboptimal film processing condi- DQE ͑ϳ0.55 at zero-spatial frequency͒ characteristics com- tions, and granularity. It also presents significant limitations pared to screen-film mammography.18,24 in detecting very subtle lesions, especially in the presence of dense glandular tissue. These limitations were well eluci- A direct conversion system does not use an intermediary dated during the preliminary development stages of digital stage and conversion is made from x-rays to electrons after mammography.13 Additional investment to develop improved interaction in a photoconductive layer, typically a-Se. While screen-film technology is unlikely because of the emergence a-Se was used more than four decades ago in xeroradiogra- of digital mammography that provides wide dynamic range phy and xeromammography, the development of advanced charge readout methods enabled its adaptation to digital and offers the convenience of digital image manipulation, 25,26 communication, and archival. mammography. The elimination of the intermediate scintillator layer with direct detection systems allows such sys- The term “digital mammography” is used for any technol- 27 ogy which employs a single or multiple detector assembly to tems to achieve high spatial resolution, and higher DQE ͑ ͒ capture an electronic image of the x-rays transmitted through characteristics 0.54 to 0.64 at zero-spatial frequency com- 17 the breast that can be displayed, stored, and communicated pared to screen-film mammography. In addition, a slot-scan electronically.14 Digital mammography is now a standard photon-counting digital mammography system that uses sili- tool for breast cancer imaging and is steadily replacing con strip detectors is in clinical use in some countries. This screen-film mammography as the preferred tool for screen- approach, in addition to providing efficient scatter rejection 28,29 ing. As of this writing, approximately 36% of all mammog- due to the slot-scan geometry, substantially reduces elec- raphy units in the United States are digital,15 and considering tronic noise contribution to the acquired image resulting in 30 the higher throughput of digital than screen-film, it is likely improved detective quantum efficiency. that more than 36% of the examinations are performed with Computed radiography ͑CR͒ uses a photostimulable phos- digital mammography. The conversion to digital is likely to phor plate typically consisting of BaF͑Br,I͒:Eu2+ crystals on accelerate and within the next three to five years digital a suitable substrate in the form of a portable cassette. When mammography will be the dominant modality. The zero- exposed to x rays, f-centers are created in proportion to x-ray spatial frequency detective quantum efficiency DQE͑0͒ of exposure and remain stable for several hours. This latent digital mammography systems is in the range of 0.45 to 0.65, image is “read out” by stimulating the photostimulable phos- which is substantially higher than ϳ0.35 or lower for screen- phor plate with a laser beam, typically in a raster fashion, film systems.16–18 Clinical trials comparing digital mammog- resulting in the emission of light photons in the ultraviolet-

Medical Physics, Vol. 35, No. 11, November 2008 4880 A. Karellas and S. Vedantham: Breast cancer imaging: A perspective 4880 blue region. The emitted light is detected by a photosensor, In CR technology, some of the important advances in- typically a photomultiplier tube, to generate an electronic clude the development of columnar stimulable phosphor image. While CR has been in clinical use for radiographic screens based on CsBr,51 development of linear readout ͑line 52 applications for nearly three decades, the development of a scan͒ technology for faster readout of the phosphor, and 53,54 dual-side readout that uses a transparent phosphor substrate integration of these approaches. However, we are not and light collection from both sides of the photostimulable aware of their transition to digital mammography as yet, but phosphor plate31 was an important contributor for improved that could likely occur in the near future. DQE ͑ϳ0.54 at zero-spatial frequency͒ of such systems.16,32 Another area of substantial interest in detector technology Outside the United States, CR based single-side read digital is the development of energy-resolving large-area photon- mammography systems using BaFI-, BaSrFBrI-, and counting detectors, which has been challenging. While sev- BaF͑Br,I͒-photostimulable phosphor plates are also in clini- eral approaches for photon-counting detectors have been proposed including scintillation detection using micro-channel cal use.33 Recent reviews of technological approaches for plates55 and gaseous detectors, it appears that semiconductor- digital mammography have been published.14,34,35 based direct-conversion photon-counting systems may be While there is no consensus on spatial resolution require- better suited for medical imaging.56 Some of the semicon- ments in digital mammography, current research suggests ductor materials that are considered promising for photon- that for indirect detection approaches, a low noise detector counting detectors include Si, GaAs, CdTe, and CdZnTe, with smaller pixel size than that used in current practice may typically bonded to a two-dimensional readout with applica- enhance visual perception of small objects such as tion specific integrated circuits, and are commonly referred 36 microcalcifications. Recently, it was observed that noise to as hybrid detectors. Several collaborative research projects had a more dominant effect than display resolution for the to develop hybrid detectors exist,57,58 increasing the pros- tasks of detecting microcalcifications and discrimination of pects for their availability in the next decade. 37 masses. The advent of digital mammography has prompted recon- Research and development to improve digital mammog- sideration of several aspects of mammographic imaging that raphy system performance characteristics and to develop translated from screen-film imaging. These include anode new detector technologies, are in progress. In indirect-type material, x-ray spectra, technique factors, and radiation dose. a-Si:H based detectors, a recent important advancement is In addition to the common target-filter combinations of Mo- the development of a continuous photodiode design rather Mo, Mo-Rh, and Rh-Rh, there is an increasing trend to use than the traditionally used discrete a-Si:H photodiode array.38 other combinations such as W–Rh, W–Ag, and W–Al with This would increase the fill factor, resulting in improved sig- digital mammography. These alternative W-target techniques nal transfer characteristics and dose efficiency. Also, incor- may allow for modest reduction in radiation dose with no 59–61 poration of compensation lines with a-Si:H based detectors apparent reduction in image quality. In addition, the ex- has been shown to reduce correlated electronic noise arising ploration of techniques such as contrast-enhanced digital from external and ambient sources.39 Methods to limit lateral mammography ͑CEDM͒ and DBT that may require x-ray diffusion of light within the scintillator either by laser etch- tubes with increased heat capacity and output also have an 40 influence on the choice of anode material. In addition, radia- ing columnar CsI: Tl or by infusion of crystalline CsI:Tl 62 41 tion dose reduction with photon counting detectors, a-Si:H within a tungsten grid matrix hold promise for improved 63,64 65 spatial resolution, but have not yet been translated to prac- indirect conversion detectors, and CR have also been tice. reported. While phantom studies indicated the possibility of 50% dose reduction with digital mammography,66 studies Recent research with direct-conversion a-Se based detec- with clinical backgrounds indicate that such a drastic dose tors have been focused mainly on understanding the tempo- reduction could adversely affect detection of microcalcifica- ral imaging characteristics ͑image lag͒ and ghosting tions and discrimination of masses substantially, and to a properties.42–44 Knowledge of these properties will be essen- lesser extent adversely affect detection of masses.67,68 Con- tial for emerging techniques of digital breast tomosynthesis ͑ ͒ tinuing technological improvements and technique refine- DBT and contrast enhanced digital mammography ments could lead to further dose reduction while maintaining ͑ ͒ CEDM that require fast image acquisition and readout. On- image quality. going investigations are aimed at improving the gain of a-Se Extensive investigations on radiation dose to the breast based detectors through avalanche multiplication process and 45,46 and its dependence on breast composition, breast thickness, in understanding its implication on noise. The develop- and x-ray spectral characteristics have been documented.69–72 ment of low-noise detectors with improved sensitivity would While it was believed that radiation dose to other organs also be beneficial to the promising technique of DBT that including the uterus would be low during a mammography requires low dose per projection view. Attempts to adapt ma- exam, until recently quantitative estimates were terials such as gallium arsenide ͑GaAs͒, cadmium zinc tellu- unavailable.73,74 A Monte Carlo computational study with an ͑ ͒ ͑ ͒ ͑ ͒ ride CdZnTe , mercuric iodide HgI2 and lead iodide PbI2 anthropomorphic software phantom indicates that the dose to that hold promise of improved quantum efficiency are yet to the uterus during the first trimester, where a women may be bear fruition due to challenges such as charge-traps, higher unaware of her pregnancy, is less than 0.03 ␮Gy per imaged leakage current, and spatial nonuniformity.47–50 breast during a bilateral two-view mammography exam.75

Medical Physics, Vol. 35, No. 11, November 2008 4881 A. Karellas and S. Vedantham: Breast cancer imaging: A perspective 4881

The use of a lead-shield further reduces this dose by a factor but its imaging ability is limited by the beam direction that is of 2 to 7, suggesting that if it is clinically necessary for a fixed and perpendicular to the face of the transducer. woman in her first trimester of pregnancy to undergo mam- In compound ultrasonography, the beam is electronically mography, then the radiation dose to the fetus would be steered for improved sampling of the anatomy that may lie minimal.75 parallel to the ultrasound beam, rendering a more complete The advantages of vigorous physical compression of the image. Harmonic imaging techniques take advantage of the breast in terms of adequate tissue separation, x-ray scatter, variation of the velocity of the ultrasonic wave through dif- and radiation dose, for producing good mammographic im- ferent tissues that produces harmonic frequencies. The pro- age quality are well known. Unfortunately, to this date, the cessing of harmonic signals leads to better selection of sig- scientific community has been unable to overcome the vig- nals by suppressing effects such as side-lobe artifacts, beam orous breast compression needs of mammography. In screen- defocusing, and reverberations, resulting in improved film mammography, it is well established that the use of images.85–87 Color Doppler and more recently sensitive anti-scatter grids improves contrast for breasts of average power Doppler ultrasound has been used for further evalua- and above average compressed thickness. However, the use- tion of the breast. fulness of anti-scatter grid is not firmly established for thin In 2002, Kolb et al. published a landmark article that and mainly adipose breasts. Current practice is to perform showed improved sensitivity ͑97% versus 74%͒ when ad- mammography with the anti-scatter grid in place for all im- junctively used with mammography compared to physical aging needs, except for magnification views. In spite of its examination with mammography.88 They also observed an advantages, anti-scatter grids do suffer from deficiencies improvement in sensitivity for dense breasts with ultrasound such as incomplete suppression of scattered radiation, reduc- compared to mammography. In addition, they noted that the tion in primary radiation reaching the detector, and time taken to perform an ultrasound exam was comparable to artifacts.29,76,77 that of a clinical breast exam. However, he also observed an With the advent of digital mammography that would al- increased in false positive rates with the use of ultrasound as low for numerical scatter correction techniques, the possibil- an adjunct to mammography. In recently published results of ity of imaging without the anti-scatter grid were studied and an ACRIN trial that included 2637 women with heteroge- showed promise of improved performance.78–80 However, neously dense breast in at least one quadrant observed that another study indicated that removal of the anti-scatter grid the diagnostic accuracy improved from 0.78 to 0.91 when could provide a modest reduction of ϳ8% in radiation dose ultrasound was adjunctively used with mammography.89 to the subject.81 Although scatter correction for images ac- However, there was also a substantial decrease in positive quired without the anti-scatter grid using numerical tech- predictive value with mammography plus ultrasound ͑11.2%͒ niques have been reported,82–84 its impact on contrast, reso- compared to mammography ͑22.6%͒ alone. Also, the median lution, noise, and artifacts are yet to be studied. At present, time to perform a bilateral ultrasound exam was 19 min. digital mammography, with the exception of slot-scanning Hence, the improved diagnostic accuracy provided by ad- systems, uses anti-scatter grids for scatter reduction. The junctive use of ultrasound to mammography has to be care- emergence of DBT where the use of an anti-scatter grid is fully weighed against the decrease in positive predictive impractical, could further advance the research on scatter value and exam duration. From the technological perspec- correction algorithms that may translate to digital mammog- tive, it can be inferred that there may be a need for a com- raphy in the future. bined dual-modality mammography-ultrasound system. Even We will continue to observe increased transition to digital if ultrasound is not adapted for screening, such a system is from screen-film mammography. Also, improvements in de- likely to be of benefit for diagnostic evaluation as it provides tector technology and transition to higher kVp techniques for co-registered dual-modality images. will provide for substantial reduction in radiation dose. The Development of a semi-automated scanning ultrasound prospects of a large-area photon-counting detector with the device integrated with a digital breast tomosynthesis ͑DBT͒ ability to provide energy resolution appears brighter. system was recently reported.90 Figure 1 shows the combined DBT-US system. Performance characteristics of the DBT component indicates minimal in-plane blur and better management of artifacts with reconstruction using general- III. ULTRASONOGRAPHY ized filtered backprojection.91 Identification of compression The role of B-mode ultrasound in breast imaging has been paddles suitable for both x-ray and ultrasound imaging,92 as largely limited to applications such as distinguishing be- well as techniques to address coverage and motion issues tween cystic versus solid masses, evaluation of palpable during ultrasound scan93 have been described. Recently, de- masses, and for needle core biopsy of masses. In recent velopment of an ultrasound computed tomography system years, the number of indications has been greatly expanded that generates reflection, attenuation, and sound speed im- and breast ultrasonography is now an essential modality in ages has been reported.94 Spatial resolution measurements breast imaging. A center frequency above 10 MHz is now indicate in-plane resolutions of 0.5 and 4 mm in reflection recommended for adequate spatial resolution by the Ameri- and transmission modes, respectively. A pilot clinical study can College of Radiology ͑ACR͒. B-mode imaging works with 50 subjects indicate the ability to routinely detect well for the established indications of breast ultrasonography, masses greater than 15 mm in size.95

Medical Physics, Vol. 35, No. 11, November 2008 4882 A. Karellas and S. Vedantham: Breast cancer imaging: A perspective 4882

and the ability to detect mammographically occult cancers in the contralateral breast.116–119 Independent clinical trials for women at high-risk of hereditary breast cancer indicate increased sensitivity with breast MRI than mammography but with variable specificity.120–131 These studies have prompted the American Cancer Society to recommend the use of MRI as a adjunct to screening mammography for women with a lifetime risk of 20%–25% or greater.132 A recent meta analysis that included 44 prior studies indicate that breast MRI has a sensitivity of 0.9 and specificity of 0.72.133 Importantly, this analysis indicated that variability in specificity was due FIG. 1. Integrated dual-modality digital breast tomosynthesis and scanning to cancer prevalence in the individual studies and due to ultrasound system. Provided by Paul L. Carson and Mitchell M. Goodsitt at the University of Michigan and Kai Thomenius at GE Global Research, interpretative criteria used to differentiate benign and malig- Niskayuna, NY. This system was developed with support by NIH R01CA nant lesions.133 With the development of lexicons for breast 91713 and Office of Naval Research grant MDA905-00-10041. MRI interpretation134 and standardization of procedures, variation in specificity is likely to be reduced. A recent two- part review addresses the current status of breast MRI.135,136 Technological improvements in transducer technology Dynamic contrast enhanced MRI ͑DCE-MRI͒ is a very im- and signal processing have contributed to the extensive portant tool for detection, diagnosis, and clinical manage- adoption of ultrasonography for diagnostic evaluation of the ment of breast cancer. However, it requires intravenous in- breast and for biopsy guidance. There is a possibility that jection of Gd-contrast agent that entails some elevated ultrasound could have an adjunctive role to screening mam- 137,138 mography for hetereogeneously dense breasts. risk. Hence, by its nature contrast-enhanced MRI is likely to be limited to a subgroup of patients. Another promising technique that has garnered substantial IV. MAGNETIC RESONANCE IMAGING interest recently is proton ͑1H͒ magnetic resonance spectros- In vitro measurements of relaxation times of tumors and copy ͑MRS͒. This technique allows for quantitative charac- normal tissue with nuclear magnetic resonance ͑NMR͒ was terization of total or composite choline concentration that has reported by Damadian in 1971.96 Subsequent to the develop- been shown to be elevated in malignant tumors compared to ment and application of local gradient fields that made im- normal breast tissue.139 While initial works were focused on 97 aging ͑NMR zeugmatography as proposed by Lauterbur ͒ 31P MRS,140–143 recent research has been primarily on the feasible, Mansfield et al. reported on imaging with surgical use of 1H MRS,144–147 in part due to its higher sensitivity 98 breast tissue samples. Ross et al. and El Yousef et al. re- compared to 31P MRS.148 MRS is a nonvasive technique that ported on some of the earliest in vivo breast MRI studies in does not require contrast injection; however, most of current 99–101 the early 80’s. Development of a coil specifically de- research has been on spectroscopic analysis of regions local- signed for breast imaging was an important technological 102 ized from prior DCE-MRI. Current studies have shown the advancement. The development of gadolinium diethylene correlation between DCE-MRI and MRS,149,150 and demon- ͑ ͒ triamine pentaacetic acid Gd-DTPA contrast agent and its strated improved sensitivity and specificity when used as an application to human imaging was an important milestone in adjunct to breast MRI.151–153 While there are interesting as- the advancement of MRI.103–108 Following the application of pects of this technique, most of the studies were performed at Gd-DTPA for contrast-enhanced breast MRI,109 initial inter- 1.5 T with voxel volume of ϳ1cm3 indicating better suit- pretation criteria were based on morphology and contrast en- ability for large tumors. Since total choline concentration hancement that were obtained with long acquisition times. may be indicative of cell replication,154 MRS is being ac- However, this did not provide substantial contrast between tively investigated and show promise for early determination tumor and proliferative changes. Hence, further research was 110–113 of the effectiveness of neoadjuvant chemotherapy for locally focused on developing fast pulse sequences that ush- 155–159 ered the era of dynamic contrast enhancement studies. An- advanced breast cancer. In addition, studies on MR spectroscopic imaging ͑MRSI͒ primarily to improve speci- other important advancement was the development of a bi- 160–162 lateral breast coil that facilitated simultaneous imaging of ficity have been reported. Importantly, one of the stud- both breasts. This allowed comparison of enhancement pat- ies describe a method to improve signal-to-noise ratio and 162 terns between the breasts at reduced cost and time. reduce acquisition time with sub-centimeter voxel volume. Currently dynamic contrast enhanced breast MRI is clini- If this technique can evolve to the point of replacing cally used to provide volumetric three-dimensional ͑3-D͒ contrast-enhanced MRI, then risks associated with contrast anatomical information and physiologic information that are media and injection can be eliminated. Although this tech- indicative of increased vascular density and vascular perme- nique is in its infancy, the concept of a screening MR exam ability changes associated with angiogenesis.114 Clinical that provides high resolution morphological information with breast MRI studies have demonstrated its ability to provide MRSI to provide physiologic information without contrast accurate diagnosis, extent of disease and multi-centricity,115 media is highly appealing. Recent reviews address the clini-

Medical Physics, Vol. 35, No. 11, November 2008 4883 A. Karellas and S. Vedantham: Breast cancer imaging: A perspective 4883 cal prospects and challenges of MRS and allied For detection of primary tumors, 18F-FDG-PET have been techniques.163–166 reported to have similar sensitivity as that of SPECT.177 A MRI already has a very important role in breast imaging meta-analysis of whole body 18F-FDG-PET that included 13 as an adjunctive tool for screening and as a diagnostic tool studies indicated an overall sensitivity of 89% and specificity for imaging lesions that are indeterminate from other modali- of 80%.178 However, the mean tumor size in those studies ties. MRI is also widely used for assessing the structural ranged from 2 to 4 cm. Characterization of a dedicated integrity of breast implants. Its role will continue to expand breast PET system using four detector heads comprising of with the development of novel image acquisition techniques LYSO crystals coupled to position-sensitive photomultiplier and technological improvements. tubes ͑PSPMTs͒ with multi-angle tomographic image acquisition capabilities was reported to achieve ϳ2 mm spatial resolution.179 Development of PET detector modules with V. RADIONUCLIDE IMAGING lutetium oxyorthosilicate ͑LSO͒ crystals coupled to Radionuclide based imaging techniques such as scinti- PSPMTs,180 and more recently LSO coupled to position sen- mammography, single-photon emission computed tomogra- sitive avalanche photodiodes with depth-of-interaction capa- phy ͑SPECT͒, positron emission mammography ͑PEM͒, and bilities have been reported.181,182 These systems can play an positron emission tomography ͑PET͒ are additional imaging important role in monitoring effectiveness of therapeutic techniques that provide for physiologic information. regimens. Scintimammography and SPECT typically use To overcome the limited sensitivity and spatial resolution 99mTc-sestamibi or 99mTc-tetrofosmin for breast cancer imag- of whole-body PET systems, a PEM system was ing. Scintimammography is used for imaging mostly pal- developed183,184 and showed promising results in a pilot pable lesions that were occult or indeterminate from other clinical study.185 Development of PEM systems using gado- imaging modalities. For palpable mass, a meta-analysis indi- linium orthosilicate ͑GSO͒ and yttrium-aluminium perov- cates that the sensitivity and specificity were 87.8% and skite ͑YAP͒ scintillators have been reported.186,187 A collabo- 87.5%, which is high.167 However, for nonpalpable lesions rative effort to develop a dedicated PEM system using the sensitivity was reduced to 66.8%.167 In an another study, cerium- and yttrium-doped lutetium orthosilicate ͑LYSO͒ the sensitivity reduced from 74.2% for larger lesions to scintillator elements coupled to avalanche photodiodes is 48.2% for lesions smaller than 1 cm.168 New technological also underway.188 These systems offer the potential of im- advances such as the development of dedicated cameras for proved resolution and sensitivity. A pilot clinical study evalu- scintimammography with improved spatial resolution has re- ating a prototype system using lutetium gadolinium oxy- newed interest in this field.169 Characterization of a dedicated orthosilicate ͑LGSO͒ scintillator elements showed the ability scintimammography system was recently reported to achieve to detect smaller lesions.189 All of the aforementioned dedi- detection of ϳ7 mm spheres bearing 99mTc.170 A clinical cated PEM systems use stationary detector heads. A multi- study to evaluate its potential with 100 subjects scheduled to institutional clinical study of a commercially available PEM undergo biopsy of 2 cm or smaller masses indicated a sub- system using translational detector heads that enrolled 94 stantial improvement in sensitivity for imaging lesions subjects with known breast cancer or suspicious lesions smaller than 1 cm.171 In an another study in which 94 high- showed high sensitivity and specificity and the ability to de- risk subjects with normal mammographic exam were evalu- tect small lesions.190 ated with a dedicated scintimammography camera using A recent review address the clinical aspects and limita- 99mTc-sestamibi detected two malignancies, both of which tions of various radionuclide-based techniques for breast were smaller than 1 cm.172 However, false-positives due to cancer imaging.191 With continued advancement of detector fibrocystic change, fibroadenoma, and fat necrosis were also technology, radionuclide-based imaging systems dedicated to observed. A study comparing dedicated scintimammography breast imaging are likely to play a significant role in thera- with conventional SPECT indicated no differences in sensi- peutic monitoring of known cancers and in diagnostic imag- tivity, but observed better performance for 1 cm or smaller ing of suspicious breast lesions. lesions with the dedicated scintimammography system.173 Further improvements, such as development of a dual-head VI. INVESTIGATIONAL MODALITIES camera and with increased spatial resolution may improve VI.A. Volumetric x-ray imaging techniques sensitivity for smaller lesions. The primary advantage of SPECT is its ability to provide While there have been considerable advances in mam- 3-D information. In SPECT imaging, the development a mography, there is one major inherent limitation in that the dedicated system for breast imaging in a prone patient posi- mammographic image reduces the three-dimensional tion with pendant breast geometry has been reported.174 This anatomy of the breast into a two-dimensional image. This system uses a scanning trajectory that closely follows the resulting superposition of normal breast structures, which breast contour. A more recent work described the develop- causes a visually distracting mask, is often referred to as ment of a dedicated breast SPECT system using CdZnTe anatomical noise and has been shown to impair lesion detectors.175 Integration of the dedicated SPECT system with detection.192–194 In addition, tissue superposition can mimic a dedicated breast CT system to provide for co-registered the presence of a lesion, resulting in increased recall rates dual-modality imaging is also in progress.176 and in increased biopsy rates, that add to the inconvenience

Medical Physics, Vol. 35, No. 11, November 2008 4884 A. Karellas and S. Vedantham: Breast cancer imaging: A perspective 4884 and anxiety of the recalled subject. Hence, there is a need to the potential for patient motion requires a detector that has develop techniques that provide depth information in breast rapid frame acquisition capability and with minimal image x-ray imaging. Currently, stereoscopic digital mammography lag. ͑SDM͒, digital breast tomosynthesis ͑DBT͒, and dedicated Current implementations of clinical prototype DBT sys- breast computed tomography ͑BCT͒ are three modalities that tems use indirect conversion a-Si:H detectors with a are being actively investigated. 100-␮m pixel pitch91 or direct conversion a-Se detectors.202,207 Depending upon the manufacturer, a-Se VI.A.1. Stereoscopic digital mammography based DBT system use a detector with 70-␮m pixel pitch operated in a 2ϫ2 binned mode202 or a detector with In stereoscopic digital mammography, two projection im- 85-␮m pixel pitch operated in unbinned or 2ϫ1 asymmetric ages spaced a few degrees apart are acquired with a digital binned mode.207,208 Pixel binning approaches allow for faster mammography system. A dedicated stereoscopic workstation readout of the detector, albeit at reduced resolution. As with displays orthogonally polarized images and are viewed by digital mammography, the detector pixel pitch and the over- the observer using passive cross-polarized glasses, so that all spatial resolution requirements for breast tomosynthesis each eye visualizes one image to provide depth perception. are not well defined. After reconstruction, there is some deg- Studies evaluating the accuracy of depth perception indicate radation of in-plane ͑plane parallel to the detector͒ spatial that 0.2 mm depth discrimination can be achieved using pro- resolution due to several factors including oblique x-ray jection pair images acquired at an angular separation of Ϯ6° incidence,209,210 blur due to tube motion within the acquired and with geometric magnification.195,196 Observer studies projection view,208 mechanical vibration of the gantry, and comparing standard monoscopic imaging with stereoscopic reconstruction related blur such as that due to interpolation. imaging using breast biopsy specimens indicate an improve- There is considerable loss of spatial resolution along the ment in detection of masses and microcalcifications, and an depth-direction ͑perpendicular to the detector plane͒ due to improved confidence for the estimation of likelihood of limited angular sampling. Hence, there is a some concern malignancy.197 Interim results from an ongoing prospective about its ability to detect subtle structures such as amorphous screening trial with high-risk women suggest that SDM re- microcalcifications. duces false-positive lesion detections by 39% and false- Until recently, estimates of glandular breast dose during negative lesion detections by 46% compared to digital mam- DBT were based on conversion factors for mammography. A mography, providing for significant improvements in Monte Carlo study provided conversion factors for DBT that sensitivity and specificity.198 However, the study used twice showed variation in glandular dose with projection angle,211 the dose of mammography. While contrast-detail experi- facilitating the application towards advanced techniques such ments with a phantom indicates that ϳ10% more radiation as tube-current modulation with changing projection angle, if dose is needed for SDM compared to mammography,199 fur- needed. While the objective for a DBT acquisition is not to ther research is needed to understand the dose requirements exceed the dose of a two-view mammogram, in a 15 projec- with clinical backgrounds. If ongoing and future clinical tri- tion acquisition for example, the detector receives substan- als demonstrate its efficacy, it has the potential for quick tially less signal per projection compared to a mammo- adaptation due to the ready availability of digital mammog- graphic view. To some extent, this can be compensated by raphy systems and dedicated stereoscopic displays.200 increasing the beam transmission though the breast with the use of W anode and higher kVp than in conventional mam- VI.A.2. Digital breast tomosynthesis mography, as suggested by modeling and phantom Digital breast tomosynthesis ͑DBT͒, a technique that re- studies,212–214 but may change as more experience is gained lies upon acquisition of multiple projection views over a lim- through clinical trials. Research in developing detectors with ited angular range to reconstruct a volumetric image, has performance characteristics suitable for DBT seems well jus- gained substantial interest primarily due to the availability of tified, in particular if higher kVp is used in the future for flat-panel detectors.91,201–203 Subsequent to the landmark ar- techniques such as contrast-enhanced DBT. ticle in 1997 by Niklason et al. that demonstrated feasibility The adverse effects of scatter on projection imaging and by modification of a digital mammography system,204 a simi- computed tomography are well known. However, its adverse lar system was used to study contrast-detail characteristics of effects in DBT have not yet been quantified. Recently, com- several reconstruction algorithms.205,206 prehensive Monte Carlo based estimates of scatter and Although in principle, implementation of DBT with a hence, scatter-to-primary ratio ͑SPR͒ was reported.215 SPR digital mammography system is straightforward, there are trends showed high dependence on compressed thickness some design aspects that have to be considered. In a well- and weak dependence on x-ray spectrum and breast glandu- designed DBT system, the x-ray tube assembly has to avoid larity, similar to mammography. Importantly, substantial spa- interference with the patient’s head during rotational move- tial variation of SPR at oblique projections was observed. ment and the rotational mechanics must provide for minimal One interesting observation in that study215 was the increase vibration. Also, the x-ray beam collimation must adapt asym- in SPR observed at breast periphery, which was apparently metrically during the scan to ensure that the x-ray field does due to the large component of x-ray scatter from the breast not extend marginally beyond the lateral edges of the detec- support plate compared to the primary x-ray component un- tor. The acquisition of multiple frames in ϳ10 s to minimize der the breast tissue. Conventional anti-scatter grids are not

Medical Physics, Vol. 35, No. 11, November 2008 4885 A. Karellas and S. Vedantham: Breast cancer imaging: A perspective 4885

FIG. 2. A clinical case showing 1.6 cm low-grade invasive ductal carcinoma with minor ductal carcinoma in situ ͑DCIS͒ component. Better visualization of the tumor is observed with DBT ͑right, B͒ compared to mammography ͑left, A͒. ͑Courtesy: Steven P. Poplack, Dartmouth Hitchcock Medical Center͒

used in DBT because of the required increase in dose ͑bucky promise.223,227 In a recently published study on their initial factor͒ and problems due to grid cut-off at oblique projection experience with DBT, most of the soft tissue abnormalities angles. While it may be possible to develop anti-scatter grids were subjectively rated as either equivalent or superior to that are designed specifically for DBT, such designs have not mammography.223 Figure 2 shows a clinical case of a woman yet materialized. Hence, accurate characterization of x-ray with 1.6 cm low-grade invasive ductal carcinoma with ductal scatter during a DBT exam can be extremely useful in the carcinoma in situ ͑DCIS͒, where the carcinoma is better vi- development of computational techniques for scatter correc- sualized with DBT ͑right͒ than with mammography ͑left͒. tion. Interim results after accrual of 1957 women from an ongoing DBT reconstruction algorithms either use variants of clinical trial indicate that DBT reduces recall rate to 4.4% back-projection technique or iterative techniques. Optimiza- compared to 7.5% with digital mammography, and unlike tion of these reconstruction methods, quantification of their mammography does not appear to show dependence with effect on resolution, noise, and artifacts as well as compara- breast density.227 With further refinements, breast tomosyn- tive analysis of these methods have been the subject of on- thesis is likely to become a clinical tool for screening, par- going research.216–222 There are two important concerns with ticularly for women with dense breasts. DBT, viz., its ability to provide adequate visualization of microcalcifications223 and “out-of-plane” artifacts that occur due to limited angular sampling. With regards to microcalcification visibility, a technique that could provide for improved morphology using back-projection or its variants was VI.A.3. Dedicated breast computed tomography recently published.217 Also, improved image quality has been Another technique that will overcome the tissue superpo- reported with an iterative algebraic reconstruction sition problem is dedicated breast computed tomography technique.218 Techniques specifically designed for suppress- ͑BCT͒, in which the subject is in a prone position and the ing artifacts are being actively investigated.219,224–226 pendant breast is imaged. The concept of a dedicated BCT In spite of some challenges, DBT enables better separa- system was envisioned in the 1970s228 and a system was tion of overlying tissues than mammography and it is likely built. Clinical trials using the dedicated BCT system229 and to play an important role in breast imaging. Breast tomosyn- with a conventional CT scanner230 suggested that injected thesis has the potential of detecting occult lesions, particu- contrast media enhanced CT could differentiate malignant larly soft tissue abnormalities that can be extremely difficult from benign lesions. However, it did not translate to clinical to detect in the presence of dense glandular tissue. Currently, practice due to the limitations with the technology available several clinical studies with human subjects are being con- at that time. Subsequently in the mid-1990s, images of sur- ducted to evaluate the clinical potential of DBT. Early indi- gical biopsy specimens acquired with a state-of-the-art scan- cations from ongoing clinical studies suggest that DBT show ner at that time were compared with specimen radiography

Medical Physics, Vol. 35, No. 11, November 2008 4886 A. Karellas and S. Vedantham: Breast cancer imaging: A perspective 4886

for breast imaging with a laboratory prototype system.240 Further studies are needed to understand tissue coverage with dedicated breast CT for the various source-detector trajectories. Initial computer simulation study and independently a receiver operating characteristic study with computer simulated BCT images suggested the possibility of detecting microcalcifications in the range of 175 to 200 ␮m.238,253 However, experimental studies with phantoms suggest that visibility of microcalcifications may be limited to ϳ300 ␮m with current technology.254,255 Considering that these studies point to a noticeable improvement with increased dose or reduced breast size,254,255 it is likely that image noise rather than resolution may be a dominant factor for limited visibility of microcalcifications. Hence, techniques for noise suppression246 may be beneficial. However, further research FIG. 3. Clinical images of a soft tissue lesion with digital mammography is needed to study its effect on artifacts, resolution, and le- ͑A: MLO view͒ and multi-planar reconstructions ͑B: Coronal, C: Axial, and D: Sagittal views͒ with dedicated BCT. ͑Courtesy: Koning Corporation, sion visualization. Additional improvements in microcalcifi- West Henrietta, NY͒ cation visualization can be potentially achieved with the use of high-resolution, low-noise detector technology such as photon-counting detectors256 or electron-multiplying images, and indicated that CT imaging can significantly im- CCDs,257 which are not yet available for large field of view prove the confidence to detect mass but was inferior for imaging. A recent review article addresses the potential ad- microcalcifications.231 vantages of BCT and the challenges that need to be over- In 2001, a landmark article by Boone et al. provided come for routine clinical use.258 quantitative estimates of radiation dose from a dedicated While the role of BCT and its efficacy need to be ascer- BCT exam and image quality achieved with cadaveric tained through clinical studies, BCT has one major advan- breast.232 The development of high-frame-rate flat-panel de- tage in that it does not require physical compression of the tectors accelerated further exploration of this technique. breast, thus greatly alleviating patient discomfort. Ongoing Works addressing radiation dose to the imaged breast232–234 clinical studies have shown exquisite anatomical detail and and other organs,235 x-ray scatter,236,237 system design,238,239 soft tissue lesion morphology. If visibility of microcalcifica- imaging trajectory,240,241 image acquisition technique tions is improved, breast CT allows for 3-D visualization of factors,242–244 resolution,245 noise,246 and artifacts 247 have its distribution that could potentially improve specificity. been published. While each of the aforementioned techniques that are tar- Independent studies with surgical mastectomy geted towards overcoming the tissue superposition problem specimens248 and with limited number of subjects249 suggest are in various stages of research, an observer study with that BCT provides for excellent anatomical detail and soft computer simulated images comparing digital mammogra- tissue lesion visualization. Figure 3 shows multi-planar re- phy, DBT and BCT showed improved accuracy to detect constructions acquired with a clinical prototype dedicated masses,259 highlighting the potential advantage of DBT and BCT system and a MLO view projection image acquired BCT over digital mammography. Among the three tech- with a digital mammography system. Excellent 3-D visual- niques ͑SDM, DBT, and BCT͒ that are being investigated to ization of the anatomy and soft tissue lesion is observed. A provide depth information, the body of knowledge is too recent study that compared visualization in BCT with lesions limited to obtain meaningful inferences about the superiority detected in screen-film mammography in 65 subjects, sug- of one technique versus the other. gest that BCT was superior for visualization of masses but was inferior for visualization of microcalcifications.250 VI.B. Contrast-enhanced x-ray imaging Some of the challenges with breast CT include simultaneous inclusion of medial and axillary aspects of the breast While investigations into the applicability of digital sub- during the scan and adequate visualization of traction angiography of the breast in the mid-1980s showed microcalcifications.250 Limitations in breast coverage with the potential for differential diagnosis for malignant and be- dedicated breast CT has been inferential, and as yet there nign tumors,260,261 the lack of appropriate imaging system have been no quantitative studies comparing tissue inclusion was a major limitation. The advent of digital mammography with mammography. Improved breast coverage can be poten- has stimulated the exploration of quicker and cost-effective tially achieved through system design including novel table alternative for breast MRI such as intravenously injected io- design251 and imaging trajectories,240,241 and with appropri- dinated contrast media enhanced imaging of the breast for ate patient positioning. Current prototype systems used in angiogenesis imaging. Two approaches for contrast- clinical studies utilize circular scan,250,252 and we are aware enhanced digital mammography are being explored. In dual- of only one implementation using a non-circular trajectory energy K-edge subtraction, two images at different energies

Medical Physics, Vol. 35, No. 11, November 2008 4887 A. Karellas and S. Vedantham: Breast cancer imaging: A perspective 4887 that straddle the K-edge of the contrast media are acquired the phase map is retrieved was recently published.287 Figure after contrast administration and subtracted.262 In temporal 4 shows conventional ͑attenuation͒ and phase contrast im- subtraction, an image acquired prior to contrast administra- ages of ACR-recommended accreditation phantom and of a tion is subtracted from the image͑s͒ acquired after contrast lumpectomy specimen acquired with a prototype system. administration.263 The former method reduces the likelihood Substantial improvement in contrast and edge-enhancement of misregistration between the two images, while the latter is is observed. These techniques are at present limited to imag- better suited for dynamic contrast enhancement studies and ing specimens. Further research is needed to translate them would require image processing for proper registration. to clinical use. Multiple pilot clinical studies, each with a small number Optical imaging of the breast such as diffuse optical to- of subjects who had suspicious findings and underwent mography ͑DOT͒, diffuse optical imaging, and diffuse opti- contrast-enhanced digital mammography, indicate enhance- cal spectroscopy is being investigated as an adjunct tech- ment of tumor and vasculature that are qualitatively similar nique. This emerging technique uses light in the near- to breast MRI.262–266 There have also been studies on opti- infrared ͑NIR͒ regime to noninvasively image total mization of the x-ray spectrum,267,268 on determination of the hemoglobin, oxygen saturation, water content, optical scat- minimum concentration of iodine required,267,269 and on in- tering, and lipid concentration.288–290 While substantial varia- vestigation of elements other than iodine that may provide tions in optical properties for normal tissues291 and tumors292 for alternate contrast media.270–272 have been observed, a recent study indicates that normal and A pilot clinical study evaluating the potential of contrast tumor tissues can be differentiated based on total hemoglo- enhanced DBT, showed characteristics that were concordant bin, hemoglobin oxygen saturation, and other parameters.293 with digital mammography and breast MRI.273 Contrast- Leaky, densely packed vasculature associated with tumor an- enhanced DBT is being actively investigated, particularly in giogenesis could contribute to increased total hemoglobin, terms of imaging technique optimization and quantification and increased metabolism in tumors could result in de- of iodine concentration.268,274,275 The role of contrast- creased oxygen saturation. NIRS has an inherent resolution enhanced conventional CT in management of breast cancer of ϳ4 to 6 mm because of the highly scattering nature of such as lymph node imaging, tumor staging, identifying tu- light. Ntziachristos et al.294 demonstrated that combining mor extent for breast conservative surgery, treatment plan- DOT with MRI anatomical maps can improve spatial reso- ning for radiotherapy, and in monitoring of cancer therapy is lution. More accurate quantification of NIRS parameters well established. A pilot study with contrast-enhanced dedi- have been reported by incorporating structural priors from cated BCT showed enhancement of malignant lesions similar MRI during NIRS reconstruction.295 In order to obtain co- to MRI.250 One potential advantage of contrast-enhanced registered dual-modality images, investigators at Dartmouth x-ray imaging is that signal intensity changes are typically have incorporated NIR spectroscopy instrumentation within linear with contrast agent uptake, unlike MRI.135 All of the an open-frame MR breast coil ͑Fig. 5͒. This combined ap- aforementioned x-ray-based contrast-enhanced imaging tech- proach has been used to demonstrate feasibility by imaging niques are in various stages of research. more than 25 women with both normal296 and disease indi- While there are promising aspects, all of these techniques cations from mammography.297 Correlation between in- require intravenous injection, which entails a slightly el- docyanine green enhancement and Gd-enhanced MRI,298 and evated risk.137 While contrast media used with x-ray imaging its ability to differentiate cysts from solid tumors299 have are considered relatively safe, risks including allergic reac- also been reported. Ongoing investigations indicate that tions and contrast nephropathy, though uncommon, are of DOT in combination with MRI hold promise for early deter- concern. Hence, there is a need to develop contrast agents mination of the effectiveness of neoadjuvant with minimal or no adverse effects. Further improvements in chemotherapy.300–302 In addition to NIRS-MRI systems, de- specificity are achievable with development of tumor- velopment of DOT imaging systems in combination with targeted agents276,277 and with better understanding of the DBT and ultrasound are also underway.303–305 A recent ar- criteria for determining malignancy such as morphology, tu- ticle provides an assessment of its future role in breast mor enhancement due to agent uptake, and agent uptake ki- imaging.306 netics. Electrical impedance spectroscopy ͑EIS͒ and microwave imaging spectroscopy ͑MIS͒ are also being explored for potential use in breast cancer detection. A recent study suggests VI.C. Alternative modalities that EIS could potentially be used as a risk assessment tool X-ray phase sensitive imaging such as in-line phase confor young women who are not routinely screened for breast trast x-ray imaging278,279 and diffraction enhanced cancer.307 In vivo microwave imaging of women with normal imaging280–283 are currently being investigated. The theoret- mammographic exam suggests that dielectric properties are ical basis and design considerations for phase contrast heterogeneous and correlate with radiographic density.308 A imaging284,285 and method to retrieve the phase map from recent two-part series on measurements of ultra-wideband attenuation and phase contrast images286 have been well ad- dielectric properties from normal and cancer tissue samples dressed. Development of a dual-detector system that uses indicate substantial variations in dielectric properties for nor- two CR cassettes for simultaneous acquisition of conven- mal tissues, and that the contrast in dielectric properties be- tional ͑attenuation͒ and phase contrast images, from which tween malignant and adipose tissues could be as high as

Medical Physics, Vol. 35, No. 11, November 2008 4888 A. Karellas and S. Vedantham: Breast cancer imaging: A perspective 4888

FIG. 4. Conventional ͑attenuation͒ images ͑A, C͒ and phase contrast images ͑B, D͒ of accreditation phantom ͑top row͒ and lumpectomy specimen ͑bottom row͒. All images were acquired at 40 kVp with same entrance exposure for attenuation and phase contrast images. These images were acquired using prototype systems developed at the University of Oklahoma ͑Hong Liu͒, in collaboration with University of Alabama at Birmingham ͑Xizeng Wu͒ and University of Iowa ͑Laurie L. Fajardo͒. ͑Courtesy: Hong Liu, University of Oklahoma͒

10:1, whereas that of malignant to ﬁbroglandular tissue could will be the primary screening modality in the next decade. be no more than 10%.309,310 A pilot clinical study that evalu- However, MRI and ultrasound will have an increasingly im- ated EIS, MIS, and NIRS indicate substantial contrast differ- portant role for imaging high risk patients and for imaging 311 ence between abnormal and normal breast tissue. A recent women with dense breasts. With increasing ﬁeld strength and 312 article addresses the status of these imaging modalities. improved homogeneity, MRS is likely to add value to dynamic contrast enhanced MRI studies. Contrast-enhanced VII. CONCLUSION x-ray imaging, scintimammography with dedicated cameras, Intense efforts are currently under way to improve the dedicated SPECT, and dedicated PET offer great potential as technological aspects of the aforementioned modalities. diagnostic evaluation tools and for clinical management. Those include advances in x-ray and gamma ray detector While prototype BCT systems have been developed and pilot technology, MRI coil design, MRI pulse sequences, tomog- clinical studies demonstrate the ability to provide high- raphic image reconstruction, signal processing, computa- resolution 3-D anatomical information, there are some chal- tional speed, and mechanical design. Based on current under- lenges that need to be addressed. NIR diffuse optics-based standing and results from ongoing research, it appears that imaging and electromagnetic imaging techniques such as EIS high-resolution, high-contrast, anatomical x-ray imaging ei- and MIS could provide for physiologic information and is ther in 2-D ͑mammography͒ or with added depth information likely to be of most value when integrated with or adjunc-

Medical Physics, Vol. 35, No. 11, November 2008 4889 A. Karellas and S. Vedantham: Breast cancer imaging: A perspective 4889

screening of high-risk subjects. This transformation to individual-risk or other classification based screening is likely to be of benefit to women. However this added layer, which can be referred to as pre-screening, does place an onus on the manner in which such classifications or risk assessments are performed and need to be carefully studied. In summary, ongoing research and recent advances indicate that the prospects of substantial improvements in early detection, accurate diagnosis, and improved monitoring of therapeutic response of breast cancer are highly promising.

ACKNOWLEDGMENTS The authors would like to thank Dr. Paul L. Carson and Dr. Mitchell M. Goodsitt at the University of Michigan, Dr. Hong Liu from the University of Oklahoma, Dr. Brian W. Pogue from Dartmouth College, Dr. Steven P. Poplack at Dartmouth Hitchcock Medical Center, and Koning Corpora- tion for providing images. This work was partially supported by National Institutes of Health ͑NIH͒ Grant No. R01- EB002123 and Grant No. R01-EB004015 from the National Institute of Biomedical Imaging and Bioengineering ͑NIBIB͒. The contents are solely the responsibility of the authors and do not necessarily represent the ofﬁcial views of the NIH or the NIBIB. Mention of company names or products does not imply endorsement. The authors have collabo- rated in the past with GE Global Research Center.

͒ a Author to whom correspondence should be addressed. Electronic mail: [email protected]. Telephone: ͑508͒ 856-1238; Fax: ͑508͒ 856-1860. 1N. Oestreicher, C. D. Lehman, D. J. Seger, D. S. Buist, and E. White, “The incremental contribution of clinical breast examination to invasive cancer detection in a mammography screening program,” AJR, Am. J. Roentgenol. 184͑2͒, 428–432 ͑2005͒. FIG. 5. Dual-modality MRI-NIR system with insert showing the NIR 2L. W. Bassett and R. H. Gold, “The evolution of mammography,” AJR, transmitter-receiver incorporated within the open breast coil. ͑Courtesy: Am. J. Roentgenol. 150͑3͒, 493–498 ͑1988͒. Brian W. Pogue, Thayer School of Engineering, Dartmouth College͒ 3R. Leborgne, “Diagnosis of tumors of the breast by simple roentgenography; calcifications in carcinomas,” Am. J. Roentgenol., Radium Ther. Nucl. Med. 65͑1͒, 1–11 ͑1951͒. 4R. L. Egan, “Experience with mammography in a tumor institution. tively used with modalities that provide for anatomical struc- Evaluation of 1,000 studies,” Radiology 75, 894–900 ͑1960͒. ture such as x-ray, ultrasound, or MRI. At present, phase- 5S. Shapiro, P. Strax, and L. Venet, “Periodic breast cancer screening in sensitive x-ray imaging that provides for improved contrast reducing mortality from breast cancer,” JAMA, J. Am. Med. Assoc. 215͑11͒, 1777–1785 ͑1971͒. and edge-enhancement has been demonstrated with speci- 6E. L. Thurfjell and J. A. Lindgren, “Breast cancer survival rates with mens and would require substantial amount of translational mammographic screening: similar favorable survival rates for women research to bring it to clinical use. From the technological younger and those older than 50 years,” Radiology 201͑2͒, 421–426 ͑1996͒. perspective, in addition to improvements with each modality, 7R. E. Hendrick, R. A. Smith, J. H. Rutledge III, and C. R. Smart, “Benefit we are likely to observe an increasing trend towards multi- of screening mammography in women aged 40-49: a new meta-analysis modality systems that combine the relative strengths of each of randomized controlled trials,” J Natl Cancer Inst Monogr 22, 87–92 modality. ͑1997͒. 8L. Tabar, B. Vitak, H. H. Chen, M. F. Yen, S. W. Duffy, and R. A. Smith, Importantly, we are likely to observe a paradigm shift in “Beyond randomized controlled trials: organized mammographic screen- the manner in which breast cancer screening will be per- ing substantially reduces breast carcinoma mortality,” Cancer 91͑9͒, formed in future. Breast cancer screening is currently per- 1724–1731 ͑2001͒. 9 formed in a standard manner for all women with mammog- The Swedish Organized Service Screening Evaluation Group, “Reduction in breast cancer mortality from organized service screening with mam- raphy. However, this level of standardization is likely to be mography: 1. Further confirmation with extended data,” Cancer Epide- replaced by a screening program where the selection of an miol. Biomarkers Prev. 15͑1͒, 45–51 ͑2006͒. imaging modality or modalities would depend on an indi- 10The Swedish Organized Service Screening Evaluation Group, “Reduction vidual’s risk and other classifications. Already elements of in breast cancer mortality from the organised service screening with mammography: 2. Validation with alternative analytic methods,” Cancer this change can be observed with the recommendation by Epidemiol. Biomarkers Prev. 15͑1͒, 52–56 ͑2006͒. American Cancer Society to adjunctively use breast MRI for 11J. L. Price and P. D. Bler, “The reduction of radiation and exposure time

Medical Physics, Vol. 35, No. 11, November 2008 4890 A. Karellas and S. Vedantham: Breast cancer imaging: A perspective 4890

in mammography,” Br. J. Radiol. 43͑508͒, 251–255 ͑1970͒. an imaging plate,” Proc. SPIE 3977, 590–600 ͑2000͒. 12E. P. Muntz and W. W. Logan, “Focal spot size and scatter suppression in 32J. A. Seibert, J. M. Boone, V. N. Cooper, and K. K. Lindfors, “Cassette- magnification mammography,” AJR, Am. J. Roentgenol. 133͑3͒, 453–459 based digital mammography,” Technol. Cancer Res. Treat. 3͑5͒, 413–427 ͑1979͒. ͑2004͒. 13R. M. Nishikawa, G. E. Mawdsley, A. Fenster, and M. J. Yaffe, 33C. Lawinski, A. MacKenzie, H. Cole, P. Blake, I. Honey, and A. Pascoal, “Scanned-projection digital mammography,” Med. Phys. 14͑5͒, 717–727 Computed Radiography (CR) Systems for Mammography. A comparative ͑1987͒. technical report. MHRA 04107 ͑Medicines and Health Products Regula- 14A. Karellas, S. Vedantham, and S. Suryanarayanan, Digital Mammogra- tory Agency ͑MHRA͒, London, 2004͒. phy Image Acquisition Technology, in RSNA Categorical Course in Diag- 34E. D. Pisano and M. J. Yaffe, “Digital mammography,” Radiology 234͑2͒, nostic Radiology Physics: Advances in Breast Imaging—Physics, Tech- 353–362 ͑2005͒. nology and Clinical Applications, edited by A. Karellas and M. L. Giger 35M. J. Yaffe and J. G. Mainprize, “Detectors for digital mammography,” ͑RSNA, Oak Brook, IL, 2004͒, p. 87–99. Technol. Cancer Res. Treat. 3͑4͒, 309–324 ͑2004͒. 15FDA US, MQSA Facility Score Card, January 2, 2008, Center for De- 36S. Suryanarayanan, A. Karellas, S. Vedantham, I. Sechopoulos, and C. J. vices and Radiological Health, http://www.fda.gov/CDRH/ D’Orsi, “Detection of simulated microcalcifications in a phantom with MAMMOGRAPHY/scorecard-statistics.html ͓Accessed: January 28, digital mammography: Effect of pixel size,” Radiology 244͑1͒, 130–137 2008͔. ͑2007͒. 16K. A. Fetterly and B. A. Schueler, “Performance evaluation of a ‘dual- 37R. S. Saunders, Jr., J. A. Baker, D. M. Delong, J. P. Johnson, and E. side read’ dedicated mammography computed radiography system,” Med. Samei, “Does image quality matter¿ Impact of resolution and noise on Phys. 30͑7͒, 1843–1854 ͑2003͒. mammographic task performance,” Med. Phys. 34͑10͒, 3971–3981 17R. S. Saunders, Jr., E. Samei, J. L. Jesneck, and J. Y. Lo, “Physical ͑2007͒. characterization of a prototype selenium-based full field digital mammog- 38Y. Ei-Mohri, L. E. Antonuk, Q. Zhao, Y. Wang, Y. Li, H. Du, and A. raphy detector,” Med. Phys. 32͑2͒, 588–599 ͑2005͒. Sawant, “Performance of a high fill factor, indirect detection prototype 18S. Vedantham, A. Karellas, S. Suryanarayanan, D. Albagli, S. Han, E. J. flat-panel imager for mammography,” Med. Phys. 34͑1͒, 315–327 ͑2007͒. Tkaczyk, C. E. Landberg, B. Opsahl-Ong, P. R. Granfors, I. Levis, C. J. 39Y. El-Mohri, L. E. Antonuk, Q. Zhao, M. Maolinbay, X. Rong, K. W. Jee, D’Orsi, and R. E. Hendrick, “Full breast digital mammography with an S. Nassif, and C. Cionca, “A quantitative investigation of additive noise amorphous silicon-based flat panel detector: Physical characteristics of a reduction for active matrix flat-panel imagers using compensation lines,” clinical prototype,” Med. Phys. 27͑3͒, 558–567 ͑2000͒. Med. Phys. 27͑8͒, 1855–1864 ͑2000͒. 19J. M. Lewin, C. J. D’Orsi, R. E. Hendrick, L. J. Moss, P. K. Isaacs, A. 40V. V. Nagarkar, S. V. Tipnis, V. B. Gaysinskiy, S. R. Miller, A. Karellas, Karellas, and G. R. Cutter, “Clinical comparison of full-field digital mam- and S. Vedantham, “New design of a structured CsI͑Tl͒ screen for digital mography and screen-film mammography for detection of breast cancer,” mammography,” Proc. SPIE 5030, 541–546 ͑2003͒. AJR, Am. J. Roentgenol. 179͑3͒, 671–677 ͑2002͒. 41A. Sawant, L. E. Antonuk, Y. El-Mohri, Q. Zhao, Y. Li, Z. Su, Y. Wang, 20P. Skaane, S. Hofvind, and A. Skjennald, “Randomized trial of screen- J. Yamamoto, H. Du, I. Cunningham, M. Klugerman, and K. Shah, “Seg- film versus full-field digital mammography with soft-copy reading in mented crystalline scintillators: an initial investigation of high quantum population-based screening program: Follow-up and final results of Oslo, efficiency detectors for megavoltage x-ray imaging,” Med. Phys. 32͑10͒, II study,” Radiology 244͑3͒, 708–717 ͑2007͒. 3067–3083 ͑2005͒. 21E. D. Pisano, C. Gatsonis, E. Hendrick, M. Yaffe, J. K. Baum, S. 42A. W. Rau, L. Bakueva, and J. A. Rowlands, “The x-ray time of flight Acharyya, E. F. Conant, L. L. Fajardo, L. Bassett, C. D’Orsi, R. Jong, and method for investigation of ghosting in amorphous selenium-based flat M. Rebner, “Diagnostic performance of digital versus film mammography panel medical x-ray imagers,” Med. Phys. 32͑10͒, 3160–3177 ͑2005͒. for breast-cancer screening,” N. Engl. J. Med. 353͑17͒, 1773–1783 43W. Zhao, G. DeCrescenzo, S. O. Kasap, and J. A. Rowlands, “Ghosting ͑2005͒. caused by bulk charge trapping in direct conversion flat-panel detectors 22E. D. Pisano, R. E. Hendrick, M. J. Yaffe, J. K. Baum, S. Acharyya, J. B. using amorphous selenium,” Med. Phys. 32͑2͒, 488–500 ͑2005͒. Cormack, L. A. Hanna, E. F. Conant, L. L. Fajardo, L. W. Bassett, C. J. 44A. K. Bloomquist, M. J. Yaffe, G. E. Mawdsley, D. M. Hunter, and D. J. D’Orsi, R. A. Jong, M. Rebner, A. N. Tosteson, and C. A. Gatsonis, Beideck, “Lag and ghosting in a clinical flat-panel selenium digital mam- “Diagnostic accuracy of digital versus film mammography: Exploratory mography system,” Med. Phys. 33͑8͒, 2998–3005 ͑2006͒. analysis of selected population subgroups in DMIST,” Radiology 246͑2͒, 45D. C. Hunt, K. Tanioka, and J. A. Rowlands, “X-ray imaging using ava- 376–383 ͑2008͒. lanche multiplication in amorphous selenium: investigation of intrinsic 23L. E. Antonuk, J. Boudry, W. Huang, D. L. McShan, E. J. Morton, J. avalanche noise,” Med. Phys. 34͑12͒, 4654–4663 ͑2007͒. Yorkston, M. J. Longo, and R. A. Street, “Demonstration of megavoltage 46D. L. Lee, “Selenium detector with a grid for selenium charge gain,” and diagnostic x-ray imaging with hydrogenated amorphous silicon ar- Proc. SPIE 5745, 216–222 ͑2005͒. rays,” Med. Phys. 19͑6͒, 1455–1466 ͑1992͒. 47J. G. Mainprize, N. L. Ford, S. Yin, E. E. Gordon, W. J. Hamilton, T. O. 24S. Suryanarayanan, A. Karellas, and S. Vedantham, “Physical character- Tumer, and M. J. Yaffe, “A CdZnTe slot-scanned detector for digital istics of a full-field digital mammography system,” Nucl. Instrum. Meth- mammography,” Med. Phys. 29͑12͒, 2767–2781 ͑2002͒. ods Phys. Res. A 533͑3͒, 560–570 ͑2004͒. 48G. Zentai, L. D. Partain, R. Pavlyuchkova, C. H. Proano, M. M. Schieber, 25J. A. Rowlands, D. M. Hunter, and N. Araj, “X-ray imaging using amor- and J. Thomas, “Dark current, sensitivity, and image lag comparison of phous selenium: a photoinduced discharge readout method for digital mercuric iodide and lead iodide x-ray imagers,” Proc. SPIE 5541,171– mammography,” Med. Phys. 18͑3͒, 421–431 ͑1991͒. 178 ͑2004͒. 26W. Zhao, J. Law, D. Waechter, Z. Huang, and J. A. Rowlands, “Digital 49Z. Su, L. E. Antonuk, Y. El-Mohri, L. Hu, H. Du, A. Sawant, Y. Li, Y. radiology using active matrix readout of amorphous selenium: detectors Wang, J. Yamamoto, and Q. Zhao, “Systematic investigation of the signal with high voltage protection,” Med. Phys. 25͑4͒, 539–549 ͑1998͒. properties of polycrystalline HgI2 detectors under mammographic, radio- 27W. Zhao, W. G. Ji, A. Debrie, and J. A. Rowlands, “Imaging performance graphic, fluoroscopic and radiotherapy irradiation conditions,” Phys. of amorphous selenium based flat-panel detectors for digital mammogra- Med. Biol. 50͑12͒, 2907–2928 ͑2005͒. phy: Characterization of a small area prototype detector,” Med. Phys. 50T. Sakellaris, G. Spyrou, G. Tzanakos, and G. Panayiotakis, “Energy, 30͑2͒, 254–263 ͑2003͒. angular and spatial distributions of primary electrons inside photocon- 28G. T. Barnes and I. A. Brezovich, “The design and performance of a ducting materials for digital mammography: Monte Carlo simulation scanning multiple slit assembly,” Med. Phys. 6͑3͒, 197–204 ͑1979͒. studies,” Phys. Med. Biol. 52͑21͒, 6439–6460 ͑2007͒. 29J. M. Boone, J. A. Seibert, C. M. Tang, and S. M. Lane, “Grid and slot 51P. J. R. Leblans, L. Struye, and P. Willems, “New needle-crystalline CR scan scatter reduction in mammography: comparison by using Monte detector,” Proc. SPIE 4320, 59–67 ͑2001͒. Carlo techniques,” Radiology 222͑2͒, 519–527 ͑2002͒. 52R. Schaetzing, R. Fasbender, and P. Kersten, “New high-speed scanning 30M. Aslund, B. Cederstrom, M. Lundqvist, and M. Danielsson, “Physical technique for computed radiography,” Proc. SPIE 4682, 511–520 ͑2002͒. characterization of a scanning photon counting digital mammography sys- 53S. Rivetti, N. Lanconelli, M. Bertolini, G. Borasi, D. Acchiappati, and A. tem based on Si-strip detectors,” Med. Phys. 34͑6͒, 1918–1925 ͑2007͒. Burani, “Performance evaluation of a direct computed radiography sys- 31S. Arakawa, W. Itoh, K. Kohda, and T. Suzuki, “Improvement of image tem by means of physical characterization and contrast detail analysis,” quality in CR mammography by detection of emissions from dual sides of Proc. SPIE 6510, 65104M ͑2007͒.

Medical Physics, Vol. 35, No. 11, November 2008 4891 A. Karellas and S. Vedantham: Breast cancer imaging: A perspective 4891

54C. Herrmann, J. Frankenberger, G. Reiser, and J. Lamotte, “Optimization 76L. W. Bassett, D. M. Farria, S. Bansal, M. A. Farquhar, P. A. Wilcox, and of a CR system comprising line-scanning and needle image plate technol- S. A. Feig, “Reasons for failure of a mammography unit at clinical image ogy with respect to examinations of extremities,” Proc. SPIE 6510, review in the American College of Radiology Mammography Accredita- 65101B ͑2007͒. tion Program,” Radiology 215͑3͒, 698–702 ͑2000͒. 55P. M. Shikhaliev, T. Xu, H. Le, and S. Molloi, “Scanning-slit photon 77P. S. Rezentes, A. de Almeida, and G. T. Barnes, “Mammography grid counting x-ray imaging system using a microchannel plate detector,” performance,” Radiology 210͑1͒, 227–232 ͑1999͒. Med. Phys. 31͑5͒, 1061–1071 ͑2004͒. 78D. P. Chakraborty, “The effect of the antiscatter grid on full-field digital 56J. Giersch, “Medical quantum X-ray imaging with 2D detectors,” Nucl. mammography phantom images,” J. Digit Imaging 12͑1͒, 12–22 ͑1999͒. Instrum. Methods Phys. Res. A 551, 125–138 ͑2005͒. 79D. P. Chakraborty, “Effect of the antiscatter grid and target/filters in full- 57M. Bech, O. Bunk, C. David, P. Kraft, C. Bronnimann, E. F. Eikenberry, field digital mammography,” Proc. SPIE 3659, 878–885 ͑1999͒. and F. Pfeiffer, “X-ray imaging with the PILATUS 100k detector,” Appl. 80W. J. Veldkamp, M. A. Thijssen, and N. Karssemeijer, “The value of Radiat. Isot. 66͑4͒,474–478͑2008͒. scatter removal by a grid in full field digital mammography,” Med. Phys. 58J. Karg, D. Niederlohner, J. Giersch, and G. Anton, “Using the Medipix2 30͑7͒, 1712–1718 ͑2003͒. detector for energy weighting,” Nucl. Instrum. Methods Phys. Res. A 546, 81G. Gennaro, L. Katz, H. Souchay, R. Klausz, C. Alberelli, and C. di 306–311 ͑2005͒. Maggio, “Grid removal and impact on population dose in full-field digital 59P. Bernhardt, T. Mertelmeier, and M. Hoheisel, “X-ray spectrum optimi- mammography,” Med. Phys. 34͑2͒, 547–555 ͑2007͒. zation of full-field digital mammography: simulation and phantom study,” 82A. H. Baydush, and C. E. Floyd, Jr., “Improved image quality in digital Med. Phys. 33͑11͒, 4337–4349 ͑2006͒. mammography with image processing,” Med. Phys. 27͑7͒, 1503–1508 60P. Toroi, F. Zanca, K. C. Young, C. van Ongeval, G. Marchal, and H. ͑2000͒. Bosmans, “Experimental investigation on the choice of the tungsten/ 83K. Nykanen and S. Siltanen, “X-ray scattering in full-field digital mam- rhodium anode/filter combination for an amorphous selenium-based digi- mography,” Med. Phys. 30͑7͒, 1864–1873 ͑2003͒. tal mammography system,” Eur. Radiol. 17͑9͒, 2368–2375 ͑2007͒. 84D. E. G. Trotter, J. E. Tkaczyk, J. Kaufhold, B. E. H. Claus, and J. W. 61D. R. Dance, A. K. Thilander, M. Sandborg, C. L. Skinner, I. A. Castel- Eberhard, “Thickness-dependent scatter correction algorithm for digital lano, and G. A. Carlsson, “Influence of anode/filter material and tube mammography,” Proc. SPIE 4682, 469–478 ͑2002͒. potential on contrast, signal-to-noise ratio and average absorbed dose in 85C. M. Sehgal, S. P. Weinstein, P. H. Arger, and E. F. Conant, “A review of mammography: A Monte Carlo study,” Br. J. Radiol. 73͑874͒, 1056–1067 breast ultrasound,” Journal of mammary gland biology and neoplasia ͑2000͒. 11͑2͒, 113–123 ͑2006͒. 62B. Heddson, K. Ronnow, M. Olsson, and D. Miller, “Digital versus 86S. P. Weinstein, E. F. Conant, and C. Sehgal, “Technical advances in screen-film mammography: A retrospective comparison in a population- breast ultrasound imaging,” Semin Ultrasound CT MR 27͑4͒, 273–283 based screening program,” Eur. J. Radiol. 64͑3͒, 419–425 ͑2007͒. ͑2006͒. 63G. Gennaro and C. di Maggio, “Dose comparison between screen/film 87F. Forsberg, C. W. Piccoli, D. A. Merton, J. J. Palazzo, and A. L. Hall, and full-field digital mammography,” Eur. Radiol. 16͑11͒, 2559–2566 “Breast lesions: imaging with contrast-enhanced subharmonic US—initial ͑2006͒. experience,” Radiology 244͑3͒, 718–726 ͑2007͒. 64K. P. Hermann, S. Obenauer, K. Marten, S. Kehbel, U. Fischer, and E. 88T. M. Kolb, J. Lichy, and J. H. Newhouse, “Comparison of the perfor- Grabbe, “Average glandular dose with amorphous silicon full-field digital mance of screening mammography, physical examination, and breast US mammography-Clinical results,” Rofo Fortschr Geb Rontgenstr Neuen and evaluation of factors that influence them: An analysis of 27,825 pa- Bildgeb Verfahr 174͑6͒, 696–699 ͑2002͒. tient evaluations,” Radiology 225͑1͒, 165–175 ͑2002͒. 65S. Weigel, R. Girnus, J. Czwoydzinski, T. Decker, S. Spital, and W. Hei- 89W. A. Berg, J. D. Blume, J. B. Cormack, E. B. Mendelson, D. Lehrer, M. ndel, “Digital mammography screening: average glandular dose and first Bohm-Velez, E. D. Pisano, R. A. Jong, W. P. Evans, M. J. Morton, M. C. performance parameters,” Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Mahoney, L. H. Larsen, R. G. Barr, D. M. Farria, H. S. Marques, and K. Verfahr 179͑9͒, 892–895 ͑2007͒. Boparai, “Combined screening with ultrasound and mammography vs 66G. Gennaro, L. Katz, H. Souchay, C. Alberelli, and C. di Maggio, “Are mammography alone in women at elevated risk of breast cancer,” JAMA, phantoms useful for predicting the potential of dose reduction in full-field J. Am. Med. Assoc. 299͑18͒, 2151–2163 ͑2008͒. digital mammography?,” Phys. Med. Biol. 50͑8͒, 1851–1870 ͑2005͒. 90A. Kapur, P. L. Carson, J. Eberhard, M. M. Goodsitt, K. Thomenius, M. 67E. Samei, R. S. Saunders, Jr., J. A. Baker, and D. M. Delong, “Digital Lokhandwalla, D. Buckley, M. A. Roubidoux, M. A. Helvie, R. C. Booi, mammography;: effects of reduced radiation dose on diagnostic perfor- G. L. LeCarpentier, R. Q. Erkamp, H. P. Chan, J. B. Fowlkes, J. A. mance,” Radiology 243͑2͒, 396–404 ͑2007͒. Thomas, and C. E. Landberg, “Combination of digital mammography 68M. Ruschin, P. Timberg, M. Bath, B. Hemdal, T. Svahn, R. S. Saunders, with semi-automated 3D breast ultrasound,” Technol. Cancer Res. Treat. E. Samei, I. Andersson, S. Mattsson, D. P. Chakrabort, and A. Tingber, 3͑4͒, 325–334 ͑2004͒. “Dose dependence of mass and microcalcification detection in digital 91J. W. Eberhard, P. Staudinger, J. Smolenski, J. Ding, A. Schmitz, J. Mc- mammography: Free response human observer studies,” Med. Phys. Coy, M. Rumsey, A. Al-Khalidy, W. Ross, C. E. Landberg, B. E. Claus, 34͑2͒, 400–407 ͑2007͒. P. Carson, M. M. Goodsitt, H. P. Chan, M. Roubidoux, J. A. Thomas, and 69J. M. Boone, “Normalized glandular dose ͑DgN͒ coefficients for arbitrary J. Osland, “High-speed large angle mammography tomosynthesis sys- X-ray spectra in mammography: computer-fit values of Monte Carlo de- tem,” Proc. SPIE 6142, 61420C ͑2006͒. rived data,” Med. Phys. 29͑5͒, 869–875 ͑2002͒. 92R. C. Booi, J. F. Krucker, M. M. Goodsitt, M. O’Donnell, A. Kapur, G. L. 70D. R. Dance, “Monte Carlo calculation of conversion factors for the es- LeCarpentier, M. A. Roubidoux, J. B. Fowlkes, and P. L. Carson, “Evalu- timation of mean glandular breast dose,” Phys. Med. Biol. 35͑9͒, 1211– ating thin compression paddles for mammographically compatible ultra- 1219 ͑1990͒. sound,” Ultrasound Med. Biol. 33͑3͒, 472–482 ͑2007͒. 71G. R. Hammerstein, D. W. Miller, D. R. White, M. E. Masterson, H. Q. 93S. P. Sinha, M. M. Goodsitt, M. A. Roubidoux, R. C. Booi, G. L. LeCar- Woodard, and J. S. Laughlin, “Absorbed radiation dose in mammogra- pentier, C. R. Thomenius, K. E. Thomenius, C. L. Chalek, and P. L. phy,” Radiology 130͑2͒, 485–491 ͑1979͒. Carson, “Automated ultrasound scanning on a dual-modality breast im- 72X. Wu, E. L. Gingold, G. T. Barnes, and D. M. Tucker, “Normalized aging system: coverage and motion issues and solutions,” J. Ultrasound average glandular dose in molybdenum target-rhodium filter and rhodium Med. 26͑5͒, 645–655 ͑2007͒. target-rhodium filter mammography,” Radiology 193͑1͒, 83–89 ͑1994͒. 94N. Duric, P. Littrup, A. Babkin, D. Chambers, S. Azevedo, R. Pevzner, 73K. A. Hatziioannou, K. Psarrakos, E. Molyvda-Athanasopoulou, G. Kitis, M. Tokarev, E. Holsapple, O. Rama, and R. Duncan, “Development of E. Papanastassiou, I. Sofroniadis, and O. Kimoundri, “Dosimetric consid- ultrasound tomography for breast imaging: technical assessment,” Med. erations in mammography,” Eur. Radiol. 10͑7͒, 1193–1196 ͑2000͒. Phys. 32͑5͒, 1375–1386 ͑2005͒. 74R. H. Behrman, M. J. Homer, W. T. Yang, and G. J. Whitman, “Mam- 95N. Duric, P. Littrup, L. Poulo, A. Babkin, R. Pevzner, E. Holsapple, O. mography and fetal dose,” Radiology 243͑2͒,605͑2007͒; author reply Rama, and C. Glide, “Detection of breast cancer with ultrasound tomog- 243͑2͒, 605–606 ͑2007͒. raphy: First result with the Computed Ultrasound Risk Evaluation 75I. Sechopoulos, S. Suryanarayanan, S. Vedantham, C. J. D’Orsi, and A. ͑CURE͒ prototype,” Med. Phys. 34͑2͒, 773–785 ͑2007͒. Karellas, “Radiation Dose to Organs and Tissues from Mammography: 96R. Damadian, “Tumor detection by nuclear magnetic resonance,” Science Monte Carlo and Phantom Study,” Radiology 246͑2͒, 434–443 ͑2008͒. 171͑976͒, 1151–1153 ͑1971͒.

Medical Physics, Vol. 35, No. 11, November 2008 4892 A. Karellas and S. Vedantham: Breast cancer imaging: A perspective 4892

97P. C. Lauterbur, “Image formation by induced local interactions: Ex- Kuhl, T. B. Julian, N. Hylton, P. Weatherall, M. O’Loughlin, S. J. Schnitt, amples employing nuclear magnetic resonance,” Nature ͑London͒ 242, C. Gatsonics, and M. D. Schnall, “Added cancer yield of MRI in screen- 190–191 ͑1973͒. ing the contralateral breast of women recently diagnosed with breast can- 98P. Mansfield, P. G. Morris, R. Ordidge, R. E. Coupland, H. M. Bishop, cer: Results from the International Breast Magnetic Resonance Consor- and R. W. Blamey, “Carcinoma of the breast imaged by nuclear magnetic tium ͑IBMC͒ trial,” J. Surg. Oncol. 92͑1͒, 9–15 ͑2005͒; discussion 92͑1͒, resonance ͑NMR͒,” Br. J. Radiol. 52͑615͒, 242–243 ͑1979͒. 15–16 ͑2005͒. 99R. J. Ross, J. S. Thompson, K. Kim, and R. A. Bailey, “Nuclear magnetic 120E. Warner, D. B. Plewes, R. S. Shumak, G. C. Catzavelos, L. S. Di resonance imaging and evaluation of human breast tissue: preliminary Prospero, M. J. Yaffe, V. Goel, E. Ramsay, P. L. Chart, D. E. Cole, G. A. clinical trials,” Radiology 143͑1͒, 195–205 ͑1982͒. Taylor, M. Cutrara, T. H. Samuels, J. P. Murphy, J. M. Murphy, and S. A. 100S. J. El Yousef, R. H. Duchesneau, R. J. Alfidi, J. R. Haaga, P. J. Bryan, Narod, “Comparison of breast magnetic resonance imaging, mammogra- and J. P. LiPuma, “Magnetic resonance imaging of the breast. Work in phy, and ultrasound for surveillance of women at high risk for hereditary progress,” Radiology 150͑3͒, 761–766 ͑1984͒. breast cancer,” J. Clin. Oncol. 19͑15͒, 3524–3531 ͑2001͒. 101S. J. El Yousef, R. J. Alfidi, R. H. Duchesneau, C. A. Hubay, J. R. Haaga, 121M. J. Stoutjesdijk, C. Boetes, G. J. Jager, L. Beex, P. Bult, J. H. Hendriks, P. J. Bryan, J. P. LiPuma, and A. E. Ament, “Initial experience with R. J. Laheij, L. Massuger, L. E. van Die, T. Wobbes, and J. O. Barentsz, nuclear magnetic resonance ͑NMR͒ imaging of the human breast,” J. “Magnetic resonance imaging and mammography in women with a he- Comput. Assist. Tomogr. 7͑2͒, 215–218 ͑1983͒. reditary risk of breast cancer,” J. Natl. Cancer Inst. 93͑14͒, 1095–1102 102C. B. Stelling, P. C. Wang, A. Lieber, S. S. Mattingly, W. O. Griffen, and ͑2001͒. D. E. Powell, “Prototype coil for magnetic resonance imaging of the 122C. K. Kuhl, S. Schrading, C. C. Leutner, N. Morakkabati-Spitz, E. Ward- female breast. Work in progress,” Radiology 154͑2͒, 457–462 ͑1985͒. elmann, R. Fimmers, W. Kuhn, and H. H. Schild, “Mammography, breast 103R. C. Brasch, H. J. Weinmann, and G. E. Wesbey, “Contrast-enhanced ultrasound, and magnetic resonance imaging for surveillance of women at NMR imaging: animal studies using gadolinium-DTPA complex,” AJR, high familial risk for breast cancer,” J. Clin. Oncol. 23͑33͒, 8469–8476 Am. J. Roentgenol. 142͑3͒, 625–630 ͑1984͒. ͑2005͒. 104D. H. Carr, J. Brown, G. M. Bydder, R. E. Steiner, H. J. Weinmann, U. 123C. K. Kuhl, R. K. Schmutzler, C. C. Leutner, A. Kempe, E. Wardelmann, Speck, A. S. Hall, and I. R. Young, “Gadolinium-DTPA as a contrast A. Hocke, M. Maringa, U. Pfeifer, D. Krebs, and H. H. Schild, “Breast agent in MRI: Initial clinical experience in 20 patients,” AJR, Am. J. MR imaging screening in 192 women proved or suspected to be carriers Roentgenol. 143͑2͒, 215–224 ͑1984͒. of a breast cancer susceptibility gene: Preliminary results,” Radiology 105D. H. Carr, J. Brown, G. M. Bydder, H. J. Weinmann, U. Speck, D. J. 215͑1͒, 267–279 ͑2000͒. Thomas, and I. R. Young, “Intravenous chelated gadolinium as a contrast 124C. D. Lehman, J. D. Blume, P. Weatherall, D. Thickman, N. Hylton, E. agent in NMR imaging of cerebral tumours,” Lancet 1͑8375͒, 484–486 Warner, E. Pisano, S. J. Schnitt, C. Gatsonis, M. Schnall, G. A. DeAnge- ͑1984͒. lis, P. Stomper, E. L. Rosen, M. O’Loughlin, S. Harms, and D. A. 106M. Laniado, H. J. Weinmann, W. Schorner, R. Felix, and U. Speck, “First Bluemke, “Screening women at high risk for breast cancer with mam- use of GdDTPA/dimeglumine in man,” Physiol. Chem. Phys. Med. NMR mography and magnetic resonance imaging,” Cancer 103͑9͒, 1898–1905 16͑2͒, 157–165 ͑1984͒. ͑2005͒. 107H. J. Weinmann, R. C. Brasch, W. R. Press, and G. E. Wesbey, “Charac- 125L. Liberman, E. A. Morris, C. L. Benton, A. F. Abramson, and D. D. teristics of gadolinium-DTPA complex: a potential NMR contrast agent,” Dershaw, “Probably benign lesions at breast magnetic resonance imaging: AJR, Am. J. Roentgenol. 142͑3͒, 619–624 ͑1984͒. Preliminary experience in high-risk women,” Cancer 98͑2͒, 377–388 108H. J. Weinmann, M. Laniado, and W. Mutzel, “Pharmacokinetics of ͑2003͒. GdDTPA/dimeglumine after intravenous injection into healthy volun- 126L. Liberman, E. A. Morris, D. D. Dershaw, A. F. Abramson, and L. K. teers,” Physiol. Chem. Phys. Med. NMR 16͑2͒, 167–172 ͑1984͒. Tan, “Ductal enhancement on MR imaging of the breast,” AJR, Am. J. 109S. H. Heywang, D. Hahn, H. Schmidt, I. Krischke, W. Eiermann, R. Roentgenol. 181͑2͒, 519–525 ͑2003͒. Bassermann, and J. Lissner, “MR imaging of the breast using gadolinium- 127M. M. Tilanus-Linthorst, I. M. Obdeijn, K. C. Bartels, H. J. de Koning, DTPA,” J. Comput. Assist. Tomogr. 10͑2͒, 199–204 ͑1986͒. and M. Oudkerk, “First experiences in screening women at high risk for 110W. A. Kaiser and E. Zeitler, “MR imaging of the breast: fast imaging breast cancer with MR imaging,” Breast Cancer Res. Treat. 63͑1͒, 53–60 sequences with and without Gd-DTPA. Preliminary observations,” Radi- ͑2000͒. ology 170͑3Pt1͒, 681–686 ͑1989͒. 128E. A. Morris, L. Liberman, D. J. Ballon, M. Robson, A. F. Abramson, A. 111J. Frahm, A. Haase, and D. Matthaei, “Rapid NMR imaging of dynamic Heerdt, and D. D. Dershaw, “MRI of occult breast carcinoma in a high- processes using the FLASH technique,” Magn. Reson. Med. 3͑2͒, 321– risk population,” AJR, Am. J. Roentgenol. 181͑3͒, 619–626 ͑2003͒. 327 ͑1986͒. 129M. Kriege, C. T. Brekelmans, C. Boetes, P. E. Besnard, H. M. Zonder- 112J. Frahm, A. Haase, and D. Matthaei, “Rapid three-dimensional MR im- land, I. M. Obdeijn, R. A. Manoliu, T. Kok, H. Peterse, M. M. Tilanus- aging using the FLASH technique,” J. Comput. Assist. Tomogr. 10͑2͒, Linthorst, S. H. Muller, S. Meijer, J. C. Oosterwijk, L. V. Beex, R. A. 363–368 ͑1986͒. Tollenaar, H. J. de Koning, E. J. Rutgers, and J. G. Klijn, “Efficacy of 113A. Haase, D. Matthaei, W. Hanicke, and J. Frahm, “Dynamic digital sub- MRI and mammography for breast-cancer screening in women with a traction imaging using fast low-angle shot MR movie sequence,” Radiol- familiar or genetic predisposition,” N. Engl. J. Med. 351͑5͒,427–437 ogy 160͑2͒, 537–541 ͑1986͒. ͑2004͒. 114J. Folkman and M. Klagsbrun, “Angiogenic factors,” Science 235͑4787͒, 130M. O. Leach, C. R. Boggis, A. K. Dixon, D. F. Easton, R. A. Eeles, D. G. 442–447 ͑1987͒. Evans, F. J. Gilbert, I. Griebsch, R. J. Hoff, P. Kessar, S. R. Lakhani, S. 115F. L. Flanagan, J. G. Murray, P. Gilligan, J. P. Stack, and J. T. Ennis, M. Moss, A. Nerurkar, A. R. Padhani, L. J. Pointon, D. Thompson, and R. “Digital subtraction in Gd-DTPA enhanced imaging of the breast,” Clin. M. Waren, “Screening with magnetic resonance imaging and mammog- Radiol. 50͑12͒, 848–854 ͑1995͒. raphy of a UK population at high familial risk of breast cancer: A pro- 116C. D. Lehman, C. Gatsonis, C. K. Kuhl, R. E. Hendrick, E. D. Pisano, L. spective multicentre cohort study ͑MARIBS͒,” Lancet 365͑9473͒, 1769– Hanna, S. Peacock, S. F. Smazal, D. D. Maki, T. B. Julian, E. R. DePeri, 1778 ͑2005͒. D. A. Bluemke, and M. D. Schnall, “MRI evaluation of the contralateral 131F. Sardanelli, F. Podo, G. D’Agnolo, A. Verdecchia, M. Santaquilani, R. breast in women with recently diagnosed breast cancer,” N. Engl. J. Med. Musumeci, G. Trecate, S. Manoukian, S. Morassut, C. de Giacomi, M. 356͑13͒, 1295–1303 ͑2007͒. Federico, L. Cortesi, S. Corcione, S. Cirillo, V. Marra, A. Cilotti, C. Di 117L. Liberman, E. A. Morris, C. M. Kim, J. B. Kaplan, A. F. Abramson, J. Maggio, A. Fausto, L. Preda, C. Zuiani, A. Contegiacomo, A. Orlacchio, H. Menell, K. J. Van Zee, and D. D. Dershaw, “MR imaging findings in M. Calabrese, L. Bonomo, E. Di Cesare, M. Tonutti, P. Panizza, and A. the contralateral breast of women with recently diagnosed breast cancer,” Del Maschio, “Multicenter comparative multimodality surveillance of AJR, Am. J. Roentgenol. 180͑2͒, 333–341 ͑2003͒. women at genetic-familial high risk for breast cancer ͑HIBCRIT study͒: 118S. G. Lee, S. G. Orel, I. J. Woo, E. Cruz-Jove, M. E. Putt, L. J. Solin, B. Interim results,” Radiology 242͑3͒, 698–715 ͑2007͒. J. Czerniecki, and M. D. Schnall, “MR imaging screening of the con- 132D. Saslow, C. Boetes, W. Burke, S. Harms, M. O. Leach, C. D. Lehman, tralateral breast in patients with newly diagnosed breast cancer: Prelimi- E. Morris, E. Pisano, M. Schnall, S. Sener, R. A. Smith, E. Warner, M. nary results,” Radiology 226͑3͒, 773–778 ͑2003͒. Yaffe, K. S. Andrews, and C. A. Russell, “American Cancer Society 119C. D. Lehman, J. D. Blume, D. Thickman, D. A. Bluemke, E. Pisano, C. guidelines for breast screening with MRI as an adjunct to mammogra-

Medical Physics, Vol. 35, No. 11, November 2008 4893 A. Karellas and S. Vedantham: Breast cancer imaging: A perspective 4893

phy,” Ca-Cancer J. Clin. 57͑2͒, 75–89 ͑2007͒. 152W. Huang, P. R. Fisher, K. Dulaimy, L. A. Tudorica, B. O’Hea, and T. M. 133N. H. Peters, I. H. Borel Rinkes, N. P. Zuithoff, W. P. Mali, K. G. Moons, Button, “Detection of breast malignancy: Diagnostic MR protocol for and P. H. Peeters, “Meta-analysis of MR imaging in the diagnosis of improved specificity,” Radiology 232͑2͒, 585–591 ͑2004͒. breast lesions,” Radiology 246͑1͒, 116–124 ͑2008͒. 153L. Bartella, S. B. Thakur, E. A. Morris, D. D. Dershaw, W. Huang, E. 134ACR, ACR Breast Imaging Reporting and Data Systems (BI-RADS): Chough, M. C. Cruz, and L. Liberman, “Enhancing nonmass lesions in Breast Imaging Atlas ͑American College of Radiology, Reston, VA, the breast: Evaluation with proton ͑1H͒ MR spectroscopy,” Radiology 2003͒. 245͑1͒, 80–87 ͑2007͒. 135C. Kuhl, “The current status of breast MR imaging. Part I. Choice of 154E. O. Aboagye and Z. M. Bhujwalla, “Malignant transformation alters technique, image interpretation, diagnostic accuracy, and transfer to clini- membrane choline phospholipid metabolism of human mammary epithe- cal practice,” Radiology 244͑2͒, 356–378 ͑2007͒. lial cells,” Cancer Res. 59͑1͒, 80–84 ͑1999͒. 136C. K. Kuhl, “Current status of breast MR imaging. Part 2. Clinical appli- 155M. Kumar, N. R. Jagannathan, V. Seenu, S. N. Dwivedi, P. K. Julka, and cations,” Radiology 244͑3͒, 672–691 ͑2007͒. G. K. Rath, “Monitoring the therapeutic response of locally advanced 137M. F. Bellin, J. A. Jakobsen, I. Tomassin, H. S. Thomsen, S. K. Morcos, breast cancer patients: Sequential in vivo proton MR spectroscopy study,” H. S. Thomsen, S. K. Morcos, T. Almen, P. Aspelin, M. F. Bellin, W. J. Magn. Reson Imaging 24͑2͒, 325–332 ͑2006͒. Clauss, H. Flaten, N. Grenier, J. M. Idee, J. A. Jakobsen, G. P. Krestin, F. 156N. R. Jagannathan, M. Kumar, V. Seenu, O. Coshic, S. N. Dwivedi, P. K. Stacul, and J. A. Webb, “Contrast medium extravasation injury: Guide- Julka, A. Srivastava, and G. K. Rath, “Evaluation of total choline from lines for prevention and management,” Eur. Radiol. 12͑11͒, 2807–2812 in-vivo volume localized proton MR spectroscopy and its response to ͑2002͒. neoadjuvant chemotherapy in locally advanced breast cancer,” Br. J. Can- 138FDA, US Public Health Advisory: Update on Magnetic Resonance Imag- cer 84͑8͒, 1016–1022 ͑2001͒. ing ͑MRI͒ Contrast Agents Containing Gadolinium and Nephrogenic Fi- 157H. M. Baek, J. H. Chen, O. Nalcioglu, and M. Y. Su, “Proton MR spec- brosing Dermopathy, Date created: December 22, 2006; updated May 23, troscopy for monitoring early treatment response of breast cancer to neo- 2007. http://www.fda.gov/Cder/Drug/advisory/ adjuvant chemotherapy,” Ann. Oncol. 19͑5͒, 1022–1024 ͑2008͒. gadolinium_agents_20061222.htm ͓Accessed: April 29, 2008͔. 158D. J. Manton, A. Chaturvedi, A. Hubbard, M. J. Lind, M. Lowry, A. 139I. S. Gribbestad, B. Sitter, S. Lundgren, J. Krane, and D. Axelson, “Me- Maraveyas, M. D. Pickles, D. J. Tozer, and L. W. Turnbull, “Neoadjuvant tabolite composition in breast tumors examined by proton nuclear mag- chemotherapy in breast cancer: Early response prediction with quantita- netic resonance spectroscopy,” Anticancer Res. 19͑3A͒, 1737–1746 tive MR imaging and spectroscopy,” Br. J. Cancer 94͑3͒, 427–435 ͑1999͒. ͑2006͒. 140A. Barzilai, A. Horowitz, A. Geier, and H. Degani, “Phosphate metabo- 159S. Meisamy, P. J. Bolan, E. H. Baker, R. L. Bliss, E. Gulbahce, L. I. lites and steroid hormone receptors of benign and malignant breast tu- Everson, M. T. Nelson, T. H. Emory, T. M. Tuttle, D. Yee, and M. Gar- mors. A nuclear magnetic resonance study,” Cancer 67͑11͒, 2919–2925 wood, “Neoadjuvant chemotherapy of locally advanced breast cancer: ͑1991͒. predicting response with in vivo ͑1͒H MR spectroscopy--a pilot study at 4 141J. S. Cohen, “Phospholipid and energy metabolism of cancer cells moni- T,” Radiology 233͑2͒, 424–431 ͑2004͒. tored by 31P magnetic resonance spectroscopy: possible clinical signifi- 160M. A. Jacobs, P. B. Barker, P. A. Bottomley, Z. Bhujwalla, and D. A. cance,” Mayo Clin. Proc. 63͑12͒, 1199–1207 ͑1988͒. Bluemke, “Proton magnetic resonance spectroscopic imaging of human 142R. Kalra, K. E. Wade, L. Hands, P. Styles, R. Camplejohn, M. Greenall, breast cancer: a preliminary study,” J. Magn. Reson Imaging 19͑1͒, G. E. Adams, A. L. Harris, and G. K. Radda, “Phosphomonoester is 68–75 ͑2004͒. associated with proliferation in human breast cancer: a 31P MRS study,” 161M. A. Jacobs, R. Ouwerkerk, A. C. Wolff, V. Stearns, P. A. Bottomley, P. Br. J. Cancer 67͑5͒, 1145–1153 ͑1993͒. B. Barker, P. Argani, N. Khouri, N. E. Davidson, Z. M. Bhujwalla, and D. 143J. M. Park and J. H. Park, “Human in-vivo 31P MR spectroscopy of A. Bluemke, “Multiparametric and multinuclear magnetic resonance im- benign and malignant breast tumors,” Korean J Radiol 2͑2͒, 80–86 aging of human breast cancer: current applications,” Technol. Cancer Res. ͑2001͒. Treat. 3͑6͒, 543–550 ͑2004͒. 144K. A. Kvistad, I. J. Bakken, I. S. Gribbestad, B. Ehrnholm, S. Lundgren, 162J. Hu, Y. Yu, Z. Kou, W. Huang, Q. Jiang, Y. Xuan, T. Li, V. Sehgal, C. H. E. Fjosne, and O. Haraldseth, “Characterization of neoplastic and nor- Blake, E. M. Haacke, and R. L. Soulen, “A high spatial resolution ͑1͒H mal human breast tissues with in vivo ͑1͒H MR spectroscopy,” J. Magn. magnetic resonance spectroscopic imaging technique for breast cancer Reson Imaging 10͑2͒, 159–164 ͑1999͒. with a short echo time,” Magn. Reson. Imaging 26͑3͒, 360–366 ͑2008͒. 145J. R. Roebuck, K. M. Cecil, M. D. Schnall, and R. E. Lenkinski, “Human 163I. S. Haddadin, A. McIntosh, S. Meisamy, C. Corum, A. L. Snyder, N. J. breast lesions: characterization with proton MR spectroscopy,” Radiology Powell, M. T. Nelson, D. Yee, M. Garwood, and P. J. Bolan, “Metabolite 209͑1͒, 269–275 ͑1998͒. quantification and high-field MRS in breast cancer,” NMR Biomed. ͑to be 146I. S. Gribbestad, T. E. Singstad, G. Nilsen, H. E. Fjosne, T. Engan, O. A. published͒. Haugen, and P. A. Rinck, “In vivo 1H MRS of normal breast and breast 164G. M. Tse, D. K. Yeung, A. D. King, H. S. Cheung, and W. T. Yang, “In tumors using a dedicated double breast coil,” J. Magn. Reson Imaging vivo proton magnetic resonance spectroscopy of breast lesions: An up- 8͑6͒, 1191–1197 ͑1998͒. date,” Breast Cancer Res. Treat. 104͑3͒, 249–255 ͑2007͒. 147D. K. Yeung, H. S. Cheung, and G. M. Tse, “Human breast lesions: 165P. Stanwell and C. Mountford, “In vivo proton MR spectroscopy of the characterization with contrast-enhanced in vivo proton MR breast,” Radiographics 27͑Suppl 1͒, S253–S266 ͑2007͒. spectroscopy—initial results,” Radiology 220͑1͒, 40–46 ͑2001͒. 166A. B. Wolbarst and W. R. Hendee, “Evolving and experimental technolo- 148R. Katz-Brull, P. T. Lavin, and R. E. Lenkinski, “Clinical utility of proton gies in medical imaging,” Radiology 238͑1͒, 16–39 ͑2006͒. magnetic resonance spectroscopy in characterizing breast lesions,” J. 167M. Liberman, F. Sampalis, D. S. Mulder, and J. S. Sampalis, “Breast Natl. Cancer Inst. 94͑16͒, 1197–1203 ͑2002͒. cancer diagnosis by scintimammography: a meta-analysis and review of 149H. M. Baek, H. J. Yu, J. H. Chen, O. Nalcioglu, and M. Y. Su, “Quanti- the literature,” Breast Cancer Res. Treat. 80͑1͒, 115–126 ͑2003͒. tative correlation between ͑1͒H MRS and dynamic contrast-enhanced 168I. Khalkhali, J. Villanueva-Meyer, S. L. Edell, J. L. Connolly, S. J. MRI of human breast cancer,” Magn. Reson. Imaging 26͑4͒, 523–531 Schnitt, J. K. Baum, M. J. Houlihan, R. M. Jenkins, and S. B. Haber, ͑2008͒. “Diagnostic accuracy of 99mTc-sestamibi breast imaging: multicenter 150M. Y. Su, H. M. Baik, H. J. Yu, J. H. Chen, R. S. Mehta, and O. Nalcio- trial results,” J. Nucl. Med. 41͑12͒, 1973–1979 ͑2000͒. glu, “Comparison of choline and pharmacokinetic parameters in breast 169C. B. Hruska, M. K. O’Connor, and D. A. Collins, “Comparison of small cancer measured by MR spectroscopic imaging and dynamic contrast field of view gamma camera systems for scintimammography,” Nucl. enhanced MRI,” Technol. Cancer Res. Treat. 5͑4͒, 401–410 ͑2006͒. Med. Commun. 26͑5͒, 441–445 ͑2005͒. 151S. Meisamy, P. J. Bolan, E. H. Baker, M. G. Pollema, C. T. Le, F. Kelcz, 170B. Mueller, M. K. O’Conner, I. Blevis, D. J. Rhodes, R. Smith, D. A. M. C. Lechner, B. A. Luikens, R. A. Carlson, K. R. Brandt, K. K. Am- Collins, and S. W. Phillips, “Evaluation of a small cadmium zinc telluride rami, M. T. Nelson, L. I. Everson, T. H. Emory, T. M. Tuttle, D. Yee, and detector for scintimammography,” J. Nucl. Med. 44͑4͒, 602–609 ͑2003͒. M. Garwood, “Adding in vivo quantitative 1H MR spectroscopy to im- 171M. K. O’Connor, S. W. Phillips, C. B. Hruska, D. J. Rhodes, and D. A. prove diagnostic accuracy of breast MR imaging: Preliminary results of Collins, “Molecular breast imaging: advantages and limitations of a scin- observer performance study at 4.0 T,” Radiology 236͑2͒, 465–475 timammographic technique in patients with small breast tumors,” Breast ͑2005͒. J. 13͑1͒, 3–11 ͑2007͒.

Medical Physics, Vol. 35, No. 11, November 2008 4894 A. Karellas and S. Vedantham: Breast cancer imaging: A perspective 4894

172R. F. Brem, J. A. Rapelyea, G. Zisman, K. Mohtashemi, J. Raub, C. B. ology 234͑2͒, 527–534 ͑2005͒. Teal, S. Majewski, and B. L. Welch, “Occult breast cancer: scintimam- 190W. A. Berg, I. N. Weinberg, D. Narayanan, M. E. Lobrano, E. Ross, L. mography with high-resolution breast-specific gamma camera in women Amodei, L. Tafra, L. P. Adler, J. Uddo, W. Stein, 3rd, and E. A. Levine, at high risk for breast cancer,” Radiology 237͑1͒, 274–280 ͑2005͒. “High-resolution fluorodeoxyglucose positron emission tomography with 173A. Spanu, P. Cottu, A. Manca, F. Chessa, D. Sanna, and G. Madeddu, compression ͑‘positron emission mammography’͒ is highly accurate in “Scintimammography with dedicated breast camera in unifocal and depicting primary breast cancer,” Breast J. 12͑4͒, 309–323 ͑2006͒. multifocal/multicentric primary breast cancer detection: a comparative 191F. Benard and E. Turcotte, “Imaging in breast cancer: Single-photon com- study with SPECT,” Int. J. Oncol. 31͑2͒, 369–377 ͑2007͒. puted tomography and positron-emission tomography,” Breast Cancer 174M. P. Tornai, J. E. Bowsher, C. N. Archer, J. Peter, R. J. Jaszczak, L. R. Res 7͑4͒, 153–162 ͑2005͒. MacDonald, B. E. Patt, and J. S. Iwanczyk, “A 3D gantry single photon 192A. E. Burgess, F. L. Jacobson, and P. F. Judy, “Human observer detection emission tomograph with hemispherical coverage for dedicated breast experiments with mammograms and power-low noise,” Med. Phys. 28͑4͒, imaging,” Nucl. Instrum. Methods Phys. Res. A 497͑1͒, 157–167 ͑2003͒. 419–437 ͑2001͒. 175C. N. Brzymialkiewicz, M. P. Tornai, R. L. McKinley, and J. E. Bowsher, 193A. E. Burgess, X. Li, and C. K. Abbey, “Visual signal detectability with “Evaluation of fully 3-D emission mammotomography with a compact two noise components: Anomalous masking effects,” J. Opt. Soc. Am. A cadmium zinc telluride detector,” IEEE Trans. Med. Imaging 24͑7͒, 868– 14͑9͒, 2420–2442 ͑1997͒. 877 ͑2005͒. 194D. P. Chakraborty and H. L. Kundel, “Anomalous nodule visibility effects 176M. L. Bradshaw, R. L. McKinley, E. Samei, C. N. Archer, and M. P. in mammography images,” Proc. SPIE 4324, 68–76 ͑2001͒. Tornai, “Initial x-ray design considerations for application specific emis- 195H. P. Chan, M. M. Goodsitt, L. M. Hadjiiski, J. E. Bailey, K. Klein, K. L. sion and transmission tomography ͑ASETT͒ of the breast,” Proceedings Darner, and B. Sahiner, “Effects of magnification and zooming on depth of the Annual Meeting of the Society of Nuclear Medicine, New Orleans, perception in digital stereomammography: An observer performance Louisiana, J. Nucl. Med. 44͑5͒, 287P ͑2003͒. study,” Phys. Med. Biol. 48͑22͒, 3721–3734 ͑2003͒. 177K. Yutani, E. Shiba, H. Kusuoka, M. Tatsumi, T. Uehara, T. Taguchi, S. I. 196M. M. Goodsitt, H. P. Chan, K. L. Darner, and L. M. Hadjiiski, “The Takai, and T. Nishimura, “Comparison of FDG-PET with MIBI-SPECT effects of stereo shift angle, geometric magnification and display zoom on in the detection of breast cancer and axillary lymph node metastasis,” J. depth measurements in digital stereomammography,” Med. Phys. 29͑11͒, Comput. Assist. Tomogr. 24͑2͒, 274–280 ͑2000͒. 2725–2734 ͑2002͒. 178M. F. Smith, S. Majewski, A. G. Weisenberger, D. A. Kieper, R. R. 197H. P. Chan, M. M. Goodsitt, M. A. Helvie, L. M. Hadjiiski, J. T. Lydick, Raylman, and T. G. Turkington, “Analysis of factors affecting positron M. A. Roubidoux, J. E. Bailey, A. Nees, C. E. Blane, and B. Sahiner, emission mammography ͑PEM͒ image formation.,” IEEE Trans. Nucl. “ROC study of the effect of stereoscopic imaging on assessment of breast Sci. 50, 53–59 ͑2003͒. lesions,” Med. Phys. 32͑4͒, 1001–1009 ͑2005͒. 179R. R. Raylman, S. Majewski, M. F. Smith, J. Proffitt, W. Hammond, A. 198D. J. Getty et al., “Improved accuracy of lesion detection in breast cancer Srinivasan, J. McKisson, V. Popov, A. Weisenberger, C. O. Judy, B. screening with stereoscopic digital mammography ͓abstract͔,” in 93rd Kross, S. Ramasubramanian, L. E. Banta, P. E. Kinahan, and K. Champ- Scientific Assembly and Annual Meeting of the Radiological Society of ley, “The positron emission mammography/tomography breast imaging North America ͑RSNA͒. RSNA Scientific Assembly and Annual Meeting and biopsy system ͑PEM/PET͒: Design, construction and phantom-based Program 2007, pp.381–382. measurements,” Phys. Med. Biol. 53͑3͒, 637–653 ͑2008͒. 199A. D. Maidment, P. R. Bakic, and M. Albert, “Effects of quantum noise 180N. K. Doshi, Y. Shao, R. W. Silverman, and S. R. Cherry, “Design and and binocular summation on dose requirements in stereoradiography,” evaluation of an LSO PET detector for breast cancer imaging,” Med. Med. Phys. 30͑12͒, 3061–3071 ͑2003͒. Phys. 27͑7͒, 1535–1543 ͑2000͒. 200D. J. Getty and P. J. Green, “Clinical medical applications for stereo- 181P. A. Dokhale, R. W. Silverman, K. S. Shah, R. Grazioso, R. Farrell, J. scopic 3D displays,” J. Soc. Inf. Disp. 15͑6͒, 377–384 ͑2007͒. Glodo, M. A. McClish, G. Entine, V. H. Tran, and S. R. Cherry, “Perfor- 201M. Bissonnette, M. Hansroul, E. Masson, S. Savard, S. Cadieux, P. War- mance measurements of a depth-encoding PET detector module based on moes, D. Gravel, J. Agopyan, B. Polischuk, W. Haerer, T. Mertelmeier, J. position-sensitive avalanche photodiode read-out,” Phys. Med. Biol. Y. Lo, Y. Chen, JTr. Dobbins, J. L. Jesneck, and S. Singh, “Digital breast 49͑18͒, 4293–4304 ͑2004͒. tomosynthesis using an amorphous selenium flat panel detector,” Proc. 182J. Zhang, P. D. Olcott, G. Chinn, A. M. Foudray, and C. S. Levine, “Study SPIE 5745, 529–540 ͑2005͒. of the performance of a novel 1 mm resolution dual-panel PET camera 202B. Ren, C. Ruth, J. Stein, A. Smith, I. Shaw, and Z. Jing, “Design and design dedicated to breast cancer imaging using Monte Carlo simulation,” performance of the prototype full field breast tomosynthesis system with Med. Phys. 34͑2͒, 689–702 ͑2007͒. selenium based flat panel detector,” Proc. SPIE 5745, 550–561 ͑2005͒. 183C. J. Thompson, K. Murthy, I. N. Weinberg, and F. Mako, “Feasibility 203A. D. Maidment, C. Ullberg, K. Lindman, L. Adelöw, J. Egerström, M. study for positron emission mammography,” Med. Phys. 21͑4͒, 529–538 Eklund, T. Francke, U. Jordung, T. Kristoffersson, L. Lindqvist, D. Mar- ͑1994͒. chal, H. Olla, E. Penton, J. Rantanen, S. Solokov, N. Weber, and H. 184K. Murthy, M. Aznar, A. M. Bergman, C. J. Thompson, J. L. Robar, R. Westerberg, “Evaluation of a photon-counting breast tomosynthesis im- Lisbona, A. Loutfi, and J. H. Gagnon, “Positron emission mammographic aging system,” Proc. SPIE 6142, 61420B ͑2006͒. instrument: initial results,” Radiology 215͑1͒, 280–285 ͑2000͒. 204L. T. Niklason, B. T. Christian, L. E. Niklason, D. B. Kopans, D. E. 185K. Murthy, M. Aznar, C. J. Thompson, A. Loutfi, R. Lisbona, and J. H. Castleberry, B. H. OpsahlOng, C. E. Landberg, P. J. Slanetz, A. A. Gia- Gagnon, “Results of preliminary clinical trials of the positron emission rdino, R. Moore, D. Albagli, M. C. DeJule, P. F. Fitzgerald, D. F. Fobare, mammography system PEM-I: A dedicated breast imaging system pro- B. W. Giambattista, R. F. Kwasnick, J. Q. Liu, S. J. Lubowski, G. E. ducing glucose metabolic images using FDG,” J. Nucl. Med. 41͑11͒, Possin, J. F. Richotte, C. Y. Wei, and R. F. Wirth, “Digital Tomosynthesis 1851–1858 ͑2000͒. in breast imaging,” Radiology 205͑2͒, 399–406 ͑1997͒. 186R. R. Raylman, S. Majewski, R. Wojcik, A. G. Weisenberger, B. Kross, V. 205S. Suryanarayanan, A. Karellas, S. Vedantham, S. P. Baker, S. J. Glick, C. Popov, and H. A. Bishop, “The potential role of positron emission mam- J. D’Orsi, and R. L. Webber, “Evaluation of linear and nonlinear tomo- mography for detection of breast cancer. A phantom study,” Med. Phys. synthetic reconstruction methods in digital mammography,” Acad. Ra- 27͑8͒, 1943–1954 ͑2000͒. diol. 8͑3͒, 219–224 ͑2001͒. 187A. Motta, A. D. Guerra, N. Belcari, S. Moehrs, D. Panetta, S. Righi, and 206S. Suryanarayanan, A. Karellas, S. Vedantham, S. J. Glick, C. J. D’Orsi, D. Valentini, “Fast 3D-EM reconstruction using Planograms for stationary S. P. Baker, and R. L. Webber, “Comparison of tomosynthesis methods planar positron emission mammography camera,” Comput. Med. Imaging used with digital mammography,” Acad. Radiol. 7͑12͒, 1085–1097 Graph. 29͑8͒, 587–596 ͑2005͒. ͑2000͒. 188P. Amaral, B. Carriço, M. Ferreira, R. Moura, C. Ortigão, P. Rodrigues, J. 207W. Zhao, B. Zhao, P. R. Fisher, P. Warmoes, T. Mertelmeier, and J. C. Da Silva, A. Trindade, and J. Varela, “Performance and quality control Orman, “Optimization of detector operation and imaging geometry for of clear-PEM detector modules,” Nucl. Instrum. Methods Phys. Res. A breast tomosynthesis,” Proc. SPIE 6510, 65101M ͑2007͒. 580͑2͒, 1123–1126 ͑2007͒. 208B. Zhao and W. Zhao, “Imaging performance of an amorphous selenium 189E. L. Rosen, T. G. Turkington, M. S. Soo, J. A. Baker, and R. E. Cole- digital mammography detector in a breast tomosynthesis system,” Med. man, “Detection of primary breast carcinoma with a dedicated, large- Phys. 35͑5͒, 1978–1987 ͑2008͒. field-of-view FDG PET mammography device: Initial experience,” Radi- 209A. Badano, I. S. Kyprianou, R. J. Jennings, and J. Sempau, “Anisotropic

Medical Physics, Vol. 35, No. 11, November 2008 4895 A. Karellas and S. Vedantham: Breast cancer imaging: A perspective 4895

imaging performance in breast tomosynthesis,” Med. Phys. 34͑11͒, 4076– 231V. Raptopoulos, J. K. Baum, M. Hochman, A. Karellas, M. J. Houlihan, 4091 ͑2007͒. and C. J. D’Orsi, “High resolution CT mammography of surgical biopsy 210J. G. Mainprize, A. K. Bloomquist, M. P. Kempston, and M. J. Yaffe, specimens,” J. Comput. Assist. Tomogr. 20͑2͒, 179–184 ͑1996͒. “Resolution at oblique incidence angles of a flat panel imager for breast 232J. M. Boone, T. R. Nelson, K. K. Lindfors, and J. A. Seibert, “Dedicated tomosynthesis,” Med. Phys. 33͑9͒, 3159–3164 ͑2006͒. breast CT: radiation dose and image quality evaluation,” Radiology 211I. Sechopoulos, S. Suryanarayanan, S. Vedantham, C. D’Orsi, and A. 221͑3͒, 657–667 ͑2001͒. Karellas, “Computation of the glandular radiation dose in digital tomo- 233J. M. Boone, N. Shah, and T. R. Nelson, “A comprehensive analysis of synthesis of the breast,” Med. Phys. 34͑1͒, 221–232 ͑2007͒. DgN͑CT͒ coefficients for pendant-geometry cone-beam breast computed 212J. Zhou, B. Zhao, and W. Zhao, “A computer simulation platform for the tomography,” Med. Phys. 31͑2͒, 226–235 ͑2004͒. optimization of a breast tomosynthesis system,” Med. Phys. 34͑3͒, 1098– 234S. C. Thacker and S. J. Glick, “Normalized glandular dose ͑DgN͒ coef- 1109 ͑2007͒. ficients for flat-panel CT breast imaging,” Phys. Med. Biol. 49͑24͒, 5433– 213 S. J. Glick and X. Gong, “Optimal spectra for indirect detector breast 5444 ͑2004͒. tomosynthesis,” Proc. SPIE 6142, 61421L ͑2006͒. 235I. Sechopoulos, S. Vedantham, S. Suryanarayanan, C. J. D’Orsi, and A. 214T. Wu, B. Liu, R. Moore, and D. B. Kopans, “Optimal acquisition tech- Karellas, “Monte Carlo and phantom study of the radiation dose to the niques for digital breast tomosynthesis screening,” Proc. SPIE 6142, body from dedicated CT of the breast,” Radiology 247͑1͒, 98–105 ͑2008͒. 61425E ͑2006͒. 236A. L. Kwan, J. M. Boone, and N. Shah, “Evaluation of x-ray scatter 215I. Sechopoulos, S. Suryanarayanan, S. Vedantham, C. J. D’Orsi, and A. properties in a dedicated cone-beam breast CT scanner,” Med. Phys. Karellas, “Scatter radiation in digital tomosynthesis of the breast,” Med. 32͑9͒, 2967–2975 ͑2005͒. Phys. 34͑2͒, 564–576 ͑2007͒. 237B. Liu, S. J. Glick, and C. Groiselle, “Characterization of scatter radiation 216F. Diekmann, H. Meyer, S. Diekmann, S. Puong, S. Muller, U. Bick, and in cone beam CT mammography,” Proc. SPIE 5745, 818–827 ͑2005͒. P. Rogalla, “Thick slices from tomosynthesis data sets: Phantom study for 238B. Chen and R. Ning, “Cone-beam volume CT breast imaging: feasibility the evaluation of different algorithms,” J. Digit Imaging ͑to be published͒. study,” Med. Phys. 29͑5͒, 755–770 ͑2002͒. 217Y. Chen, J. Y. Lo, and J. T. Dobbins, 3rd, “Importance of point-by-point 239J. M. Boone, Breast CT: Its prospect for breast cancer screening and back projection correction for isocentric motion in digital breast tomosyn- diagnosis,inAdvances in breast imaging: Physics, Technology and Clini- thesis: Relevance to morphology of structures such as microcalcifica- cal Applications, Categorical Course in Diagnostic Radiology Physics, tions,” Med. Phys. 34͑10͒, 3885–3892 ͑2007͒. edited by A. Karellas and M. L. Giger ͑Radiological Society of North 218Y. Zhang, H. P. Chan, B. Sahiner, J. Wei, M. M. Goodsitt, L. M. Hadji- America ͑RSNA͒, Oak Brook, IL, 2004͒. iski, J. Ge, and C. Zhou, “A comparative study of limited-angle cone- 240R. L. McKinley, C. N. Bryzmialkiewicz, P. Madhav, and M. P. Tornai, beam reconstruction methods for breast tomosynthesis,” Med. Phys. “Investigation of cone-beam acquisitions implemented using a novel 33͑10͒, 3781–3795 ͑2006͒. dedicated mammotomography system with unique arbitrary orbit capabil- 219T. Wu, R. H. Moore, and D. B. Kopans, “Voting strategy for artifact ity,” Proc. SPIE 5745, 609–617 ͑2005͒. reduction in digital breast tomosynthesis,” Med. Phys. 33͑7͒, 2461–2471 241K. Zeng, H. Yu, L. L. Fajardo, and G. Wang, “Cone-beam mammo- ͑2006͒. computed tomography from data along two tilting arcs,” Med. Phys. 220J. T. Rakowski and M. J. Dennis, “A comparison of reconstruction algo- 33͑10͒, 3621–3633 ͑2006͒. rithms for C-arm mammography tomosynthesis,” Med. Phys. 33͑8͒, 242J. M. Boone, A. L. Kwan, J. A. Seibert, N. Shah, K. K. Lindfors, and T. 3018–3032 ͑2006͒. R. Nelson, “Technique factors and their relationship to radiation dose in 221T. Mertelmeier, J. Orman, W. Haerer, and M. K. Dudam, “Optimizing pendant geometry breast CT,” Med. Phys. 32͑12͒, 3767–3776 ͑2005͒. filtered backprojection reconstruction for a breast tomosynthesis proto- 243S. J. Glick, S. Thacker, X. Gong, and B. Liu, “Evaluating the impact of type device,” Proc. SPIE 6142, 61420F ͑2006͒. X-ray spectral shape on image quality in flat-panel CT breast imaging,” 222Y. Chen, J. Y. Lo, J. A. Baker, and J. Tr. Dobbins, “Gaussian frequency Med. Phys. 34͑1͒, 5–24 ͑2007͒. blending algorithm with matrix inversion tomosynthesis ͑MITS͒ and fil- 244R. L. McKinley, M. P. Tornai, E. Samei, and M. L. Bradshaw, “Simula- tered back projection ͑FBP͒ for better digital breast tomosynthesis recon- tion study of a quasi-monochromatic beam for x-ray computed mammo- struction,” Proc. SPIE 6142, 61420E ͑2006͒. tomography,” Med. Phys. 31͑4͒, 800–813 ͑2004͒. 223S. P. Poplack, T. D. Tosteson, C. A. Kogel, and H. M. Nagy, “Digital 245A. L. Kwan, J. M. Boone, K. Yang, and S. Y. Huang, “Evaluation of the breast tomosynthesis: initial experience in 98 women with abnormal digi- spatial resolution characteristics of a cone-beam breast CT scanner,” Med. tal screening mammography,” AJR, Am. J. Roentgenol. 189͑3͒, 616–623 Phys. 34͑1͒, 275–281 ͑2007͒. ͑2007͒. 246J. Zhong, R. Ning, and D. Conover, “Image denoising based on multi- 224C. Badea, Z. Kolitsi, and N. Pallikarakis, “A wavelet-based method for scale singularity detection for cone beam CT breast imaging,” IEEE removal of out-of-plane structures in digital tomosynthesis,” Comput. Trans. Med. Imaging 23͑6͒, 696–703 ͑2004͒. Med. Imaging Graph. 22͑4͒, 309–315 ͑1998͒. 247M. C. Altunbas, C. C. Shaw, L. Chen, C. Lai, X. Liu, T. Han, and T. 225Z. Kolitsi, G. Panayiotakis, and N. Pallikarakis, “A method for selective Wang, “A post-reconstruction method to correct cupping artifacts in cone removal of out-of-plane structures in digital tomosynthesis,” Med. Phys. beam breast computed tomography,” Med. Phys. 34͑7͒, 3109–3118 20͑1͒, 47–50 ͑1993͒. ͑2007͒. 226J. Ge, H. P. Chan, Y. Zhang, B. Sahiner, J. Wei, and L. M. Hadjiiski, 248W. T. Yang, S. Carkaci, L. Chen, C. J. Lai, A. Sahin, G. J. Whitman, and “Digital tomosynthesis mammography: An interplane artifact reduction C. C. Shaw, “Dedicated cone-beam breast CT: Feasibility study with method for microcalcifications on reconstructed slices based on 3D geo- surgical mastectomy specimens,” AJR, Am. J. Roentgenol. 189͑6͒, 1312– metrical information,” in 92nd Scientific Assembly and Annual Meeting 1315 ͑2007͒. of the RSNA. RSNA Scientific Assembly and Annual Meeting Program 249J. M. Boone, A. L. Kwan, K. Yang, G. W. Burkett, K. K. Lindfors, and T. 2006, p. 230. R. Nelson, “Computed tomography for imaging the breast,” Journal of 227R. H. Moore et al., “Initial callback rates for conventional and digital mammary gland biology and neoplasia 11͑2͒, 103–111 ͑2006͒. breast tomosynthesis mammography comparison in the screening set- 250K. K. Lindfors, J. M. Boone, T. R. Nelson, K. Yang, A. L. Kwan, and D. ting,” in 93rd Scientific Assembly and Annual Meeting of the Radiologi- F. Miller, “Dedicated breast CT: Initial clinical experience,” Radiology cal Society of North America ͑RSNA͒. Scientific Assembly and Annual 246͑3͒, ’725–733 ͑2008͒. Meeting Program 2007, p. 381. 251D. J. Crotty, P. Madhav, R. L. McKinley, and M. P. Tornai, “Investigating 228R. W. Redington and J. L. Henkes, Jr., “Mammography,” U.S. Patent, No. novel patient bed designs for use in a hybrid dual modality dedicated 3D 3,973,126, General Electric Co., Shenectady, NY, August 3, 1976. breast imaging system,” Proc. SPIE 6510, 65101H ͑2007͒. 229C. H. Chang, J. L. Sibala, S. L. Fritz, S. J. Dwyer, 3rd, A. W. Templeton, 252R. Ning, D. Conover, Y. Yu, Y. Zhang, W. Cai, R. Betancourt-Benitez, F. Lin, and W. R. Jewell, “Computed tomography in detection and diag- and X. Lu, “A novel cone beam breast CT scanner: system evaluation,” nosis of breast cancer,” Cancer 46͑4 Suppl͒, 939–946 ͑1980͒. Proc. SPIE 6510, 651030 ͑2007͒. 230C. H. Chang, D. E. Nesbit, D. R. Fisher, S. L. Fritz, S. J. Dwyer, 3rd, A. 253X. Gong, A. A. Vedula, and S. J. Glick, “Microcalcification detection W. Templeton, F. Lin, and W. R. Jewell, “Computed tomographic mam- using cone-beam CT mammography with a flat-panel imager,” Phys. mography using a conventional body scanner,” AJR, Am. J. Roentgenol. Med. Biol. 49͑11͒, 2183–2195 ͑2004͒. 138͑3͒, 553–558 ͑1982͒. 254C. J. Lai, C. C. Shaw, L. Chen, M. C. Altunbas, X. Liu, T. Han, T. Wang,

Medical Physics, Vol. 35, No. 11, November 2008 4896 A. Karellas and S. Vedantham: Breast cancer imaging: A perspective 4896

W. T. Yang, G. J. Whitman, and S. J. Tu, “Visibility of microcalcification energy contrast enhanced digital breast tomosynthesis,” Proc. SPIE 6913, in cone beam breast CT: Effects of X-ray tube voltage and radiation 69130Z ͑2008͒. dose,” Med. Phys. 34͑7͒, 2995–3004 ͑2007͒. 275R. Saunders, E. Samei, C. Badea, H. Yuan, K. Ghaghada, Y. Qi, L. W. 255A. L. Kwan, K. Yang, K. K. Lindfors, T. R. Nelson, and J. M. Boone, Hedlund, and S. Mukundan, “Optimization of dual energy contrast en- “Visualization of micro-calcifications in a prototype breast CT ͓abstract͔,” hanced breast tomosynthesis for improved mammographic lesion detec- Med. Phys. 33, 1990 ͑2006͒. tion and diagnosis,” Proc. SPIE 6913, 69130Y ͑2008͒. 256P. M. Shikhaliev, “Tilted angle CZT detector for photon counting/energy 276C. T. Badea, E. Samei, K. Ghaghada, R. Saunders, H. Yuan, Y. Qi, L. W. weighting x-ray and CT imaging,” Phys. Med. Biol. 51͑17͒, 4267–4287 Hedlund, and S. Mukundan, “Utility of a prototype liposomal contrast ͑2006͒. agent for x-ray imaging of breast cancer: A proof of concept using 257S. Rudin, A. T. Kuhls, G. K. Yadava, G. C. Josan, Y. Wu, R. N. Chityala, micro-CT in small animals,” Proc. SPIE 6913, 691303 ͑2008͒. H. S. Rangwala, N. C. Ionita, K. R. Hoffmann, and D. R. Bednarek, “New 277G. H. Simon, Y. Fu, K. Berejnoi, L. S. Fournier, V. Lucidi, B. Yeh, D. M. light-amplifier-based detector designs for high spatial resolution and high Shames, and R. C. Brasch, “Initial computed tomography imaging expe- sensitivity CBCT mammography and fluoroscopy,” Proc. SPIE 6142, rience using a new macromolecular iodinated contrast medium in experi- 61421R ͑2006͒. mental breast cancer,” Invest. Radiol. 40͑9͒, 614–620 ͑2005͒. 258S. J. Glick, “Breast CT,” Annu. Rev. Biomed. Eng. 9, 501–526 ͑2007͒. 278S. W. Wilkins, T. E. Gureyev, D. Gao, A. Pogany, and A. W. Stevenson, 259X. Gong, S. J. Glick, B. Liu, A. A. Vedula, and S. Thacker, “A computer “Phase-contrast imaging using polychromatic hard X-rays,” Nature ͑Lon- simulation study comparing lesion detection accuracy with digital mam- don͒ 384, 335–338 ͑1996͒. mography, breast tomosynthesis, and cone-beam CT breast imaging,” 279Y. Suzuki, N. Yagi, and K. Uesugi, “X-ray refraction-enhanced imaging Med. Phys. 33͑4͒, 1041–1052 ͑2006͒. and a method for phase retrieval for a simple object,” J. Synchrotron 260A. C. Watt, L. V. Ackerman, P. C. Shetty, M. Burke, M. Flynn, C. Radiat. 9͑Pt 3͒, 160–165 ͑2002͒. Grodsinsky, G. Fine, and S. Wilderman, “Differentiation between benign 280D. Chapman, W. Thomlinson, R. E. Johnston, D. Washburn, E. Pisano, N. and malignant disease of the breast using digital subtraction angiography Gmur, Z. Zhong, R. Menk, F. Arfelli, and D. Sayers, “Diffraction en- of the breast,” Cancer 56͑6͒, 1287–1292 ͑1985͒. hanced x-ray imaging,” Phys. Med. Biol. 42͑11͒, 2015–2025 ͑1997͒. 261A. C. Watt, L. V. Ackerman, J. P. Windham, P. C. Shetty, M. W. Burke, 281M. O. Hasnah, Z. Zhong, O. Oltulu, E. Pisano, R. E. Johnston, D. Sayers, M. J. Flynn, C. Grodinsky, G. Fine, and S. J. Wilderman, “Breast lesions: W. Thomlinson, and D. Chapman, “Diffraction enhanced imaging con- Differential diagnosis using digital subtraction angiography,” Radiology trast mechanisms in breast cancer specimens,” Med. Phys. 29͑10͒,2216– 159͑1͒, 39–42 ͑1986͒. 2221 ͑2002͒. 262J. M. Lewin, P. K. Isaacs, V. Vance, and F. J. Larke, “Dual-energy 282E. D. Pisano, R. E. Johnston, D. Chapman, J. Geradts, M. V. Iacocca, C. contrast-enhanced digital subtraction mammography: feasibility,” Radiol- A. Livasy, D. B. Washburn, D. E. Sayers, Z. Zhong, M. Z. Kiss, and W. ogy 229͑1͒, 261–268 ͑2003͒. C. Thomlinson, “Human breast cancer specimens: diffraction-enhanced 263R. A. Jong, M. J. Yaffe, M. Skarpathiotakis, R. S. Shumak, N. M. Dan- imaging with histologic correlation—improved conspicuity of lesion de- joux, A. Gunesekara, and D. B. Plewes, “Contrast-enhanced digital mam- tail compared with digital radiography,” Radiology 214͑3͒, 895–901 mography: Initial clinical experience,” Radiology 228͑3͒, 842–850 ͑2000͒. ͑2003͒. 283S. Fiedler, A. Bravin, J. Keyrilainen, M. Fernandez, P. Suortti, W. Thom- 264F. Diekmann, S. Diekmann, F. Jeunehomme, S. Muller, B. Hamm, and U. linson, M. Tenhunen, P. Virkkunen, and M. Karjalainen-Lindsberg, “Im- Bick, “Digital mammography using iodine-based contrast media: Initial aging lobular breast carcinoma: comparison of synchrotron radiation clinical experience with dynamic contrast medium enhancement,” Invest. DEI-CT technique with clinical CT, mammography and histology,” Phys. Radiol. 40͑7͒, 397–404 ͑2005͒. Med. Biol. 49͑2͒, 175–188 ͑2004͒. 265F. Diekmann, S. Diekmann, M. Taupitz, U. Bick, K. J. Winzer, C. Hutt- 284X. Wu and H. Liu, “A new theory of phase-contrast x-ray imaging based ner, S. Muller, F. Jeunehomme, and B. Hamm, “Use of iodine-based on Wigner distributions,” Med. Phys. 31͑9͒, 2378–2384 ͑2004͒. contrast media in digital full-field mammography—initial experience,” 285X. Wu and H. Liu, “Clinical implementation of x-ray phase-contrast im- Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 175͑3͒, 342–345 aging: theoretical foundations and design considerations,” Med. Phys. ͑2003͒. 30͑8͒, 2169–2179 ͑2003͒. 266C. Dromain, C. Balleyguier, S. Muller, M. C. Mathieu, F. Rochard, P. 286X. Wu and H. Liu, “Clarification of aspects in in-line phase-sensitive Opolon, and R. Sigal, “Evaluation of tumor angiogenesis of breast carci- x-ray imaging,” Med. Phys. 34͑2͒, 737–743 ͑2007͒. noma using contrast-enhanced digital mammography,” AJR, Am. J. 287F. Meng, A. Yan, G. Zhou, X. Wu, and H. Liu, “Development of a dual- Roentgenol. 187͑5͒, W528–537 ͑2006͒. detector X-ray imaging system for phase retrieval study,” Nucl. Instrum. 267M. Skarpathiotakis, M. J. Yaffe, A. K. Bloomquist, D. Rico, S. Muller, A. Methods Phys. Res. B 254͑2͒, 300–306 ͑2007͒. Rick, and F. Jeunehomme, “Development of contrast digital mammogra- 288A. Corlu, R. Choe, T. Durduran, K. Lee, M. Schweiger, S. R. Arridge, E. phy,” Med. Phys. 29͑10͒, 2419–2426 ͑2002͒. M. C. Hillman, and A. G. Yodh, “Diffuse optical tomography with spec- 268M. Saito, “Dual-energy approach to contrast-enhanced mammography us- tral constraints and wavelength optimization,” Appl. Opt. 44͑11͒, 2082– ing the balanced filter method: spectral optimization and preliminary 2093 ͑2005͒. phantom measurement,” Med. Phys. 34͑11͒, 4236–4246 ͑2007͒. 289S. Srinivasan, B. W. Pogue, B. Brooksby, S. Jiang, H. Dehghani, C. 269P. Baldelli, A. Bravin, C. Di Maggio, G. Gennaro, A. Sarnelli, A. Taibi, Kogel, W. A. Wells, S. Poplack, and K. D. Paulsen, “Near-infrared char- and M. Gambaccini, “Evaluation of the minimum iodine concentration acterization of breast tumors in-vivo using spectrally-constrained recon- for contrast-enhanced subtraction mammography,” Phys. Med. Biol. struction,” Technol. Cancer Res. Treat. 4͑5͒, 513–526 ͑2005͒. 51͑17͒, 4233–4251 ͑2006͒. 290S. Srinivasan, B. W. Pogue, S. Jiang, H. Dehghani, and K. D. Paulsen, 270F. Diekmann, A. Sommer, R. Lawaczeck, S. Diekmann, H. Pietsch, U. “Spectrally constrained chromophore and scattering near-infrared tomog- Speck, B. Hamm, and U. Bick, “Contrast-to-noise ratios of different ele- raphy provides quantitative and robust reconstruction,” Appl. Opt. 44͑10͒, ments in digital mammography: evaluation of their potential as new con- 1858–1869 ͑2005͒. trast agents,” Invest. Radiol. 42͑5͒, 319–325 ͑2007͒. 291N. Shah, A. E. Cerussi, D. Jakubowski, D. Hsiang, J. Butler, and B. J. 271R. Lawaczeck, F. Diekmann, S. Diekmann, B. Hamm, U. Bick, W. R. Tromberg, “Spatial variations in optical and physiological properties of Press, H. Schirmer, K. Schon, and H. J. Weinmann, “New contrast media healthy breast tissue,” J. Biomed. Opt. 9͑3͒, 534–540 ͑2004͒. designed for x-ray energy subtraction imaging in digital mammography,” 292R. L. van Veen, H. J. Sterenborg, A. W. Marinelli, and M. Menke- Invest. Radiol. 38͑9͒, 602–608 ͑2003͒. Pluymers, “Intraoperatively assessed optical properties of malignant and 272S. Suryanarayanan, I. Sechopoulos, S. Vedantham, and A. Karellas, “Fea- healthy breast tissue used to determine the optimum wavelength of con- sibility of low dose x-ray contrast enhanced digital mammography with trast for optical mammography,” J. Biomed. Opt. 9͑6͒, 1129–1136 ͑2004͒. gold nanoparticles,” Med. Phys. 34͑6͒, 2360 ͑2007͒. 293C. Zhou, R. Choe, N. Shah, T. Durduran, G. Yu, A. Durkin, D. Hsiang, R. 273S. C. Chen, A. K. Carton, M. Albert, E. F. Conant, M. D. Schnall, and A. Mehta, J. Butler, A. Cerussi, B. J. Tromberg, and A. G. Yodh, “Diffuse D. Maidment, “Initial clinical experience with contrast-enhanced digital optical monitoring of blood flow and oxygenation in human breast cancer breast tomosynthesis,” Acad. Radiol. 14͑2͒, 229–238 ͑2007͒. during early stages of neoadjuvant chemotherapy,” J. Biomed. Opt. 12͑5͒, 274S. Puong, X. Bouchevreau, N. Duchateau, R. Iordache, and S. Muller, 051903 ͑2007͒. “Optimization of beam parameters and iodine quantification in dual- 294V. Ntziachristos, A. G. Yodh, M. D. Schnall, and B. Chance, “MRI-

Medical Physics, Vol. 35, No. 11, November 2008 4897 A. Karellas and S. Vedantham: Breast cancer imaging: A perspective 4897

guided diffuse optical spectroscopy of malignant and benign breast le- phy,” Phys. Med. Biol. 52͑12͒, 3619–3641 ͑2007͒. sions,” Neoplasia 4͑4͒, 347–354 ͑2002͒. 304C. Li, H. Zhao, B. Anderson, and H. Jiang, “Multispectral breast imaging 295B. Brooksby, S. Jiang, H. Dehghani, B. W. Pogue, K. D. Paulsen, J. B. using a ten-wavelength, 64ϫ64 source/detector channels silicon Weaver, C. Kogel, and S. P. Poplack, “Combining near-infrared tomog- photodiode-based diffuse optical tomography system,” Med. Phys. 33͑3͒, raphy and magnetic resonance imaging to study in vivo breast tissue: 627–636 ͑2006͒. Implementation of a Laplacian-type regularization to incorporate mag- 305Q. Zhu, N. Chen, and S. H. Kurtzman, “Imaging tumor angiogenesis by netic resonance structure,” J. Biomed. Opt. 10͑5͒, 051504 ͑2005͒. use of combined near-infrared diffusive light and ultrasound,” Opt. Lett. 296B. Brooksby, B. W. Pogue, S. Jiang, H. Dehghani, S. Srinivasan, C. 28, 337–339 ͑2003͒. Kogel, T. D. Tosteson, J. Weaver, S. P. Poplack, and K. D. Paulsen, 306B. J. Tromberg, B. W. Pogue, K. D. Paulsen, A. G. Yodh, D. A. Boas, and “Imaging breast adipose and fibroglandular tissue molecular signatures by A. E. Cerussi, “Assessing the future of diffuse optical imaging technolo- using hybrid MRI-guided near-infrared spectral tomography,” Proc. Natl. gies for breast cancer management,” Med. Phys. 35͑6͒, 2443–2451 Acad. Sci. U.S.A. 103͑23͒, 8828–8833 ͑2006͒. ͑2008͒. 297C. M. Carpenter, B. W. Pogue, S. Jiang, H. Dehghani, X. Wang, K. D. 307A. Stojadinovic, A. Nissan, C. D. Shriver, E. A. Mittendorf, M. D. Akin, Paulsen, W. A. Wells, J. Forero, C. Kogel, J. B. Weaver, S. P. Poplack, V. Dickerson, S. Lenington, L. D. Platt, T. Stavros, S. R. Goldstein, O. and P. A. Kaufman, “Image-guided optical spectroscopy provides Moskovitz, Z. Gallimidi, S. I. Fields, A. Yeshaya, T. M. Allweis, R. molecular-specific information in vivo: MRI-guided spectroscopy of Manassa, T. Pappo, R. X. Ginor, R. B. D’Agostino, and D. Gur, “Elec- breast cancer hemoglobin, water, and scatterer size,” Opt. Lett. 32͑8͒, trical impedance scanning as a new breast cancer risk stratification tool 933–935 ͑2007͒. for young women,” J. Surg. Oncol. 97͑2͒, 112–120 ͑2008͒. 298V. Ntziachristos, A. G. Yodh, M. Schnall, and B. Chance, “Concurrent 308P. M. Meaney, M. W. Fanning, T. Raynolds, C. J. Fox, Q. Fang, C. A. MRI and diffuse optical tomography of breast after indocyanine green Kogel, S. P. Poplack, and K. D. Paulsen, “Initial clinical experience with enhancement,” Proc. Natl. Acad. Sci. U.S.A. 97͑6͒, 2767–2772 ͑2000͒. microwave breast imaging in women with normal mammography,” Acad. 299X. Gu, Q. Zhang, M. Bartlett, L. Schutz, L. L. Fajardo, and H. Jiang, Radiol. 14͑2͒, 207–218 ͑2007͒. “Differentiation of cysts from solid tumors in the breast with diffuse 309M. Lazebnik, L. McCartney, D. Popovic, C. B. Watkins, M. J. Lindstrom, optical tomography,” Acad. Radiol. 11͑1͒, 53–60 ͑2004͒. J. Harter, S. Sewall, A. Magliocco, J. H. Booske, M. Okoniewski, and S. 300B. J. Tromberg, A. Cerussi, N. Shah, M. Compton, A. Durkin, D. Hsiang, C. Hagness, “A large-scale study of the ultrawideband microwave dielec- J. Butler, and R. Mehta, “Imaging in breast cancer: diffuse optics in breast tric properties of normal breast tissue obtained from reduction surgeries,” cancer: detecting tumors in pre-menopausal women and monitoring neo- Phys. Med. Biol. 52͑10͒, 2637–2656 ͑2007͒. adjuvant chemotherapy,” Breast Cancer Research 7͑6͒, 279–285 ͑2005͒. 310M. Lazebnik, D. Popovic, L. McCartney, C. B. Watkins, M. J. Lindstrom, 301N. Shah, J. Gibbs, D. Wolverton, A. Cerussi, N. Hylton, and B. J. Trom- J. Harter, S. Sewall, T. Ogilvie, A. Magliocco, T. M. Breslin, W. Temple, berg, “Combined diffuse optical spectroscopy and contrast-enhanced D. Mew, J. H. Booske, M. Okoniewski, and S. C. Hagness, “A large-scale magnetic resonance imaging for monitoring breast cancer neoadjuvant study of the ultrawideband microwave dielectric properties of normal, chemotherapy: a case study,” J. Biomed. Opt. 10͑5͒, 051503 ͑2005͒. benign and malignant breast tissues obtained from cancer surgeries,” 302D. B. Jakubowski, A. E. Cerussi, F. Bevilacqua, N. Shah, D. Hsiang, J. Phys. Med. Biol. 52͑20͒, 6093–6115 ͑2007͒. Butler, and B. J. Tromberg, “Monitoring neoadjuvant chemotherapy in 311S. P. Poplack, T. D. Tosteson, W. A. Wells, B. W. Pogue, P. M. Meaney, breast cancer using quantitative diffuse optical spectroscopy: A case A. Hartov, C. A. Kogel, S. K. Soho, J. J. Gibson, and K. D. Paulsen, study,” J. Biomed. Opt. 9͑1͒, 230–238 ͑2004͒. “Electromagnetic breast imaging: results of a pilot study in women with 303G. Boverman, Q. Fang, S. A. Carp, E. L. Miller, D. H. Brooks, J. Selb, R. abnormal mammograms,” Radiology 243͑2͒, 350–359 ͑2007͒. H. Moore, D. B. Kopans, and D. A. Boas, “Spatio-temporal imaging of 312R. J. Brenner and Y. Parisky, “Alternative breast-imaging approaches,” the hemoglobin in the compressed breast with diffuse optical tomogra- Radiol. Clin. North Am. 45͑5͒, 907–923 ͑2007͒.

Medical Physics, Vol. 35, No. 11, November 2008 PET/CT in radiation oncology ͒ Tinsu Pana and Osama Mawlawi Department of Imaging Physics, M. D. Anderson Cancer Center, The University of Texas, Houston, Texas 77030 ͑Received 27 January 2008; revised 3 June 2008; accepted for publication 26 August 2008; published 14 October 2008͒ PET/CT is an effective tool for the diagnosis, staging and restaging of cancer patients. It combines the complementary information of functional PET images and anatomical CT images in one imaging session. Conventional stand-alone PET has been replaced by PET/CT for improved patient comfort, patient throughput, and most importantly the proven clinical outcome of PET/CT over that of PET and that of separate PET and CT. There are over two thousand PET/CT scanners installed worldwide since 2001. Oncology is the main application for PET/CT. Fluorine-18 deoxyglucose is the choice of radiopharmaceutical in PET for imaging the glucose uptake in tissues, correlated with an increased rate of glycolysis in many tumor cells. New molecular targeted agents are being developed to improve the accuracy of targeting different disease states and assessing therapeutic response. Over 50% of cancer patients receive radiation therapy ͑RT͒ in the course of their disease treatment. Clinical data have demonstrated that the information provided by PET/CT often changes patient management of the patient and/or modiﬁes the RT plan from conventional CT simulation. The application of PET/CT in RT is growing and will become increasingly important. Continuing improvement of PET/CT instrumentation will also make it easier for radiation oncologists to integrate PET/CT in RT. The purpose of this article is to provide a review of the current PET/CT technology, to project the future development of PET and CT for PET/CT, and to discuss some issues in adopting PET/CT in RT and potential improvements in PET/CT simulation of the thorax in radiation therapy. © 2008 American Association of Physicists in Medicine. ͓DOI: 10.1118/1.2986145͔

Key words: PET/CT, 4D CT, cine CT, MIP CT, average CT

I. INTRODUCTION raise their arms over the head during the PET/CT scan. The

1 CT images are adapted for attenuation correction and tumor PET/CT was developed in 1998. It was not until 2001 when 1 2 localization of the PET data. There are over 2000 PET/CT the first commercial PET/CT scanner became available. scanners installed worldwide, and stand-alone PET scanners Prior to the technology of PET/CT, the CT and the PET data have not been in production since 2006.5 Fluorine-18 deoxy- were acquired in two different scanners. Fusion of the PET glucose ͑18F-FDG͒ is the major radiopharmaceutical in and CT data was performed with software techniques.3 Reg- PET/CT and has been approved for diagnosis and staging of istration of the PET and CT data was more successful for the nonsmall-cell lung cancer ͑NSCLC͒, colorectal cancer, brain studies with rigid transformation4 but less accurate for esophageal cancer, head and neck cancer, lymphoma, and the other regions of the body, in particular in the thorax and melanoma since 1998.8 In addition, PET/CT has been ap- the abdomen, due to the difficulty in repositioning the patient in two separate sessions and the nonrigid nature of the proved for staging and restaging and for therapeutic monitor- 1,5 ing of breast cancer. organs. Average error in the fusion of separate PET and CT 18 brain images was in the order of 2–3 mm.3 This error in- The average F-FDG PET sensitivity and specificity ͑ creased to 5–11 mm when fusing separate PET and CT body across all oncology application are estimated at 84% based ͒ ͑ images of the thorax.6 The advent of PET/CT scanners has on 18 402 patient studies and 88% based on 14 264 patient ͒ 9 facilitated the hardware fusion of PET and CT data sets by studies , respectively, according to Gambhir et al. from a transporting the patient between the PET and CT compo- collection of 419 articles from 1993 to 2000. Specifically, the nents of the scanner without repeating patient setup. It has sensitivity of PET ranged from 84% to 86%, the specificity been shown that hardware fusion is more accurate than soft- ranged from 88% to 93%, and the accuracy ranged from 87% 9 ware fusion in diagnosis, staging and restaging of many can- to 90%. The addition of PET significantly improves the di- cer types, in particular in the area of tumor infiltration of agnosis of lung cancer with the sensitivity of 96% and speci- adjacent structures that could not be conclusively assessed ficity of 73% ͑as compared to sensitivity of 67% for CT using the separate CT and PET data.7 alone͒, and the staging with the sensitivity of 83% and speci- The fast scan speed of CT has shortened a normal imag- ficity of 91%, respectively ͑as compared to sensitivity of ing session of about 1 h with a stand-alone PET to less than 64% and specificity of 74% for CT alone͒. 30 min with a PET/CT. This time savings has a major impact The additional clinical values of PET/CT to PET alone or on patient comfort in particular for patients who may need to separate PET and CT have also been documented. The first

4955 Med. Phys. 35 „11…, November 2008 0094-2405/2008/35„11…/4955/12/$23.00 © 2008 Am. Assoc. Phys. Med. 4955 4956 T. Pan and O. Mawlawi: PET/CT in radiation oncology 4956 study was published by Kluetz et al.10 using the first proto- as opposed to the accurate setup of patients in the treatment type PET/CT scanner. It was found that hardware registration position with external laser lights and a flat table support enables physicians to more precisely discriminate between needed for radiation oncology. Collaboration between the physiologic and malignant 18F-FDG uptake and more accu- two disciplines is critical to the success of PET/CT for RT. rately localize lesions. Hany et al.11 compared the data of Application of PET/CT in nuclear medicine is a task of PET/CT and PET alone in 53 patients for the diagnosis or detection based on the standardized uptake value ͑SUV͒.60,61 suspicion of malignancy. Of 287 lesions, the sensitivity, The physicians can sometimes read through the artifacts such specificity, and accuracy increased from 90%, 93%, and 91% as the ones caused by respiratory motion,62–65 implanted for PET alone, to 98%, 99%, and 98% for PET/CT. Bar- metal such as dental filling,66–68 pace makers,69,70 Shalom et al.12 evaluated 204 patients with 586 suspicious prosthetics,71 and surgical clips, and intravenous72 or oral lesions by interpreting PET and CT data together or PET and contrast media.73 Radiation oncologists may not be familiar CT data separately. They found that interpretation of PET with the images in PET/CT imaging and their associated ar- and CT together provided additional information over the tifacts. They generally depend on the diagnosis and staging separate interpretation of PET and CT in 99 patients ͑49%͒ of the nuclear medicine physicians for RT planning.74–76 with 178 lesions ͑30%͒. PET/CT improved characterization Both the location and extent of tumor are critical in RT and of equivocal lesions as definitely benign in 10% of sites and may not be fully captured in the nuclear medicine report. In as definitely malignant in 5% of sites. The results of PET/CT addition, there is still no standard for delineating the gross had an impact on the management of 28 patients ͑14%͒. tumor volume ͑GTV͒ in PET images. The workstations used Lardinois et al.13 compared the diagnostic accuracy of for evaluating PET/CT images in nuclear medicine are usu- PET/CT with that of CT alone, that of PET alone, and that of ally not equipped with planning software utilities required conventional visual correlation of PET and CT in determin- for RT. Reproduction of SUV may be difficult once the ing the stage of disease in 50 patients with proven or sus- PET/CT images are transferred to planning workstations in pected NSCLC. PET/CT provided additional information in RT.77,78 It is critical to ensure the PET/CT scan data are 20 of 49 patients. PET/CT had better diagnostic accuracy and acquired, processed and transferred correctly for RT. more accurate nodal staging than CT alone, PET alone, or Migration from stand-alone PET to PET/CT has improved visual correlation of PET and CT. registration between the CT and PET data from hardware Over 50% of all patients with cancer receive radiation fusion, in particular in the area outside the thorax and the therapy ͑RT͒ during the course of their disease abdomen such us the head and neck area. However, PET/CT management.14 Applications of PET to RT have been re- has also introduced a new problem, namely the misalignment ported in head and neck,15–26 lung,19,27–40 breast,41 between the PET and CT data in the thorax and the abdomen esophageal,42,43 non-Hodgkin’s lymphoma,30,44 due to patient respiration and the different scan speeds of CT gynecologic,19,45 rectal,46,47 anal,19 and prostate with and PET.62–65,79–89 The first clinical investigation addressing 18F-choline.48 Studies have also found that PET has advan- the impact of misalignment was conducted by Osman et al.89 tages over CT in the standardization of volume They observed that curvelinear cold artifacts paralleling the delineation,29,49,50 in the reduction of the risk for geometrical dome of the diaphragm at the lung bases were frequently misses,36 in the reduction of mediastinal nodal failure rate,51 noted in PET/CT images. However, clinically they reported in the minimization of radiation dose to the nontarget that this artifact resulted in significant inaccurate localization organs,19,26,52 and in the assessment of tumor burden, blood of lesions for only 2% in a study of 300 patients. Gould et flow, tissue inflammation, and hypoxia.53–58 Integration of al.86 reported in a cohort of 259 patients for cardiac PET/CT functional PET data with anatomical CT data should be a imaging, 40% of the patient data exhibited false positive de- standard in RT.59 fects due to misalignment. It is evident from these two stud- There are some challenges in PET/CT imaging for RT. ies that the severity of misalignment is dependent on the area The most challenging one is with reimbursement. Many pa- of interest. Misalignment between PET and CT may not be a tients are referred to a PET scan for diagnosis before receiv- significant issue in a whole body PET/CT scan when the ing RT. The time between diagnosis and RT is too short for a lesions may not be in the lungs, liver, and esophageal and not second PET to be reimbursable. In this situation, the diag- close to the diaphragm. However, it becomes a significant nostic images of PET or PET/CT are fused using software issue in cardiac PET/CT imaging when the heart is right with the simulation CT images for RT. As of today, there is above the diaphragm. Coaching patients to breath-hold in an no reimbursement for a simulation PET/CT. Unlike a whole effort to mitigate the artifact was not very successful. In a body PET/CT for diagnosis, a simulation PET/CT only needs study of 100 patients undergoing PET/CT with breath-hold at to be performed with a limited coverage much like in a simu- midexpiration CT by Pan et al.,80 50% of the patients exhib- lation CT. A simulation PET/CT may be performed or em- ited the curvelinear cold artifacts in the PET images caused bedded in a whole body PET/CT scanner for staging, restag- by respiratory motion. In a recent study of 216 consecutive ing, or assessment of the treatment response in the course of patients undergoing free breathing CT in PET/CT by Chi et treatment. Integration of PET/CT in RT also involves at least al.,90 68% of the patient data exhibited either the curvelinear the following two disciplines of people working together: cold artifacts or tumor misalignment. Misalignment due to Nuclear medicine and radiation oncology. Patient throughput breathing has been shown to cause variation in SUV,80 criti- is an important concern in the practice of nuclear medicine, cal to delineation of gross tumor volume in the PET data. We

Medical Physics, Vol. 35, No. 11, November 2008 4957 T. Pan and O. Mawlawi: PET/CT in radiation oncology 4957

TABLE I. Properties of major PET detectors.

Relative light output Thickness for 90% Scintillator ͓NaI͑Tl͒=100͔ Decay time ͑ns͒ efﬁciency at 511 keV ͑cm͒

BGO 15 300 2.4 GSO 25 60 3.3 LSO, LYSO 80 40 2.7

will highlight and project the technology advancement of for identifying the first interaction of the photon and the PET/CT, propose imaging techniques that will help improve detector; and ͑5͒ reconstruction algorithm that models the registration of the PET and CT data in the thorax, and em- degradation from emission of the positron to detection of the phasize the particular requirements of PET/CT and for radia- photons and that is capable of deconvolving the degradation tion oncology. to improve the resolution. Noncolinearity and detector size are the predominant factors contributing to the degradation 5 II. PET DETECTOR of spatial resolution for the clinical PET scanner. Some preclinical PET scanners have been shown to achieve spatial The PET of a PET/CT scanner today is distinguished by resolution of 0.4 mm with a ring diameter of 2 cm and a the scintillator materials used for the detection of 511 keV detector size of 0.25 mm.98 The spatial resolution of the annihilation photons. The major materials are bismuth ger- clinical PET scanner is about 5–8 mm,99 and can still be minate oxide ͑BGO͒, gadolinium oxyorthosilicate ͑GSO͒, lu- improved in the future. The impact of improving spatial res- tetium oxyorthosilicate ͑LSO͒, and LYSO ͑LSO doped with 91–93,95–97 olution may be more significant in diagnosis than in RT. This a small amount of yttrium͒. BGO has a slow decay is mainly due to the clinical target volume and planning tar- time and a low light output leading to relatively poor timing get volume margins that are added to the GTV thereby re- and energy resolution. It has a high stopping power to cap- ducing the advantage of PET imaging resolution.77 ture most of the photons reaching the detector. The new materials of LSO and LYSO have a fast decay time and a high light output leading to improved timing and energy reso- IV. TIME-OF-FLIGHT PET lution. Their stopping power is slightly inferior to that of Conventional reconstruction of PET images assumes that BGO. Intermediate to both is GSO, which has a higher light the annihilation event of a positron and an electron detected output and a faster decay time than BGO and yet is not as by a pair of detector elements 180-deg apart, is equally likely efficient as BGO or LSO/LYSO in stopping the 511 keV to occur at any point along the line defined by this pair of photons. Table I lists the attributes of different detector ma- detector elements. This assumption has served well for many terial used in commercially available PET/CT scanners. It is years when detectors with short decay time, high light out- clear that LSO/LYSO has and will become the detector of put, and fast electronics were not available. The short decay choice in the future PET/CT as manufacturers have chosen time of new detector material such as LSO and LYSO com- either LSO or LYSO as their new PET scintillation material. bined with fast electronics has enabled time-of-flight ͑TOF͒ PET. The timing resolution to locate an annihilation event to 96 III. SPATIAL RESOLUTION OF PET within 5 mm of PET resolution is approximately 30 ps. The current commercial TOF PET has the timing resolution The limit spatial resolution of clinical PET scanners with 96 of about 600 ps ͑Ref. 100͒ and can locate an annihilation a ring diameter of 80 cm is about 2 mm. There are basi- event to within 18 cm which in turn improves contrast. The cally five factors that determine the spatial resolution: ͑1͒ gain in signal to noise ratio in PET images with TOF is positron range: the distance between the point of emission of proportional to the object size and inversely proportional to the positron to the point of annihilation of the positron with the timing resolution.100 Current technology of 600 ps timing the electron. The higher the kinetic energy of the positron, resolution shows improvement of signal to noise ratio for the longer is the distance to the site of annihilation. This large patients. The future improvement of timing resolution distance is depend on the isotope; ͑2͒ noncolinearity: devia- will further reduce noise and improve the signal to noise tion from the assumed emissions of two 511 keV photons at ratio for all patients. This benefit can also be translated into 180 deg from the point of annihilation. The larger the ring shorter scan time or reduced injected radiopharmaceutical diameter is; the more non-colinearity becomes; ͑3͒ detector dose to the patient and reduced radiation exposure to the geometry: smaller detector element of size d leads to better technologist. spatial resolution of size d/2; ͑4͒ photon interaction in the detector: Compton scattering is the dominate interaction between the 511 keV photon and the detector. Multiple inter- V. TWO-DIMENSIONAL AND THREE-DIMENSIONAL actions are required to stop the photon in the detector. Some PET IMAGING interactions may even spread over to adjacent detector ele- PET data can be acquired in two-dimensional ͑2D͒ or ments. Typical detector elements are in the size of 4–6 mm three-dimensional ͑3D͒ mode. In 2D mode, a collimation square and 2–3 cm thick.94 The result is some uncertainty ͑septa͒ is positioned between detector rings in the axial di-

Medical Physics, Vol. 35, No. 11, November 2008 4958 T. Pan and O. Mawlawi: PET/CT in radiation oncology 4958 rection. The collimation minimizes the scatter and provides a motion. 4D CT may be needed for accurate quantification of uniform sensitivity profile along the cranial-caudal direction. 4D PET data as each phase of PET data may need its own An overlap of only 1 cm is needed to compensate for the CT data for attenuation correction.108 Although, it is still lower sensitivity of the edge slices between two bed posi- cumbersome to acquire 4D PET data due to its prolonged tions in order to provide a uniform sensitivity along the axial acquisition time, it is expected that with the new LSO/LYSO direction in a whole body PET/CT scan. On the other hand, detector, large detector coverage for higher sensitivity, and 3D PET imaging does not utilize septa during data acquisi- the advent of 3D image reconstruction to better cope with the tion. It has higher sensitivity but more randoms and scatters increased noise from randoms and scatters in 3D data acqui- than 2D PET. Due to its nonuniform sensitivity profile ͑high sition, the limitation in acquisition time will be minimized at the center of the detector with a linear drop to the edge of and 4D PET will become a clinically feasible solution to the detector͒, it normally requires up to 50% detector overlap improving the quantification accuracy of tumor in motion. between two bed positions. With the improvement of 3D reconstruction techniques101 and better modeling of the randoms and scatters,102 it has been shown that 3D PET results VII. LARGE BORE PET/CT in better image quality than 2D PET with less injection of Most current commercially available PET/CT scanners 18F-FDG.103 This has resulted in lower radiation exposure to have a 70 cm bore size for both PET and CT scanners. Early the patients, nursing staff and technologists. Therefore, 3D models had a smaller bore size in PET than in CT.110 How- PET imaging is bound to become the standard mode of im- ever, it is clear that the bore size will have to increase to aging in the future. Some manufacturers of PET/CT scanners accommodate PET/CT simulation of the breast patients and provide 3D only capabilities on their systems. some large patients. The CT scanner of 85 cm bore size was introduced in 2000 to address this issue.111 Today most of the PET/CT scanners have 50 cm standard field of view in CT VI. FOUR-DIMENSIONAL PET IMAGING image reconstruction with up to 60–65 cm extended field of Four-dimensional ͑4D͒ PET was first developed for car- view reconstruction.110 This was accomplished by extrapolat- diac imaging to assess myocardial motion and to obtain ejec- ing the truncated projection data in CT normally in the tion fraction.104 It has been adopted for tumor imaging of the anterior-posterior views to match the total attenuation mea- thorax in the last several years.105–107 When data are acquired sured in the none-truncated projection data in the lateral in 4D or gated mode, the data are split into several exclusive views.112–114 This approach may not provide accurate CT bins. For example, there can be 8 bins of 500 ms for an numbers for RT. A correct solution to the truncation problem average respiratory cycle of 4 s. Because of insufficient sta- would be to increase the detector fan angle to avoid trunca- tistics of photons obtained in PET imaging of 3–6 min for tion by increasing the number of detector elements. One the 8 bins in each bed location, the duration of a 4D PET manufacturer has increased the detector size to better control scan is normally prolonged to over 10 min to compensate for the truncation problem up to 70 cm, and one manufacturer the fewer photons recorded in each bin. Image reconstruction has offered a PET/CT with 85 cm bore size for both PET and is performed on the data of each bin and the result is a set of CT. It is expected that bore size of 85 cm should become a 3D PET images over a respiratory cycle for the assessment standard and the CT detector size should be increased to of tumor motion and quantification. Even though, the num- accommodate up to 70 cm CT image reconstruction without ber of photons in each bin is small, resulting in higher noise truncation for RT. in the 4D images; the 4D images can potentially be used for accurate assessment of FDG uptake.108 4D PET has not taken off due to its complexity and limited workflow in which 4D VIII. MULTISLICE CT PET had to be performed in a separate session after a routine PET needs CT data for tumor localization, attenuation PET/CT scan on most of the PET/CT scanners, prolonging correction, and quantification. PET acquires data over the acquisition time and impacting patient comfort. In our 3–6 min for a 15-cm superior-inferior coverage.115 With a opinion, an ideal PET/CT imaging session should take less clinical whole-body scan from base of the skull to midthigh than 20 min. Any duration beyond that will increase the po- of about 100 cm, the acquisition time for PET data is about tential for patient motion. 18–21 min for 3 min/bed in 2D data acquisition. To improve PET/CT scanners have recently been equipped with list- the CT image quality of the thorax and the abdomen, the mode data acquisition whereby events from each coincidence patient is normally asked to raise his/her arms over the head pair of 511 keV photons are stored in a list stream for later during data acquisition of the CT and the PET data. In this reconstruction. It has been demonstrated that the list-mode position, an average person may not be able to remain sta- data acquisition can be performed with either cardiac or res- tionary for over 20 min. Figure 1 demonstrates an example piratory triggering during a normal static image of patient motion in the middle of a scan. If patient motion is acquisition.109 This functionality offers the capability of ret- not accounted for, the PET images may not be reliable for rospectively sorting the coincidence events into multiple diagnosis. Incorporation of CT has greatly improved the phases/bins for the reconstruction of 4D PET images. Cur- throughput of PET/CT scan and patient comfort when a CT rent PET scanners can be configured to acquire data which scan of 100 cm can be performed in less than 20 s on a can produce both static and 4D PET data to freeze tumor modern 16-slice PET/CT with good image quality.

Medical Physics, Vol. 35, No. 11, November 2008 4959 T. Pan and O. Mawlawi: PET/CT in radiation oncology 4959

FIG. 1. Effect of a patient motion at the 9th min during a single bed acquisition of 15 min. The CT ͑before PET scan͒ and PET images of the ﬁrst 9 min were in ͑a͒ and ͑b͒, respectively. The CT ͑after PET scan͒ and PET images of the last 6 min were in ͑c͒ and ͑d͒, respectively. The mean SUVs of the region of interest pointed by the arrow were 2.7 in ͑b͒, 1.2 in ͑d͒ and 2.1 in ͑e͒ of total 15 min acquisition.

The first prototype PET/CT was with a single-slice CT imaging. Both applications are critical to RT. ͑SSCT͒,1 which was the major CT scanner in diagnostic radiology at the time. A CT scan would take 5–10 min with this prototype PET/CT.10 Today almost all the PET/CT scan- IX. AVERAGE CT ners are with multislice CT ͑MSCT͒, and the number of de- The issue of potential misalignment between the CT and tector channels or slices has increased from 2 to 64 in the last the PET data in the thorax and the abdomen was discovered several years. In general, 16-slice CT is sufficient for tumor soon after PET/CT was introduced, and has become the most imaging and 64-slice CT is necessary for coronary artery CT widely addressed issue in PET/CT.5,65,79,80,85,86,89,116–119 imaging of the heart. A 64-slice CT can provide high spatial MSCT normally acquires data at a very high temporal reso- resolution of 0.5 mm in 3D, fast temporal resolution of lution of less than 1 s, while PET acquires data in several 100–200 ms at a gantry rotation cycle time of less than min.65,85 Mismatch in temporal resolution leads to a potential 0.35 s, and short breath-hold time of less than 10 s, critical mismatch of the tumor positions between the CT and the to coronary artery imaging. One vendor has made available PET data, and compromises the quantification of the PET 320-slice CT of 16 cm coverage to image the heart in a data and the determination of PET GTV. Current design of single gantry rotation. Perfusion CT, which requires a cine PET/CT only matched the spatial resolutions of CT and PET scan of over 30–50 s at the same location for assessing the by blurring the CT images to match the PET images in spa- function of tumor by analyzing the dynamics of injected io- tial resolution.94 No attempt has been made to match the dine contrast in and out of the tumor, may require more than temporal resolutions of CT and PET. 64 slices for its expanded coverage of more than 4 cm. A Since the PET data is time averaged, it was recognized 16-slice CT covers only 2–2.4 cm per gantry rotation. Incor- that PET data can be a more accurate representation of the poration of MSCT in PET/CT has and will have a profound 3D volume encompassing the tumor motion.120 However, impact on improving the registration between the CT and the quantification of the PET data relies on the CT data. If the PET data, and the assessment of tumor motion in 4D CT CT data are not matched with the PET data in position, quan-

Medical Physics, Vol. 35, No. 11, November 2008 4960 T. Pan and O. Mawlawi: PET/CT in radiation oncology 4960

(A)

(B)

18 FIG. 2. Effect of misalignment to the assessment of lymph node F-FDG uptake. The CT, PET corrected with the CT, and fused PET-CT images with misalignment were in ͑a͒ from left to right. The ACT, PET corrected with the ACT, and fused PET-CT images in ͑b͒. The maximum SUV of the lymph node identified by a cross was 4.6 in ͑a͒ and 7.5 in ͑b͒. The misalignment caused the change of maximum SUV by 63%. (C) tification of the PET data will be compromised. The impact becomes severe when the tumor is near the diaphragm such FIG. 3. The PET/CT images of a 69 year-old female patient with an esophageal tumor after an induction chemotherapy. ͑a͒ shows an axial slice of the as some lung, liver, and esophageal tumors. fused clinical CT and PET image at the level of the esophageal tumor ͑left͒ Mismatch between the CT and PET data can be identified and the PET image in coronal view ͑right͒. The radiology report indicated by a curvelinear cold artifact paralleling the dome of the the patient had a positive response to the chemotherapy. After removal of diaphragm at the lung bases or photopenic region in the PET misalignment by the AVG CT, the tumor reappeared in the same PET data set in ͑b͒. The arrows point to the tumor location. The gross target volumes images. We normally spend more time in exhale than in in- drawn in the images of ͑a͒ and ͑b͒ are shown in blue and in green, respec- hale. The PET data averaged over several minutes is closer to tively, in ͑c͒. The patient was treated with the tumor volume in green, and the end-expiration than end-inspiration phase. If the CT data the radiology report was corrected by the AVG CT. are acquired in or near the end-inspiration phase, the inflated lung due to inspiration will be bigger than the deflated lung. The larger area of the inflated lungs in CT renders less at- discouraged.79,121 Figure 4 shows a clinic example of the tenuation correction in the reconstruction of the PET data same patient scanned with slow-scan CT of 4 s and ACT of resulting in a photopenic region identified as the misaligned fast gantry rotation of 0.5 s for 4 s. Cine-CT and low-pitch region. Several measures have been proposed to mitigate this helical CT ͑pitchϽ0.1͒ scans can be adopted to obtain ACT problem. Coaching patient to hold-breath at midexpiration and both have been utilized in 4D CT imaging.122–124 How- during CT acquisition was suggested,62 and the outcomes ever, it is not clear whether the setup of 4D CT imaging for were mixed because coaching patient to hold breath at cer- the assessment of tumor motion is ideal for obtaining ACT tain state may not be reliable both from the patient and the when the majority of PET/CT scanners are in nuclear medi- technologist operating the PET/CT scanner perspectives. An- cine and are without a respiratory monitoring device for 4D other approach to improve registration between the CT and CT. A practical approach is to acquire ACT without a respi- the PET data is to bring the temporal resolution of the CT ratory monitoring device to improve quantification of the images to that of the PET data.80 Recognizing the fact that PET data.79,125 The additional radiation dose for ACT was PET is averaged over many breath cycles, an average CT estimated to be from 5 to 50 mGy and the additional scan ͑ACT͒ image of about one breath cycle has been shown to time is less than a couple of minutes and will not signifi- improve registration between the CT and the PET data. Fig- cantly impact the overall scan time of a PET/CT procedure. ures 2 and 3 show two examples of misalignemnt between ACT can also be derived from 4D CT, incorporation of ACT the CT and the PET data corrected by ACT to improve the for attenuation correction of the PET data should be made assessment of lymph node 18F-FDG uptake and the accuracy available in the future. ACT can also be used for dose calcu- of tumor targeting for RT. This concept has also been shown lation due to its time-averaging of CT numbers.126 Selection effective in improving registration between the CT and the of optimum parameters for acquiring ACT with cine-CT or PET data in cardiac PET/CT imaging.79 low-pitch helical CT has also been investigated.88 Acquiring ACT can be accomplished by scanning at the MSCT can acquire the ACT data over the chest and the same slice location over a breath cycle at a very high speed abdomen in less than a couple of minutes due to its large gantry rotation for a subsecond temporal resolution. The CT detector coverage over SSCT. It can also provide a sequence images, almost free of motion artifacts, in a respiratory cycle of almost motion-free cine CT images at the same slice lo- are averaged for ACT. The conventional approach with slow- cation due to its subsecond gantry rotation. The marriage of scan CT for ACT is ineffective and should be MSCT and PET in PET/CT thus has provided a platform for

Medical Physics, Vol. 35, No. 11, November 2008 4961 T. Pan and O. Mawlawi: PET/CT in radiation oncology 4961

FIG. 4. The RACT and the SSCT images of a patient with an average breath cycle of 4 s. The SSCT images in ͑a͒ were taken with one single CT gantry rotation of 4 s, and the two images were 2.5 mm apart and 2.5 mm thick. The corresponding RACT images in ͑b͒, obtained by averaging the cine CT images, were averaged from 4 s of data collection over eight gantry rotations. The ACT images were almost free of reconstruction artifacts, which were observedin the SSCT images ͑reproduced from Fig. 11 of Ref. 79͒.

registration of the CT and the PET data, directly impacting XI. 4D CT IMAGING RT. 4D CT ͑Refs. 122–124͒ has found its acceptance in RT for providing the gated CT images of multiple phases over a respiratory cycle to assist contouring the extent of tumor motion. 4D CT takes less time in acquisition than 4D PET X. MAXIMUM INTENSITY PROJECTION CT does. It normally takes less than 2 min ͑like ACT͒ to cover Maximum intensity projection ͑MIP͒ CT images can be 40 cm in the superior-inferior direction on an 8- or 16-slice derived by finding the maximum pixel value at each pixel CT. Two data acquisition modes have been used in 4D CT. location from all the phases of 4D CT ͑Ref. 123͒ or cine CT One is cine CT and the other one is low-pitch helical CT. 125 Both acquisitions scan any point in space for over one breath images. It has been shown that MIP CT images are effec- ͑ / ͒ tive in depicting the extent of tumor motion.127,128 For pe- cycle plus one or 2 3 gantry rotation cycle. Cine CT uses ripheral lung tumors ͑surrounded by the lower density air in less radiation and generates thinner slices than low-pitch he- ͒ lical CT. On the other hand, low-pitch helical CT has an the lungs , MIP CT images can be used to assist the deter- 131 mination of the tumor target volume and to avoid ambiguity advantage over cine CT in acquisition time. The cine CT in using a threshold of SUV to determine the target volume based 4D CT is available on 4, 8, 16, and 64-slice CT scan- in PET. Any 18F-FDG uptake in the lungs should be sup- ners, and the low pitch helical CT based 4D CT is only ported by tissues with or without motion. Any PET GTV available on newer 16- and 64-slice CT scanners. Multislice determined with a threshold should not exceed the boundary CT has significantly improved the speed of 4D CT data ac- in the MIP images. Both MIP and ACT images can be de- quisition and made 4D CT clinically acceptable. It is ex- rived without gating.79,125 Their application for treatment pected that 4D CT will become an integral part of PET/CT planning for stereotactic RT has been demonstrated.129 Their imaging of the thorax and 4D CT will be incorporated in the applications for PET/CT in RT are expected to become im- quantification of 4D PET as each phase of gated PET image portant as they can be applicable to most of the PET/CT needs its own gated CT image for attenuation correction.108,132–134 The ACT and MIP images can be de- scanners without the hardware setup for 4D CT. MIP CT can 125 help determine the tumor volume in the thorax. Figure 5 rived from 4D CT or directly from cine CT. shows an example of determining the extent of PET GTV with MIP CT. A similar concept has been attempted with XII. DETERMINATION OF TUMOR CONTOUR IN regular helical CT data for peripheral NSCLC by Biehl et PET al.,130 when the boarder of the tumor can be identified by the Determination of tumor volume in PET image is normally helical CT data. performed with SUV threshold͑s͒. This is an important yet

Medical Physics, Vol. 35, No. 11, November 2008 4962 T. Pan and O. Mawlawi: PET/CT in radiation oncology 4962

FIG. 5. The MIP CT and PET images of a patient. The MIP CT in ͑a͒ is displayed with ͑window,level͒=͑400,40͒ and PET in ͑b͒ with the highest intensity=40% of the maximum SUV in the tumor. The images of ͑a͒ and ͑b͒ are displayed again with ͑1000,−700͒ in ͑c͒ and the highest density=20% in ͑d͒, respectively. The tumor contour in ͑c͒ is superimposed in ͑a͒, ͑b͒, and ͑d͒ to demonstrate the effect on tumor size by display parameters. controversial issue, in particular for the lung tumors im- will be a very active area of research. Input from MIP and pacted by the respiratory motion. To determine the gross tu- 4D CT images will be very important and complementary to mor volume in PET, it is generally based on the visual inter- this endeavor. Contouring a tumor in PET/CT images should pretation by the experienced nuclear medicine physician.35 be an integral process with complementary inputs of both Some suggested an absolute threshold of 2.5,37,135 or a PET and CT images. threshold between 15% and 50% of the maximum SUV 27,35,37,136–138 130 ͑mSUV͒. Recent studies by Biehl et al. and XIII. WORKFLOW Nestle et al.78 suggested that no single SUV can reliably be PET/CT simulation of the chest and abdomen poses a used for segmentation of the PET tumor volume, and that an challenge for registration of the CT and the PET data. We individualized threshold should be derived in consideration can acquire the list mode PET data with the physiologic trig- of the size, location, nonuniform distribution of 18F-FDG gers of respiratory or cardiac nature. Two sets of PET data activity of the tumor. Most of the discussions have been with can be reconstructed: one to generate the static PET data for the data of stand-alone PET. The issue may be further com- an initial whole-body diagnosis; and the other to generate a plicated in PET/CT. Any misalignment can further compro- gated or 4D PET data over a certain anatomical region using mise the quantiﬁcation of the PET data. Erdi et al.132 re- the list mode data and physiologic triggers. Static PET data ported that different phases of 4D CT image can cause up to should be attenuation corrected with ACT. 4D PET data 24% variation of mSUV in the PET data. Pan et al.80 ob- should be corrected with 4D CT data. The images for radia- served a variation of more than 50% mSUV between the tion therapy should be free of misalignment and truncation PET data with ACT and the same PET data with helical CT. artifacts which can be accomplished using a large bore Chi et al.90 investigated the effects of misalignment to the PET/CT and a large detector CT, respectively. All the data determination of PET GTV and found that GTV centroid acquisition should be performed in 20 min to improve pa- location could shift by 2.4 mm and GTV volume change tient comfort and avoid potential patient motion. could be as high as 154% for the tumors of less than 50 cm3. Partial volume also impacts the determination of SUV. Partial volume is caused by the limited spatial resolution of XIV. SUMMARY PET scanners ͑5–8 mm͒, and renders a blurry look of the There has been a tremendous growth in the use of PET image. Partial volume mostly affects smaller tumor PET/CT scanners over the past several years. The combina- sizes of less than 1–1.6 cm or 2 times the PET resolution. In tion of faster detector of LSO/LYSO and faster electronics addition, studies have shown that SUV is a function of up- has made the TOF PET/CT feasible in improving the image take time between injection of 18F-FDG and data quality of PET. The improvement in 3D reconstruction with acquisition.61,139,140 Care should be taken to ensure the same accurate modeling of randoms and scatters has also made 3D uptake time for the same patient imaged in a multiple of PET more attractive than 2D PET. The beneﬁts of 3D include PET/CT sessions during the course of diagnosis, treatment, the reduction of both the injected radiopharmaceutical dose and staging. Tumor volume determined by PET may be more to the patient and the radiation exposure to the nursing staff indicative of the GTV plus motion since PET data are ac- and the technologists. The large bore PET/CT and the large quired over several min. PET GTV delineation has been and detector CT will make the positioning of a large patient in

Medical Physics, Vol. 35, No. 11, November 2008 4963 T. Pan and O. Mawlawi: PET/CT in radiation oncology 4963 the scanner much easier and minimize the truncation of CT Davis, U. M. Lutolf, T. F. Hany, and I. F. Ciernik, “PET/CT staging ͑ ͒ images, respectively. Application of PET/CT for radiation followed by intensity-modulated radiotherapy IMRT improves treatment outcome of locally advanced pharyngeal carcinoma: A matched-pair com- therapy is expected to grow albeit there are some challenges. parison,” Radiat. Oncol. Invest. June 2–22 ͑2007͒. Reimbursement would be feasible when more clinical data to 17D. Wang et al., “Initial experience of FDG-PET/CT guided IMRT of support PET/CT simulation become available. A similar head-and-neck carcinoma,” Int. J. Radiat. Oncol., Biol., Phys. 65, 143– ͑ ͒ challenge was experienced during the adaptation of CT simu- 151 2006 . 18A. C. Riegel, A. M. Berson, S. Destian, T. Ng, L. B. Tena, R. J. Mitnick, lation in the 1990s when the radiation oncologists were not and P. S. Wong, “Variability of gross tumor volume delineation in head- familiar with GTV delineation on the CT images. With the and-neck cancer using CT and PET/CT fusion,” Int. J. Radiat. Oncol., development of 4D CT, the difficulties in the simulation of Biol., Phys. 65, 726–732 ͑2006͒. 19 the thorax and abdomen have largely been minimized. Fur- I. F. Ciernik, E. Dizendorf, B. G. Baumert, B. Reiner, C. Burger, J. B. Davis, U. M. Lutolf, H. C. Steinert, and G. K. Von Schulthess, “Radiation ther improvement in registration of the PET and CT data by treatment planning with an integrated positron emission and computer ACT, MIP, 4D CT, and 4D PET will improve the registration tomography ͑PET/CT͒: A feasibility study,” Int. J. Radiat. Oncol., Biol., in the thorax and the abdomen. Furthermore, data acquisition Phys. 57, 853–863 ͑2003͒. 20 should be less than 20 min to simulate the patient condition M. R. Vernon, M. Maheshwari, C. J. Schultz, M. A. Michel, S. J. Wong, B. H. Campbell, B. L. Massey, J. F. Wilson, and D. Wang, “Clinical in a treatment session. outcomes of patients receiving integrated PET/CT-guided radiotherapy for head and neck carcinoma,” Int. J. Radiat. Oncol., Biol., Phys. 70, ͒ a Author to whom correspondence should be addressed. Present address: 678–684 ͑2008͒. The University of Texas, M.D. Anderson Cancer Center, Department of 21H. Ashamalla, A. Guirgius, E. Bieniek, S. Rafla, A. Evola, G. Goswami, Imaging Physics—Unit 56, 1515 Holcome Blvd., Houston, TX 77030. R. Oldroyd, B. Mokhtar, and K. Parikh, “The impact of positron emission Telephone: 713-563-2714; Fax: 713-563-2720. Electronic mail: tomography/computed tomography in edge delineation of gross tumor [email protected] volume for head and neck cancers,” Int. J. Radiat. Oncol., Biol., Phys. 68, 1T. Beyer, D. W. Townsend, T. Brun, P. E. Kinahan, M. Charron, R. 388–395 ͑2007͒. Roddy, J. Jerin, J. Young, L. Byars, and R. Nutt, “A combined PET/CT 22P. H. Ahn and M. K. Garg, “Positron emission tomography/computed scanner for clinical oncology,” J. Nucl. Med. 41, 1369–1379 ͑2000͒. tomography for target delineation in head and neck cancers,” Semin Nucl. 2D. W. Townsend and T. Beyer, “A combined PET/CT scanner: The path Med. 38, 141–148 ͑2008͒. to true image fusion,” Br. J. Radiol. 75, S24–S30 ͑2002͒. 23B. Dietl and J. Marienhagen, “The therapeutic impact of ͑18͒F-FDG 3B. F. Hutton and M. Braun, “Software for image registration: Algorithms, whole body PET. A radiooncologist’s view,” Nuklearmedizin 44, 8–14 accuracy, efficacy,” Semin Nucl. Med. 33, 180–192 ͑2003͒. ͑2005͒. 4J. West et al., “Comparison and evaluation of retrospective intermodality 24X. K. Zheng, L. H. Chen, Q. S. Wang, H. B. Wu, H. M. Wang, Y. Q. brain image registration techniques,” J. Comput. Assist. Tomogr. 21, 554– Chen, W. P. Yan, Q. S. Li, and Y. K. Xu, “Influence of FDG-PET on 566 ͑1997͒. computed tomography-based radiotherapy planning for locally recurrent 5D. W. Townsend, “Positron emission tomography/computed tomogra- nasopharyngeal carcinoma,” Int. J. Radiat. Oncol., Biol., Phys. 69, 1381– phy,” Semin Nucl. Med. 38, 152–166 ͑2008͒. 1388 ͑2007͒. 6R. L. Wahl, L. E. Quint, R. D. Cieslak, A. M. Aisen, R. A. Koeppe, and 25R. H. Ireland, K. E. Dyker, D. C. Barber, S. M. Wood, M. B. Hanney, W. C. R. Meyer, “‘Anatometabolic’ tumor imaging: Fusion of FDG PET with B. Tindale, N. Woodhouse, N. Hoggard, J. Conway, and M. H. Robinson, CT or MRI to localize foci of increased activity,” J. Nucl. Med. 34, “Nonrigid image registration for head and neck cancer radiotherapy treat- 1190–1197 ͑1993͒. ment planning with PET/CT,” Int. J. Radiat. Oncol., Biol., Phys. 68, 7P. Reinartz, F. J. Wieres, W. Schneider, A. Schur, and U. Buell, “Side-by- 952–957 ͑2007͒. side reading of PET and CT scans in oncology: Which patients might 26D. L. Schwartz et al., “FDG-PET/CT-guided intensity modulated head profit from integrated PET/CT?,” Eur. J. Nucl. Med. Mol. Imaging 31, and neck radiotherapy: A pilot investigation,” Head Neck 27, 478–487 1456–1461 ͑2004͒. ͑2005͒. 8E. M. Rohren, T. G. Turkington, and R. E. Coleman, “Clinical applica- 27L. J. Vanuytsel, J. F. Vansteenkiste, S. G. Stroobants, P. R. De Leyn, W. tions of PET in oncology,” Radiology 231, 305–332 ͑2004͒. De Wever, E. K. Verbeken, G. G. Gatti, D. P. Huyskens, and G. J. 9S. S. Gambhir, J. Czernin, J. Schwimmer, D. H. Silverman, R. E. Cole- Kutcher, “The impact of ͑18͒F-fluoro-2-deoxy-D-glucose positron emis- man, and M. E. Phelps, “A tabulated summary of the FDG PET litera- sion tomography ͑FDG-PET͒ lymph node staging on the radiation treat- ture,” J. Nucl. Med. 42, 1S–93S ͑2001͒. ment volumes in patients with non-small cell lung cancer,” Radiother. 10P. G. Kluetz, C. C. Meltzer, V. L. Villemagne, P. E. Kinahan, S. Chander, Oncol. 55, 317–324 ͑2000͒. M. A. Martinelli, and D. W. Townsend, “Combined PET/CT imaging in 28J. Y. Chang, L. Dong, H. Liu, G. Starkschall, P. Balter, R. Mohan, Z. oncology. Impact on patient management,” Clin Positron Imaging 3, 223– Liao, J. D. Cox, and R. Komaki, “Image-guided radiation therapy for 230 ͑2000͒. non-small cell lung cancer,” J. Thorac. Oncol. 3, 177–186 ͑2008͒. 11T. F. Hany, H. C. Steinert, G. W. Goerres, A. Buck, and G. K. von 29H. Ashamalla, S. Rafla, K. Parikh, B. Mokhtar, G. Goswami, S. Kambam, Schulthess, “PET diagnostic accuracy: Improvement with in-line PET-CT H. Abdel-Dayem, A. Guirguis, P. Ross, and A. Evola, “The contribution system: Initial results,” Radiology 225, 575–581 ͑2002͒. of integrated PET/CT to the evolving definition of treatment volumes in 12R. Bar-Shalom, N. Yefremov, L. Guralnik, D. Gaitini, A. Frenkel, A. radiation treatment planning in lung cancer,” Int. J. Radiat. Oncol., Biol., Kuten, H. Altman, Z. Keidar, and O. Israel, “Clinical performance of Phys. 63, 1016–1023 ͑2005͒. PET/CT in evaluation of cancer: Additional value for diagnostic imaging 30E. Brianzoni et al., “Radiotherapy planning: PET/CT scanner perfor- and patient management,” J. Nucl. Med. 44, 1200–1209 ͑2003͒. mances in the definition of gross tumour volume and clinical target vol- 13D. Lardinois, W. Weder, T. F. Hany, E. M. Kamel, S. Korom, B. Seifert, ume,” Eur. J. Nucl. Med. Mol. Imaging 32, 1392–1399 ͑2005͒. G. K. von Schulthess, and H. C. Steinert, “Staging of non-small-cell lung 31D. De Ruysscher et al., “Effects of radiotherapy planning with a dedi- cancer with integrated positron-emission tomography and computed to- cated combined PET-CT-simulator of patients with non-small cell lung mography,” N. Engl. J. Med. 348, 2500–2507 ͑2003͒. cancer on dose limiting normal tissues and radiation dose-escalation: A 14V. Gregoire, K. Haustermans, X. Geets, S. Roels, and M. Lonneux, “PET- planning study,” Radiother. Oncol. 77,5–10͑2005͒. based treatment planning in radiotherapy: A new standard?,” J. Nucl. 32A. H. Klopp, J. Y. Chang, S. L. Tucker, E. P. Sulman, P. A. Balter, H. H. Med., Suppl. 48, 68S–77S ͑2007͒. Liu, M. K. Bucci, H. A. Macapinlac, R. Komaki, and J. D. Cox, “In- 15F. Paulsen, J. Scheiderbauer, S. M. Eschmann, K. Brechtel, M. Klein, C. trathoracic patterns of failure for non-small-cell lung cancer with Pfannenberg, A. Mondry, T. Hehr, C. Belka, and M. Bamberg, “First positron-emission tomography/computed tomography-defined target de- experiences of radiation treatment planning with PET/CT,” Strahlenther. lineation,” Int. J. Radiat. Oncol., Biol., Phys. 69, 1409–1416 ͑2007͒. Onkol. 182, 369–375 ͑2006͒. 33C. Greco, K. Rosenzweig, G. L. Cascini, and O. Tamburrini, “Current 16S. Rothschild, G. Studer, B. Seifert, P. Huguenin, C. Glanzmann, J. B. status of PET/CT for tumour volume definition in radiotherapy treatment

Medical Physics, Vol. 35, No. 11, November 2008 4964 T. Pan and O. Mawlawi: PET/CT in radiation oncology 4964

planning for non-small cell lung cancer ͑NSCLC͒,” Lung Cancer 57, ing tumor volumes for non-small-cell lung cancer?,” Int. J. Radiat. On- 125–134 ͑2007͒. col., Biol., Phys. 62, 70–75 ͑2005͒. 34G. L. Ceresoli, G. M. Cattaneo, P. Castellone, G. Rizzos, C. Landoni, V. 51D. De Ruysscher et al., “Selective mediastinal node irradiation based on Gregorc, R. Calandrino, E. Villa, C. Messa, A. Santoro, and F. Fazio, FDG-PET scan data in patients with non-small-cell lung cancer: A pro- “Role of computed tomography and ͓18F͔ fluorodeoxyglucose positron spective clinical study,” Int. J. Radiat. Oncol., Biol., Phys. 62, 988–994 emission tomography image fusion in conformal radiotherapy of non- ͑2005͒. small cell lung cancer: A comparison with standard techniques with and 52A. van Baardwijk, B. G. Baumert, G. Bosmans, M. van Kroonenburgh, S. without elective nodal irradiation,” Tubercle 93,88–96͑2007͒. Stroobants, V. Gregoire, P. Lambin, and D. De Ruysscher, “The current 35U. Nestle et al., “18F-deoxyglucose positron emission tomography ͑FDG- status of FDG-PET in tumour volume definition in radiotherapy treatment PET͒ for the planning of radiotherapy in lung cancer: High impact in planning,” Cancer Treat Res. 32, 245–260 ͑2006͒. patients with atelectasis,” Int. J. Radiat. Oncol., Biol., Phys. 44, 593–597 53R. D. Stewart and X. A. Li, “BGRT: Biologically guided radiation ͑1999͒. therapy—The future is fast approaching,” Med. Phys. 34, 3739–3751 36Y. E. Erdi, K. Rosenzweig, A. K. Erdi, H. A. Macapinlac, Y. C. Hu, L. E. ͑2007͒. Braban, J. L. Humm, O. D. Squire, C. S. Chui, S. M. Larson, and E. D. 54C. C. Ling, J. Humm, S. Larson, H. Amols, Z. Fuks, S. Leibel, and J. A. Yorke, “Radiotherapy treatment planning for patients with non-small cell Koutcher, “Towards multidimensional radiotherapy ͑MD-CRT͒: Biologi- lung cancer using positron emission tomography ͑PET͒,” Radiother. On- cal imaging and biological conformality,” Int. J. Radiat. Oncol., Biol., col. 62,51–60͑2002͒. Phys. 47, 551–560 ͑2000͒. 37J. Bradley, W. L. Thorstad, S. Mutic, T. R. Miller, F. Dehdashti, B. A. 55C. C. Ling and X. A. Li, “Over the next decade the success of radiation Siegel, W. Bosch, and R. J. Bertrand, “Impact of FDG-PET on radiation treatment planning will be judged by the immediate biological response therapy volume delineation in non-small-cell lung cancer,” Int. J. Radiat. of tumor cells rather than by surrogate measures such as dose maximiza- Oncol., Biol., Phys. 59, 78–86 ͑2004͒. tion and uniformity,” Med. Phys. 32, 2189–2192 ͑2005͒. 38F. M. Kong, K. A. Frey, L. E. Quint, R. K. Ten Haken, J. A. Hayman, M. 56K. S. Chao, W. R. Bosch, S. Mutic, J. S. Lewis, F. Dehdashti, M. A. Kessler, I. J. Chetty, D. Normolle, A. Eisbruch, and T. S. Lawrence, “A Mintun, J. F. Dempsey, C. A. Perez, J. A. Purdy, and M. J. Welch, “A pilot study of ͓18F͔fluorodeoxyglucose positron emission tomography novel approach to overcome hypoxic tumor resistance: Cu-ATSM-guided scans during and after radiation-based therapy in patients with non small- intensity-modulated radiation therapy,” Int. J. Radiat. Oncol., Biol., Phys. cell lung cancer,” J. Clin. Oncol. 25, 3116–3123 ͑2007͒. 49, 1171–1182 ͑2001͒. 39M. P. Mac Manus, R. J. Hicks, D. L. Ball, V. Kalff, J. P. Matthews, E. 57Z. Lin, J. Mechalakos, S. Nehmeh, H. Schoder, N. Lee, J. Humm, and C. Salminen, P. Khaw, A. Wirth, D. Rischin, and A. McKenzie, “F-18 fluo- C. Ling, “The influence of changes in tumor hypoxia on dose-painting rodeoxyglucose positron emission tomography staging in radical radio- treatment plans based on ͑18͒F-FMISO positron emission tomography,” therapy candidates with nonsmall cell lung carcinoma: Powerful correla- Int. J. Radiat. Oncol., Biol., Phys. 70, 1219–1228 ͑2008͒. tion with survival and high impact on treatment,” Cancer 92, 886–895 58I. Serganova, J. Humm, C. Ling, and R. Blasberg, “Tumor hypoxia im- ͑2001͒. aging,” Clin. Cancer Res. 12, 5260–5264 ͑2006͒. 40M. T. Munley, L. B. Marks, C. Scarfone, G. S. Sibley, E. F. Patz, Jr., T. G. 59K. Mah, C. B. Caldwell, Y. C. Ung, C. E. Danjoux, J. M. Balogh, S. N. Turkington, R. J. Jaszczak, D. R. Gilland, M. S. Anscher, and R. E. Ganguli, L. E. Ehrlich, and R. Tirona, “The impact of ͑18͒FDG-PET on Coleman, “Multimodality nuclear medicine imaging in three-dimensional target and critical organs in CT-based treatment planning of patients with radiation treatment planning for lung cancer: Challenges and prospects,” poorly defined non-small-cell lung carcinoma: A prospective study,” Int. Lung Cancer 23, 105–114 ͑1999͒. J. Radiat. Oncol., Biol., Phys. 52, 339–350 ͑2002͒. 41E. C. Ford, W. C. Lavely, D. A. Frassica, L. T. Myers, F. Asrari, R. L. 60K. R. Zasadny and R. L. Wahl, “Standardized uptake values of normal Wahl, and R. C. Zellars, “Comparison of FDG-PET/CT and CT for de- tissues at PET with 2-͓fluorine-18͔-fluoro-2-deoxy-D-glucose: Variations lineation of lumpectomy cavity for partial breast irradiation,” Int. J. Ra- with body weight and a method for correction,” Radiology 189, 847–850 diat. Oncol., Biol., Phys. 71, 595–602 ͑2008͒. ͑1993͒. 42C. Everitt and T. Leong, “Influence of F-fluorodeoxyglucose-positron 61J. W. Keyes, Jr., “SUV: Standard uptake or silly useless value?,” J. Nucl. emission tomography on computed tomography-based radiation treatment Med. 36, 1836–1839 ͑1995͒. planning for oesophageal cancer,” Australas Radiol. 50, 271–274 ͑2006͒. 62G. W. Goerres, C. Burger, M. R. Schwitter, T. N. Heidelberg, B. Seifert, 43T. Leong et al., “A prospective study to evaluate the impact of FDG-PET and G. K. von Schulthess, “PET/CT of the abdomen: Optimizing the on CT-based radiotherapy treatment planning for oesophageal cancer,” patient breathing pattern,” Eur. Radiol. 13, 734–739 ͑2003͒. Radiother. Oncol. 78, 254–261 ͑2006͒. 63T. Beyer, G. Antoch, T. Blodgett, L. F. Freudenberg, T. Akhurst, and S. 44M. Hutchings, A. Loft, M. Hansen, A. K. Berthelsen, and L. Specht, Mueller, “Dual-modality PET/CT imaging: The effect of respiratory mo- “Clinical impact of FDG-PET/CT in the planning of radiotherapy for tion on combined image quality in clinical oncology,” Eur. J. Nucl. Med. early-stage Hodgkin lymphoma,” Eur. J. Haematol. 78, 206–212 ͑2007͒. Mol. Imaging 30, 588–596 ͑2003͒. 45J. Esthappan, S. Chaudhari, L. Santanam, S. Mutic, J. Olsen, D. M. Mac- 64G. W. Goerres, C. Burger, E. Kamel, B. Seifert, A. H. Kaim, A. Buck, T. donald, D. A. Low, A. K. Singh, and P. W. Grigsby, “Prospective clinical C. Buehler, and G. K. Von Schulthess, “Respiration-induced attenuation trial of positron emission tomography/computed tomography image- artifact at PET/CT: Technical considerations,” Radiology 226, 906–910 guided intensity-modulated radiation therapy for cervical carcinoma with ͑2003͒. positive para-aortic lymph nodes,” Int. J. Radiat. Oncol., Biol., Phys. ͑in 65T. Beyer, S. Rosenbaum, P. Veit, J. Stattaus, S. P. Muller, F. P. Difilippo, press͒. H. Schoder, O. Mawlawi, F. Roberts, A. Bockisch, and H. Kuhl, “Respi- 46I. F. Ciernik, M. Huser, C. Burger, J. B. Davis, and G. Szekely, “Auto- ration artifacts in whole-body ͑18͒F-FDG PET/CT studies with combined mated functional image-guided radiation treatment planning for rectal PET/CT tomographs employing spiral CT technology with 1 to 16 detec- cancer,” Int. J. Radiat. Oncol., Biol., Phys. 62, 893–900 ͑2005͒. tor rows,” Eur. J. Nucl. Med. Mol. Imaging 32, 1429–1439 ͑2005͒. 47D. A. Patel, S. T. Chang, K. A. Goodman, A. Quon, B. Thorndyke, S. S. 66G. W. Goerres, T. F. Hany, E. Kamel, G. K. von Schulthess, and A. Buck, Gambhir, A. McMillan, B. W. Loo, Jr., and A. C. Koong, “Impact of “Head and neck imaging with PET and PET/CT: Artefacts from dental integrated PET/CT on variability of target volume delineation in rectal metallic implants,” Eur. J. Nucl. Med. Mol. Imaging 29, 367–370 ͑2002͒. cancer,” Technol. Cancer Res. Treat. 6, 31–36 ͑2007͒. 67G. W. Goerres, D. T. Schmid, and G. K. Eyrich, “Do hardware artefacts 48I. F. Ciernik, D. W. Brown, D. Schmid, T. Hany, P. Egli, and J. B. Davis, influence the performance of head and neck PET scans in patients with “3D-segmentation of the 18F-choline PET signal for target volume defi- oral cavity squamous cell cancer?,” Dentomaxillofac Radiol. 32, 365–371 nition in radiation therapy of the prostate,” Technol. Cancer Res. Treat. 6, ͑2003͒. 23–30 ͑2007͒. 68E. M. Kamel, C. Burger, A. Buck, G. K. von Schulthess, and G. W. 49R. J. Steenbakkers et al., “Reduction of observer variation using matched Goerres, “Impact of metallic dental implants on CT-based attenuation CT-PET for lung cancer delineation: A three-dimensional analysis,” Int. J. correction in a combined PET/CT scanner,” Eur. Radiol. 13, 724–728 Radiat. Oncol., Biol., Phys. 64, 435–448 ͑2006͒. ͑2003͒. 50J. L. Fox, R. Rengan, W. O’Meara, E. Yorke, Y. Erdi, S. Nehmeh, S. A. 69S. Bujenovic, F. Mannting, R. Chakrabarti, and D. Ladnier, “Artifactual Leibel, and K. E. Rosenzweig, “Does registration of PET and planning 2-deoxy-2-͓͑18͒F͔fluoro-D-glucose localization surrounding metallic ob- CT images decrease interobserver and intraobserver variation in delineat- jects in a PET/CT scanner using CT-based attenuation correction,” Mol.

Medical Physics, Vol. 35, No. 11, November 2008 4965 T. Pan and O. Mawlawi: PET/CT in radiation oncology 4965

Imaging Biol. 5, 20–22 ͑2003͒. correction of the PET data from PET/CT,” Med. Phys. 34, 2039–2047 70F. P. DiFilippo and R. C. Brunken, “Do implanted pacemaker leads and ͑2007͒. ICD leads cause metal-related artifact in cardiac PET/CT?,” J. Nucl. Med. 89M. M. Osman, C. Cohade, Y. Nakamoto, L. T. Marshall, J. P. Leal, and R. 46, 436–443 ͑2005͒. L. Wahl, “Clinically significant inaccurate localization of lesions with 71G. W. Goerres, S. I. Ziegler, C. Burger, T. Berthold, G. K. Von Schulth- PET/CT: Frequency in 300 patients,” J. Nucl. Med. 44, 240–243 ͑2003͒. ess, and A. Buck, “Artifacts at PET and PET/CT caused by metallic hip 90P. M. Chi, O. Mawlawi, D. Luo, Z. Liao, H. A. Macapinlac, and T. Pan, prosthetic material,” Radiology 226, 577–584 ͑2003͒. “Effects of respiration-averaged CT on PET/CT quantification and its 72A. K. Berthelsen, S. Holm, A. Loft, T. L. Klausen, F. Andersen, and L. potential impact on GTV delineation,” Int. J. Radiat. Oncol., Biol., Phys. Hojgaard, “PET/CT with intravenous contrast can be used for PET attenu- ͑accepted͒. ation correction in cancer patients,” Eur. J. Nucl. Med. Mol. Imaging 32, 91D. W. Townsend, “A combined PET/CT scanner: The choices,” J. Nucl. 1167–1175 ͑2005͒. Med. 42, 533–534 ͑2001͒. 73C. Cohade, M. Osman, Y. Nakamoto, L. T. Marshall, J. M. Links, E. K. 92D. W. Townsend, “Physical principles and technology of clinical PET Fishman, and R. L. Wahl, “Initial experience with oral contrast in PET/ imaging,” Ann. Acad. Med. Singapore 33, 133–145 ͑2004͒. CT: Phantom and clinical studies,” J. Nucl. Med. 44, 412–416 ͑2003͒. 93D. W. Townsend, T. Beyer, and T. M. Blodgett, “PET/CT scanners: A 74M. P. Mac Manus, R. J. Hicks, J. P. Matthews, A. McKenzie, D. Rischin, hardware approach to image fusion,” Semin Nucl. Med. 33, 193–204 E. K. Salminen, and D. L. Ball, “Positron emission tomography is supe- ͑2003͒. rior to computed tomography scanning for response-assessment after radi- 94D. W. Townsend, J. P. Carney, J. T. Yap, and N. C. Hall, “PET/CT today cal radiotherapy or chemoradiotherapy in patients with non-small-cell and tomorrow,” J. Nucl. Med., Suppl. 45, 4S–14S ͑2004͒. lung cancer,” J. Clin. Oncol. 21, 1285–1292 ͑2003͒. 95D. W. Townsend and S. R. Cherry, “Combining anatomy and function: 75R. J. Hicks, M. P. Mac Manus, J. P. Matthews, A. Hogg, D. Binns, D. The path to true image fusion,” Eur. Radiol. 11, 1968–1974 ͑2001͒. Rischin, D. L. Ball, and L. J. Peters, “Early FDG-PET imaging after 96S. R. Cherry, “The 2006 Henry N. Wagner lecture: Of mice and men ͑and radical radiotherapy for non-small-cell lung cancer: Inflammatory positrons͒—Advances in PET imaging technology,” J. Nucl. Med. 47, changes in normal tissues correlate with tumor response and do not con- 1735–1745 ͑2006͒. found therapeutic response evaluation,” Int. J. Radiat. Oncol., Biol., Phys. 97T. M. Blodgett, C. C. Meltzer, and D. W. Townsend, “PET/CT: Form and 60, 412–418 ͑2004͒. function,” Radiology 242, 360–385 ͑2007͒. 76M. Macmanus, I. D’Costa, S. Everitt, J. Andrews, T. Ackerly, D. Binns, 98J. R. Stickel and S. R. Cherry, “High-resolution PET detector design: E. Lau, D. Ball, L. Weih, and R. J. Hicks, “Comparison of CT and pos- modelling components of intrinsic spatial resolution,” Phys. Med. Biol. itron emission tomography/CT coregistered images in planning radical 50, 179–195 ͑2005͒. radiotherapy in patients with non-small-cell lung cancer,” Australas. Ra- 99O. Mawlawi, D. A. Podoloff, S. Kohlmyer, J. J. Williams, C. W. Stearns, diol. 51, 386–393 ͑2007͒. R. F. Culp, and H. Macapinlac, “Performance characteristics of a newly 77J. Brunetti, A. Caggiano, B. Rosenbluth, and C. Vialotti, “Technical as- developed PET/CT scanner using NEMA standards in 2D and 3D pects of positron emission tomography/computed tomography fusion modes,” J. Nucl. Med. 45, 1734–1742 ͑2004͒. planning,” Semin Nucl. Med. 38, 129–136 ͑2008͒. 100S. Surti, A. Kuhn, M. E. Werner, A. E. Perkins, J. Kolthammer, and J. S. 78U. Nestle, S. Kremp, A. Schaefer-Schuler, C. Sebastian-Welsch, D. Hell- Karp, “Performance of Philips Gemini TF PET/CT scanner with special wig, C. Rube, and C. M. Kirsch, “Comparison of different methods for consideration for its time-of-flight imaging capabilities,” J. Nucl. Med. delineation of 18F-FDG PET-positive tissue for target volume definition 48, 471–480 ͑2007͒. in radiotherapy of patients with non-Small cell lung cancer,” J. Nucl. 101P. E. Kinahan and J. S. Karp, “Figures of merit for comparing reconstruc- Med. 46, 1342–1348 ͑2005͒. tion algorithms with a volume-imaging PET scanner,” Phys. Med. Biol. 79T. Pan, O. Mawlawi, D. Luo, H. H. Liu, P. C. Chi, M. V. Mar, G. Gladish, 39, 631–642 ͑1994͒. M. Truong, J. Erasmus, Jr., Z. Liao, and H. A. Macapinlac, “Attenuation 102R. Leahy and C. Byrne, “Recent developments in iterative image recon- correction of PET cardiac data with low-dose average CT in PET/CT,” struction for PET and SPECT,” IEEE Trans. Med. Imaging 19, 257–260 Med. Phys. 33, 3931–3938 ͑2006͒. ͑2000͒. 80T. Pan, O. Mawlawi, S. A. Nehmeh, Y. E. Erdi, D. Luo, H. H. Liu, R. 103V. Bettinardi, P. Mancosu, M. Danna, G. Giovacchini, C. Landoni, M. Castillo, R. Mohan, Z. Liao, and H. A. Macapinlac, “Attenuation correc- Picchio, M. C. Gilardi, A. Savi, I. Castiglioni, M. Lecchi, and F. Fazio, tion of PET images with respiration-averaged CT images in PET/CT,” J. “Two-dimensional vs three-dimensional imaging in whole body onco- Nucl. Med. 46, 1481–1487 ͑2005͒. logic PET/CT: A discovery-STE phantom and patient study,” Q. J. Nucl. 81J. A. Nye, F. Esteves, and J. R. Votaw, “Minimizing artifacts resulting Med. Mol. Imaging 51, 214–223 ͑2007͒. from respiratory and cardiac motion by optimization of the transmission 104E. J. Hoffman, M. E. Phelps, G. Wisenberg, H. R. Schelbert, and D. E. scan in cardiac PET/CT,” Med. Phys. 34, 1901–1906 ͑2007͒. Kuhl, “Electrocardiographic gating in positron emission computed to- 82T. Ishimori, T. Saga, Y. Nagata, Y. Nakamoto, T. Higashi, M. Mamede, T. mography,” J. Comput. Assist. Tomogr. 3, 733–739 ͑1979͒. Mukai, Y. Negoro, T. Aoki, M. Hiraoka, and J. Konishi, “18F-FDG and 105S. A. Nehmeh, Y. E. Erdi, C. C. Ling, K. E. Rosenzweig, H. Schoder, S. 11C-methionine PET for evaluation of treatment response of lung cancer M. Larson, H. A. Macapinlac, O. D. Squire, and J. L. Humm, “Effect of after stereotactic radiotherapy,” Ann. Nucl. Med. 18, 669–674 ͑2004͒. respiratory gating on quantifying PET images of lung cancer,” J. Nucl. 83G. J. Cook, E. A. Wegner, and I. Fogelman, “Pitfalls and artifacts in Med. 43, 876–881 ͑2002͒. 18FDG PET and PET/CT oncologic imaging,” Semin Nucl. Med. 34, 106S. A. Nehmeh, Y. E. Erdi, C. C. Ling, K. E. Rosenzweig, O. D. Squire, L. 122–133 ͑2004͒. E. Braban, E. Ford, K. Sidhu, G. S. Mageras, S. M. Larson, and J. L. 84A. Martinez-Moller, M. Souvatzoglou, N. Navab, M. Schwaiger, and S. Humm, “Effect of respiratory gating on reducing lung motion artifacts in G. Nekolla, “Artifacts from misaligned CT in cardiac perfusion PET/CT PET imaging of lung cancer,” Med. Phys. 29, 366–371 ͑2002͒. studies: Frequency, effects, and potential solutions,” J. Nucl. Med. 48, 107S. A. Nehmeh, Y. E. Erdi, K. E. Rosenzweig, H. Schoder, S. M. Larson, 188–193 ͑2007͒. O. D. Squire, and J. L. Humm, “Reduction of respiratory motion artifacts 85T. Beyer, G. Antoch, S. Muller, T. Egelhof, L. S. Freudenberg, J. Debatin, in PET imaging of lung cancer by respiratory correlated dynamic PET: and A. Bockisch, “Acquisition protocol considerations for combined Methodology and comparison with respiratory gated PET,” J. Nucl. Med. PET/CT imaging,” J. Nucl. Med., Suppl. 45, 25S–35S ͑2004͒. 44, 1644–1648 ͑2003͒. 86K. L. Gould, T. Pan, C. Loghin, N. P. Johnson, A. Guha, and S. Sdringola, 108S. A. Nehmeh et al., “Four-dimensional ͑4D͒ PET/CT imaging of the “Frequent diagnostic errors in cardiac PET/CT due to misregistration of thorax,” Med. Phys. 31, 3179–3186 ͑2004͒. CT attenuation and emission PET images: A definitive analysis of causes, 109P. E. Kinahan, H. Vesselle, L. MacDonald, A. M. Alessio, S. Kohlmyer, consequences, and corrections,” J. Nucl. Med. 48, 1112–1121 ͑2007͒. and T. Lewellen, “Whole-body respiratory gated PET/CT,” J. Nucl. Med. 87K. L. Gould, T. Pan, C. Loghin, N. P. Johnson, and S. Sdringola, “Reduc- Meeting Abstracts, May 2006; 47, 187P. ing radiation dose in rest-stress cardiac PET/CT by single poststress cine 110O. Mawlawi, T. Pan, and H. A. Macapinlac, “PET/CT imaging tech- CT for attenuation correction: Quantitative validation,” J. Nucl. Med. ͑in niques, considerations, and artifacts,” J. Thorac. Imaging 21, 99–110 press͒. ͑2006͒. 88P. C. Chi, O. Mawlawi, S. A. Nehmeh, Y. E. Erdi, P. A. Balter, D. Luo, R. 111J. L. Garcia-Ramirez, S. Mutic, J. F. Dempsey, D. A. Low, and J. A. Mohan, and T. Pan, “Design of respiration averaged CT for attenuation Purdy, “Performance evaluation of an 85-cm-bore x-ray computed tomog-

Medical Physics, Vol. 35, No. 11, November 2008 4966 T. Pan and O. Mawlawi: PET/CT in radiation oncology 4966

raphy scanner designed for radiation oncology and comparison with cur- 126M. A. Admiraal, D. Schuring, and C. W. Hurkmans, “Dose calculations rent diagnostic CT scanners,” Int. J. Radiat. Oncol., Biol., Phys. 52, 1123– accounting for breathing motion in stereotactic lung radiotherapy based 1131 ͑2002͒. on 4D-CT and the internal target volume,” Radiother. Oncol. 86, 55–60 112T. Beyer, A. Bockisch, H. Kuhl, and M. J. Martinez, “Whole-body 18F- ͑2008͒. FDG PET/CT in the presence of truncation artifacts,” J. Nucl. Med. 47, 127R. W. Underberg, F. J. Lagerwaard, B. J. Slotman, J. P. Cuijpers, and S. 91–99 ͑2006͒. Senan, “Use of maximum intensity projections ͑MIP͒ for target volume 113J. S. Maltz, S. Bose, H. P. Shukla, and A. R. Bani-Hashemi, “CT trunca- generation in 4DCT scans for lung cancer,” Int. J. Radiat. Oncol., Biol., tion artifact removal using water-equivalent thicknesses derived from Phys. 63, 253–260 ͑2005͒. truncated projection data,” Conf. Proc. IEEE Eng. Med. Biol. Soc. 2007, 128J. D. Bradley, A. N. Nofal, I. M. El Naqa, W. Lu, J. Liu, J. Hubenschmidt, 2907–2911 ͑2007͒. D. A. Low, R. E. Drzymala, and D. Khullar, “Comparison of helical, 114O. Mawlawi, J. J. Erasmus, T. Pan, D. D. Cody, R. Campbell, A. H. Lonn, maximum intensity projection ͑MIP͒, and averaged intensity ͑AI͒ 4D CT S. Kohlmyer, H. A. Macapinlac, and D. A. Podoloff, “Truncation artifact imaging for stereotactic body radiation therapy ͑SBRT͒ planning in lung on PET/CT: Impact on measurements of activity concentration and as- cancer,” Radiother. Oncol. 81, 264–268 ͑2006͒. sessment of a correction algorithm,” AJR, Am. J. Roentgenol. 186, 1458– 129A. C. Riegel, J. Y. Chang, S. S. Vedam, V. Johnson, P. M. Chi, and T. Pan, 1467 ͑2006͒. “Cine CT without a respiratory surrogate in planning of stereotactic ra- 115K. R. Britton, G. Starkschall, S. L. Tucker, T. Pan, C. Nelson, J. Y. Chang, diotherapy for non-small cell lung cancer,” Int. J. Radiat. Oncol., Biol., J. D. Cox, R. Mohan, and R. Komaki, “Assessment of gross tumor vol- Phys. ͑in press͒. ume regression and motion changes during radiotherapy for non-small- 130K. J. Biehl, F. M. Kong, F. Dehdashti, J. Y. Jin, S. Mutic, I. El Naqa, B. cell lung cancer as measured by four-dimensional computed tomogra- A. Siegel, and J. D. Bradley, “18F-FDG PET definition of gross tumor phy,” Int. J. Radiat. Oncol., Biol., Phys. ͑in press͒. volume for radiotherapy of non-small cell lung cancer: Is a single stan- 116W. V. Vogel, J. A. van Dalen, B. Wiering, H. Huisman, F. H. Corstens, T. dardized uptake value threshold approach appropriate?,” J. Nucl. Med. J. Ruers, and W. J. Oyen, “Evaluation of image registration in PET/CT of 47, 1808–1812 ͑2006͒. the liver and recommendations for optimized imaging,” J. Nucl. Med. 48, 131T. Pan, “Comparison of helical and cine acquisitions for 4D-CT imaging 910–919 ͑2007͒. with multislice CT,” Med. Phys. 32, 627–634 ͑2005͒. 117M. M. Osman, C. Cohade, Y. Nakamoto, and R. L. Wahl, “Respiratory 132Y. E. Erdi et al., “The CT motion quantitation of lung lesions and its motion artifacts on PET emission images obtained using CT attenuation impact on PET-measured SUVs,” J. Nucl. Med. 45, 1287–1292 ͑2004͒. correction on PET-CT,” Eur. J. Nucl. Med. Mol. Imaging 30, 603–606 133S. A. Nehmeh et al., “Quantitation of respiratory motion during 4D- ͑2003͒. PET/CT acquisition,” Med. Phys. 31, 1333–1338 ͑2004͒. 118G. W. Goerres, E. Kamel, B. Seifert, C. Burger, A. Buck, T. F. Hany, and 134C. C. Nagel, G. Bosmans, A. L. Dekker, M. C. Ollers, D. K. De Ruyss- G. K. Von Schulthess, “Accuracy of image coregistration of pulmonary cher, P. Lambin, A. W. Minken, N. Lang, and K. P. Schafers, “Phased lesions in patients with non-small cell lung cancer using an integrated attenuation correction in respiration correlated computed tomography/ PET/CT system,” J. Nucl. Med. 43, 1469–1475 ͑2002͒. positron emitted tomography,” Med. Phys. 33, 1840–1847 ͑2006͒. 119G. W. Goerres, E. Kamel, T. N. Heidelberg, M. R. Schwitter, C. Burger, 135A. C. Paulino and P. A. Johnstone, “FDG-PET in radiotherapy treatment and G. K. von Schulthess, “PET-CT image co-registration in the thorax: planning: Pandora’s box?,” Int. J. Radiat. Oncol., Biol., Phys. 59,4–5 influence of respiration,” Eur. J. Nucl. Med. Mol. Imaging 29, 351–360 ͑2004͒. ͑2002͒. 136Y. E. Erdi, O. Mawlawi, S. M. Larson, M. Imbriaco, H. Yeung, R. Finn, 120C. B. Caldwell, K. Mah, M. Skinner, and C. E. Danjoux, “Can PET and J. L. Humm, “Segmentation of lung lesion volume by adaptive pos- provide the 3D extent of tumor motion for individualized internal target itron emission tomography image thresholding,” Cancer 80, 2505–2509 volumes? A phantom study of the limitations of CT and the promise of ͑1997͒. PET,” Int. J. Radiat. Oncol., Biol., Phys. 55, 1381–1393 ͑2003͒. 137T. R. Miller and P. W. Grigsby, “Measurement of tumor volume by PET 121P. J. Keall et al., “The management of respiratory motion in radiation to evaluate prognosis in patients with advanced cervical cancer treated by oncology report of AAPM Task Group 76,” Med. Phys. 33, 3874–3900 radiation therapy,” Int. J. Radiat. Oncol., Biol., Phys. 53, 353–359 ͑2002͒. ͑2006͒. 138J. D. Kiffer, S. U. Berlangieri, A. M. Scott, G. Quong, M. Feigen, W. 122D. A. Low et al., “A method for the reconstruction of four-dimensional Schumer, C. P. Clarke, S. R. Knight, and F. J. Daniel, “The contribution synchronized CT scans acquired during free breathing,” Med. Phys. 30, of 18F-fluoro-2-deoxy-glucose positron emission tomographic imaging to 1254–1263 ͑2003͒. radiotherapy planning in lung cancer,” Lung Cancer 19, 167–177 ͑1998͒. 123T. Pan, T. Y. Lee, E. Rietzel, and G. T. Chen, “4D-CT imaging of a 139S. Beaulieu, P. Kinahan, J. Tseng, L. K. Dunnwald, E. K. Schubert, P. volume influenced by respiratory motion on multi-slice CT,” Med. Phys. Pham, B. Lewellen, and D. A. Mankoff, “SUV varies with time after 31, 333–340 ͑2004͒. injection in ͑18͒F-FDG PET of breast cancer: Characterization and 124P. J. Keall, G. Starkschall, H. Shukla, K. M. Forster, V. Ortiz, C. W. method to adjust for time differences,” J. Nucl. Med. 44, 1044–1050 Stevens, S. S. Vedam, R. George, T. Guerrero, and R. Mohan, “Acquiring ͑2003͒. 4D thoracic CT scans using a multislice helical method,” Phys. Med. 140L. M. Hamberg, G. J. Hunter, N. M. Alpert, N. C. Choi, J. W. Babich, and Biol. 49, 2053–2067 ͑2004͒. A. J. Fischman, “The dose uptake ratio as an index of glucose metabo- 125T. Pan, X. Sun, and D. Luo, “Improvement of the cine-CT based 4D-CT lism: Useful parameter or oversimplification?,” J. Nucl. Med. 35,1308– imaging,” Med. Phys. 34, 4499–4503 ͑2007͒. 1312 ͑1994͒.

Medical Physics, Vol. 35, No. 11, November 2008 Planning and delivery of intensity-modulated radiation therapy ͒ Cedric X. Yua Department of Radiation Oncology, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, Maryland 21201 Christopher J. Amies Siemens Medical Solutions USA, Inc., Oncology Care Systems Group, 4040 Nelson Avenue, Concord, California 94520 Michelle Svatos Translational Research, Varian Medical Systems, 3100 Hansen Way M/S E263 Palo Alto, California 94304-1038 ͑Received 9 May 2008; revised 11 August 2008; accepted for publication 18 September 2008; published 6 November 2008͒ Intensity modulated radiation therapy ͑IMRT͒ is an advanced form of external beam radiation therapy. IMRT offers an additional dimension of freedom as compared with field shaping in three- dimensional conformal radiation therapy because the radiation intensities within a radiation field can be varied according to the preferences of locations within a given beam direction from which the radiation is directed to the tumor. This added freedom allows the treatment planning system to better shape the radiation doses to conform to the target volume while sparing surrounding normal structures. The resulting dosimetric advantage has shown to translate into clinical advantages of improving local and regional tumor control. It also offers a valuable mechanism for dose escalation to tumors while simultaneously reducing radiation toxicities to the surrounding normal tissue and sensitive structures. In less than a decade, IMRT has become common practice in radiation oncology. Looking forward, the authors wonder if IMRT has matured to such a point that the room for further improvement has diminished and so it is pertinent to ask what the future will hold for IMRT. This article attempts to look from the perspective of the current state of the technology to predict the immediate trends and the future directions. This article will ͑1͒ review the clinical experience of IMRT; ͑2͒ review what we learned in IMRT planning; ͑3͒ review different treatment delivery techniques; and finally, ͑4͒ predict the areas of advancements in the years to come. © 2008 Ameri- can Association of Physicists in Medicine. ͓DOI: 10.1118/1.3002305͔

Key words: radiation therapy, intensity modulation, treatment planning, radiotherapy delivery, IMRT

I. OVERVIEW therapy. The use of overlapping cone-beam arcs13,14 to deliver modulated beam intensities around the patient, re- Intensity modulated radiation therapy ͑IMRT͒ has been ferred to as intensity modulated arc therapy ͑IMAT͒, was widely adopted as a new tool in radiation therapy to deliver also proposed but has not been widely adopted for clinical high doses of radiation to the tumor while providing maxi- use yet. mal sparing of surrounding critical structures. What facilitated the quick dissemination of IMRT technology was not With nearly 10 years of clinical application, both short- hard clinical evidence but rather the individually calculated term and long-term clinical results of IMRT treatments are and visually illustrated dosimetric advantages. Because such emerging. Its ability to shape the high dose volume to con- dosimetric advantage was obvious, wide clinical adoption of form to the shape of the target tissues allows the decrease of IMRT preceded any randomized clinical trials. In the U.S., irradiation related sequelae by limiting the dose delivered to the increased reimbursement for the technology also fueled the surrounding normal tissues. The same dose shaping ca- the speed of clinical dissemination. Early studies indicated pability also allows the physicians to escalate doses to cer- that with IMRT, radiation doses to sensitive structures could tain tumors to enhance local control. Both dosimetric and be reduced significantly while maintaining sufficient dose clinical advantages have been demonstrated for almost all 15 coverage to the targeted tumorous tissues.1–9 Both rotational common anatomical sites, though the largest number of and gantry-fixed IMRT techniques have been implemented applications has been for prostate cancer and cancers of the 15 clinically using dynamic multileaf collimation head and neck region. IMRT has allowed the physicians to ͑DMLC͒.1,3–6,10–14 In gantry-fixed IMRT, multiple coplanar escalate the dose to the prostate while reducing the toxicities and noncoplanar beams at different orientations, each with to the rectum and bladder, resulting in improved local control spatially modulated beam intensities, are used.1,3,12 Rota- and reduced complications as compared with conventional tional IMRT, as it is practiced today, mainly employs tempo- three-dimensional ͑3D͒ conformal therapy.16–19 IMRT has rally modulated fan beams,5,6 commonly known as tomo- also shown greater capability in sparing salivary functions in

5233 Med. Phys. 35 „12…, December 2008 0094-2405/2008/35„12…/5233/9/$23.00 © 2008 Am. Assoc. Phys. Med. 5233 5234 Yu, Amies, and Svatos: IMRT planning and delivery 5234 patients receiving radiation therapy for head and neck further advancement in the near future. IMRT technology cancers.20–23 Rather than delivering the prescribed dose to consists of planning methods and delivery technologies. If the entire pelvis, IMRT was able to spare the small bowel, IMRT continues to advance, improvements must be made in the bladder and the rectum, resulting in significantly lower these two areas. It is therefore crucial to summarize what we GI toxicities.24–28 The use of IMRT instead of wedge pairs have learned in these two key aspects of the technology. for tangential whole breast irradiation has resulted in improved dose uniformity,29–32 which in turn resulted in significantly reduced acute and chronic toxicities.33 IMRT has also II. IMRT TREATMENT PLANNING been combined with stereotactic localization for delivering radiosurgery treatments to intracranial and extracranial sites The key technology for IMRT planning is computer opti- using linear accelerators.9,34,35 Other sites of application in- mization. Although relatively new in radiation oncology, clude lung,36–38 gastrointestinal tumors,38–41 pediatric computer optimization is not new and has been used for tumors,42–44 and soft tissue sarcoma.45 operations research and other fields of theoretical and applied These data indicate that for certain clinical cases, there is research. Almost all the algorithms that have been used in a direct translation between dosimetric advantage and im- other fields, including simulated annealing,7,46 gradient proved clinical outcome. With more emerging clinical data search,68,69 genetic algorithms,70,71 and linear and nonlinear pointing to the same conclusion, IMRT as a technology will programming,72–74 have been applied to plan IMRT treat- continue to be an important technique in external beam ra- ments. diation therapy. There have also been significant efforts on how the opti- The way IMRT spares critical structures is by redistribut- mization problem is formulated. Universal to all the optimi- ing the normal tissue dose to less critical regions and to zation methods, the objectives of each treatment plan are reducing the high dose volume to just cover the target. For a reduced to a single value by the objective function or cost given integral dose to the target, the integral dose to the function. The objectives of the treatment can be expressed surrounding structures is roughly constant as dictated by the according to the desired dose distributions7,46,75 or in terms physics of dose deposition.46 In many cases, the use of IMRT of biological objectives.68,76 Essentially, when the objective results in a greater volume of surrounding normal tissues function is formulated to closely depict the desirable features receiving a lower dose as compared with traditional three- of the radiation dose distribution, the quality of the candidate dimensional conformal therapy. This phenomenon raises sig- plans is judged more accurately during the optimization pro- nificant concerns for pediatric applications of IMRT.47,48 cess. Therefore, as long as the objectives are defined to ap- While the long term clinical results of using IMRT for inop- propriately reflect what is really clinically optimal, the re- erable nonsmall lung cancer are promising,38 its use for me- sults are generally clinically meaningful and acceptable. sothelioma following extrapleural pneumonectomy showed a Different commercial treatment planning systems use differ- high rate of fatal pulmonary toxicity.49,50 A high mean lung ent optimization algorithms, and slightly different dose or dose and a higher percentage of lung volume receiving biological dose, in the form of equivalent uniform dose, ob- 20 Gy were clear predictors of fatal pulmonary toxicity. jectives. In general and except for certain limitations in the Another issue of using IMRT for treating tumors in the implementation and planner experience, there is no clinically thorax and abdominal regions is the breathing induced target meaningful difference in plan quality when using different motion. As illustrated by Yu et al.,51 the interplay between approaches. the target motion and the movement of the beam to achieve Complex treatment planning problems often involve mul- intensity modulation could cause unintended hot and cold tiple targets with many surrounding normal structures. The spots in excess of 100% in a given fraction of treatment. objectives specified for these structures are often in conflict. Different motion management strategies have been proposed In such complex situations, it is hard if not impossible to or applied clinically, including gating the radiation beam52 optimally describe what is truly desired before a plan is op- and dynamically tracking the tumor with DMLC53 or with timized. In the situation where one cannot achieve optimality couch counter motion.54 for all the objectives simultaneously, the optimal solution Clinical use of IMRT has also brought many changes in becomes the optimal trade-off among these objectives. There clinical practice. Owing to its ability to reduce dose to sur- have been several approaches proposed by different re- rounding structures, IMRT has allowed physicians to escalate searchers for dealing with such conflicting objectives. One of dose to the prostate gland to improve local control.55–57 The the approaches is to specify the treatment objective as a reduced toxicity also encouraged the use of hypofraction- probability density function rather than as a rigid dose ation schemes.58–61 The ability of IMRT to paint more com- objective.77 If the most desired dose is not attainable by the plex dose distributions also allowed the increased use of con- optimizer, other doses are acceptable but less preferred. Con- comitant boost and the treatment of target within targets.60,61 sequently, during the optimization process, the prescription The purpose of this article is not to provide an extensive dose is allowed to deviate, with a certain preference level, review of IMRT technology. Such reviews can be found in from the most desired dose. Another approach is to build a recent books62,63 and review articles.64–67 We attempt to pre- database of plans by varying the emphasis of different objec- dict from what we learned in the last 10 years of develop- tives. Using an interactive plan navigation tool, the trade-offs ment and clinical practice of IMRT the potential direction of between different objectives can be made explicitly based on

Medical Physics, Vol. 35, No. 12, December 2008 5235 Yu, Amies, and Svatos: IMRT planning and delivery 5235 the user’s clinical goals.78 The resultant plans from this ap- a result, the residual room for improvements in plan quality proach are also called Pareto-optimal plans. under existing delivery systems has diminished over the One of the tasks in treatment planning for external beam years of refinements in treatment planning algorithms and radiation therapy is to determine the number of beams to use methods. and their orientations. For conventional treatments, beam angles used for different treatment sites are well established. With IMRT, the task of beam angle selection is more com- III. IMRT TREATMENT DELIVERY plicated and less intuitive because of more complex interactions and mutual compensations among the different beam Most IMRT treatment deliveries require the use of the angles as the result of computer optimized beam intensities. multileaf collimator ͑MLC͒, which was originally developed As the result, beam angle optimization has been one of the for shaping radiation fields. The ability of the MLC to easily areas of intensive investigation. Haas et al.79 employed ge- change and dynamically vary the field shapes was quickly netic algorithms to search for the best beam orientations. explored for IMRT delivery. Over the years, linear accelera- Rowbottom et al.80 and Stein et al.81 used simulated anneal- tor vendors have not only improved the reliability of MLCs ing algorithms to perform beam angle optimization by com- but also made the leaf width smaller. Smaller leaf widths paring thousands of sets of fixed number of beams sampled allow the treatment planning system to use finer beamlet size from a constrained or unconstrained space of beam orienta- during optimization for achieving better plan quality.88 tions. Pugachev et al.82 also reported different schemes of IMRT treatments are delivered using either fixed beam beam angle optimization with the simulated annealing algo- angles or rotational beams. Both forms of delivery were pro- rithm. Although all these studies demonstrated some effects posed and developed at the start of the IMRT technology.89 of beam angle selection on plan quality, the degree of im- Although the technology is termed “intensity modulation,” provements has been small. It is thus reasonable to conclude the intensity variation is actually achieved by temporal that the mutual interactions and compensations among the modulation, allowing different beamlets to be irradiated for beams under intensity optimization also made beam angle different durations. selection less influential on plan quality as compared with Most of the IMRT treatments delivered today use a few three-dimensional conformal therapy. fixed beam directions. The treatment planning system has In spite of years of refinements in IMRT planning, argu- converted the optimal intensity distributions into deliverable ably, the quality of treatment plans has not improved much overlapping field segments. Because the conversion is not from that of the early days. The explanation may be rooted in within the optimization process and MLC motion constraints the basic principles of inverse planning. For each patient, the have to be considered during such conversion, it may intro- anatomy dictates a unique set of preferred beam orientations duce differences between the treatment plans using the opti- and, in each beam orientation and radiation field, the pre- mal intensity distributions and that achievable with overlap- ferred locations through which radiation is directed to the ping field segments.11 These field segments, also called tumor. If more freedom is given to make use of these intrin- subfields, can be delivered dynamically, i.e., MLC transition- sic preferences in treatment planning, either performed by a ing through the shapes of the subfields dynamically when the human planner or by a computer optimization system, better beam is on. They can also be delivered one segment at a time plans can be generated. IMRT provides an additional free- such that the MLC is not moving during irradiation. dom as compared with 3D conformal radiation therapy be- Up to now, rotational IMRT treatments have primarily cause the radiation intensities within a radiation field can be been delivered using tomotherapy,5,6 an approach where a varied according to the location preferences. However, there binary collimator ͑open/close͒ is used to control the amount is a fundamental limit to which the quality of treatment plans of exposure time of a small width of the fan beam, or a can be improved. This limit is defined by the physics of the beamlet. The fraction of time a leaf is in the “open” position radiation dose deposition and by the degrees of freedom that at a given beam angle determines the relative “intensity” of are given to the computer optimization routine. There are radiation at that angle. Because the fan beam can only irra- indications that the required degree of intensity variation for diate a slice of the patient at a given time, larger tumors are achieving the optimal plan quality for a large majority of treated by either stepping the table one slice at a time5 or cases is relatively small. For example, Ludlum et al.83 opti- continuously.6 The latter is called helical tomotherapy be- mized IMRT plans for different challenging cancer sites us- cause the trajectory of the radiation source relative to the ing different number of intensity levels. They found that re- patient is a helix. Tomotherapy™ ͑Madision, WI͒ offers a ducing the number of intensity levels from 10 to 3 only cause “turn-key” approach to IMRT implementation with the plan- minor degradations in dose distribution. Comparisons among ning system specifically designed for the delivery unit. To- different treatment planning and delivery approaches84–87 motherapy utilizes all coplanar beam angles and the intensity have not yield any approach with clinically meaningful su- variations of the beamlets are not constrained by the me- periority. These studies and our own experience led us to chanical limits of the binary MLC. Therefore, theoretically believe that with the current state of the radiation delivery speaking, tomotherapy provides a planning system with the systems and without new advances to provide additional de- freedom to use highly modulated beams to create more con- grees of freedom, IMRT has approached its limits in the formal treatment plans then MLC delivery with fixed cone quality of treatment plans that can be physically achieved. As beams.

Medical Physics, Vol. 35, No. 12, December 2008 5236 Yu, Amies, and Svatos: IMRT planning and delivery 5236

Another rotational IMRT approach, called IMAT, was proaches to metabolic imaging, and the emergence of a new suggested by Yu.13 Instead of rotating fan beams around the generation of radiation treatment delivery systems. patient, IMAT uses cone beams shaped with conventional MLCs. IMAT delivers optimized intensity distributions for IV.A. Quality improvements large number of beams spaced every 5–10 deg around the Based on 10 years of experience with IMRT, we have patient. Optimized intensity distributions are translated into a learned that the opportunities in improving plan quality are stack of superimposed irregular fields of uniform beam in- limited within the constraint of present linac/MLC delivery. tensities and delivered by overlapping arcs with synchro- To improve the quality of IMRT treatment plans, we must nized gantry rotation and field shape variations. As the gan- inject new degrees of freedom. This may require an overhaul try is rotating around the patient and the radiation beam is of existing technologies. A new generation of treatment de- on, it is important that the subfields of adjacent beam angles livery systems is emerging. One of such machines is pro- do not require the MLC leaves to travel very long distances. posed by Kamino et al.91 Besides the IMRT capability and Ensuring such connectedness of adjacent subfields for improved image guidance features, a notable feature is that smooth leaf motion is of great concern in the leaf sequencing the linear accelerator head can be pivoted. By offering non- algorithm for IMAT.13,14 Effective planning tools for IMAT coplanar beams easily without couch rotations, such machine have only been developed recently.84,90 provides new degrees of freedom into the solutions, and, Comparisons between IMRT plans for different delivery therefore, has the potential of improving the qualities of methods have been conducted. In a comparison of tomo- treatment plans. therapy and MLC delivery, Mavroidis et al. found that linear Several new machines currently under development incor- accelerator delivery with a MLC has slight advantage over porate image guidance from Magnetic resonance imaging tomotherapy for most sites other than head and neck.85 Simi- ͑MRI͒. The design of the Renaissance™ ͑ViewRay, Inc., lar results have been found by Muzik et al.86 Cao et al.87 Cleveland, OH͒ incorporates real-time MR imaging and mul- compared the treatment plan quality of IMAT plans and to- tihead Co-60 rotational delivery. The use of MRI for image motherapy plans for ten cases including head and neck, lung, guidance may provide improved soft tissue contrast for im- brain, and prostate. It was found that these two kinds of proved targeting accuracy. rotational delivery methods are also equivalent for most These new technologies are aimed for delivering radiation cases. For cases where noncoplanar beams are desirable, treatments to all sites. As the room for quality improvements such as for intracranial tumors and some head and neck is further squeezed, technologies specific for particular treat- cases, the use of partial noncoplanar arcs in IMAT was found ment sites may also emerge to take advantage of the anatomy to be more advantageous.87 Shepard et al. compared IMAT and biology of such specific sites. plans with IMRT 84 and found that the employment of rota- As machines increase in complexity, it becomes harder for tional IMRT is advantageous for most of the cases. a generic treatment planning system to fully utilize the ma- It is important to note that there are many other issues chines capabilities. Diversity in delivery systems forces the besides plan quality that are associated with different deliv- planning system to be more specifically tailored to the treat- ery techniques. These include the efficiency of planning, de- ment machine. Treatment planning systems designed specifi- livery, and quality assurance, the complexity and reliability cally for a delivery device as a turn-key solution will become of delivery, and the total monitor units required to deliver the the most common configuration. prescribed dose. IMRT is not limited to the use of photons. It has been demonstrated that the IMRT principle can also be applied to 92 93,94 IV. FUTURE DIRECTIONS OF ADVANCEMENTS electrons and protons. The fast introduction of proton OF IMRT beams in radiation therapy would allow us to push the limit of achievable plan quality higher than using only photons. Revolutionary advances in biology and genomics have brought a wave of new molecular therapeutic agents for IV.B. Efficiency improvements fighting cancer and the continued acceleration in the direction will mark a new era of cancer therapies. However, mo- The fact that treatment plans of different complexity de- lecular agents have not been shown to eliminate local thera- signed for different delivery methods can achieve similar pies. Therefore, we do not see that the role of radiation quality of treatments suggest that there is substantial room therapy will diminish in this new era. The dose shaping ca- for improving the workflow and efficiency. Past attempts in pabilities of IMRT make it an essential tool for better inte- improving treatment efficiency include the use of direct ap- gration of radiation with chemotherapy and molecular thera- erture optimization95 and the development of single arc peutic agents. IMAT.96–100 The areas in which IMRT technology can be improved Instead of optimizing intensity maps and then translating include ͑1͒ the quality of treatment plans, ͑2͒ the accuracy of the intensity maps into deliverable segments, Shepard et al.95 treatment delivery, and ͑3͒ the efficiency of both planning proposed and developed a method called “direct aperture op- and delivery of IMRT treatments. We predict that the ad- timization” ͑DAO͒ that directly optimizes the shapes and vances in these areas will be driven by factors including weights of MLC segments simultaneously in one step. The on-line and real-time image guidance, individualized ap- planner determines the number of beams to use and the num-

Medical Physics, Vol. 35, No. 12, December 2008 5237 Yu, Amies, and Svatos: IMRT planning and delivery 5237 ber of apertures desired at each of the beams. The planning IV.C. Improving the accuracy of IMRT delivery with system optimizes the aperture shape and aperture weights image guidance simultaneously. Physical constraints of the MLC are consid- Besides improving efficiency, great opportunities also ex- ered in the optimization process. With a small number of ist for improving the accuracy of treatment delivered by us- apertures, the resulting plan quality generally rivals that ing on-board image guidance. The advent of on-board cone based on intensity optimization which requires large number beam computed tomography ͑CBCT͒ and in-room CT with 101 102 of apertures. Earl et al. and Kim et al. also demon- high soft tissue contrast opens new opportunities for high- strated that even with overlapping rectangular fields formed precision radiation therapy.106 The success of the image by independent jaws, IMRT type of dose distribution can be guided radiation therapy ͑IGRT͒ lies not only in the ability to achieved for prostate, breast, and even head and neck cases, acquire the images but largely in how we use the images to if the aperture shapes and weights are optimized with DAO. achieve our goal of controlling more cancers while decreas- Earl et al. illustrated that DAO can also be applied for the ing the normal tissue toxicities. In many cases, the tumor not optimization of IMAT plans.103 The possibility of varying only changes its location but also its shape and the relative dose rates during gantry rotation and irradiation also opens geometrical relationship with its surrounding normal struc- the opportunity for delivering IMRT-like plans with a single tures. Consequently, simply shifting the patient does not arc rotation. In proposing the IMAT idea, Yu13 has predicted guarantee optimal treatments. Therefore, reoptimizing the that, with reasonable number of beam angles, the quality of IMRT plan or adapting an existing plan to the “anatomy of an IMRT or IMAT plan depends on the number of total seg- the day” will increasingly become an active area of research. ments, or aperture variations. Given enough aperture varia- Recognizing the impracticality of a full-fledged daily re- tions, a single arc should be able to achieve IMRT-like plan planning with current technology, several researchers have recently proposed methods for incorporating the deformable quality. Beam intensity modulation is not a fundamental re- 107 quirement for achieving optimal treatment plans. The ability component into an online correction strategy. Wu et al. to take advantage of the preferred angles and locations, have shown that for tomotherapy delivery, intensities can be modified online with given transformation parameters or through which the radiation is directed to the tumor, is the with a quick reoptimization. Mohan et al.108 proposed to de- key to achieve optimal dose distributions. For example, the form the intensity patterns as an online correction strategy. CyberKnife™ system104 ͑Accuray, Sunnyvale, CA͒, which Feng et al.109 have proposed a scheme that deforms the ap- uses small circular x-ray beams generated by an x-band lin- erture shapes of the IMRT segments by using the deforma- ear accelerator mounted on a robot to deliver the radiation to tion matrix derived from the planning image set and the im- the target, does not explicitly modulate the intensity of a ages of the day. Ahunbay et al.110 developed a similar beam, but is able to deliver highly conformal treatments. scheme but added aperture weight optimization after aperture The feasibility of delivering IMRT with a single arc was 98 deformation. These schemes have shown to be able to ap- first demonstrated by Cameron et al. Using a DAO scheme proach the plan quality resulting from reoptimization using as Earl et al. but employing a more efficient way for select- the images of the day. ing the initial aperture shapes, Ulrich et al. also showed that As computer technology continue to advance, such short IMRT-like dose distributions can be achieved with a single cuts as described above may no longer be needed. Replan- 97 arc. When optimizing a large number of beam apertures ning using the images of the day will become a reality. The from large number of beam angles, the scheme by Ulrich and advance of IGRT will make imaging, planning and treatment Earl can take a long time for the optimization to converge. delivery all performed in a single session. Under the new Otto devised a coarse-to-fine optimization scheme that starts “image-plan-treat” process, initial imaging and planning will with a small number of beams with large angular spacing and become merely a first look into what degree of dose confor- gradually inserts new beam angles to be optimized.96 The mity is achievable. With experience and confidence, the ini- computer optimizes the aperture shapes and weights simul- tial planning may even be eliminated. Such a procedure, taneously as in DAO. Tang et al.99 illustrated that a single arc which has been the norm for radiosurgery, will allow further IMAT plan can be derived from a multiarc IMAT plan by shrinkage of PTV margins and encourage radiation oncolo- spacing the stacked apertures to the neighboring angles. Us- gists to revise the current dose fractionation schemes. There ing graph algorithms, Wang et al.100 have shown that IMRT are three technologies that will enable for this image-plan- plans optimized with 36 fields can be sequenced into and treat scheme. delivered with a single arc. The pressure for more efficient ͑1͒ Imaging systems integrated with delivery machines will IMRT delivery will encourage linear accelerator vendors to be faster and provide greater image quality before and offer different single arc IMAT solutions. during treatment. Currently, the gantry speed is setting In addition to rotational delivery, the use of higher dose the limit on the speed of image acquisition for imaging rates, either by the improvements in acceleration technology systems mounted on the treatment gantry. The image or by eliminating the flattening filter, could also be explored quality achievable with CBCT also does not match that for efficiency gains.105 As IMRT becomes easier to plan and of fan beam CT units because of the limitations of the to deliver, the need for traditional beam modifiers such as the reconstruction algorithms for CBCT and the added ra- use of physical wedges will diminish. diation scatter contributions. These limitations will be

Medical Physics, Vol. 35, No. 12, December 2008 5238 Yu, Amies, and Svatos: IMRT planning and delivery 5238

corrected in the long-term by the emergence of new de- such as DAO and single arc IMAT. The rapid adaptation of signs of on-line imaging systems, new imaging recon- IGRT will encourage the integration of IMRT planning and struction and scatter subtraction algorithms, and/or new delivery with on-line imaging. Strategies of on-line plan ad- on-line imaging strategies. aptation and on-line replanning will be the emphasis in the ͑2͒ Dose calculation and optimization can be performed near future. The adoption of biology and molecular imaging within a couple of minutes. Computational speeds have guidance will push IMRT into dose painting paradigm in the been increasing rapidly according to Moore’s law. Other long term. innovations, such as the use of special hardware for dose a͒ computation,111 further push the envelope of planning Author to whom correspondence should be addressed. Electronic mail: [email protected] speed. 1 ͑ ͒ A. Brahme, “Optimization of stationary and moving beam radiation 3 Fast image registration will allow the structures delin- therapy techniques,” Radiother. Oncol. 12, 129–140 ͑1988͒. eated by the physicians on a previously acquired image 2T. Bortfeld, D. Kahler, T. Waldron, and A. Boyer, “X-ray field compen- set to be transferred to the images of the day in very sation with multileaf collimators,” Int. J. Radiat. Oncol., Biol., Phys. ͑ ͒ ͑ ͒ short time. Although three-dimensional deformable im- 28 3 , 723–730 1994 . 3A. Boyer, and C. Yu, “Intensity-modulated radiation therapy with dy- age registration has been theoretically solved for de- namic multileaf collimators,” Semin. Radiat. Oncol., 9͑1͒,48–59͑1999͒. cades, practical applications of these algorithms in radia- 4C. Burman, C. Chui, G. Kutcher, S. Leibel, M. Zelefsky, T. LoSasso, S. tion therapy are new and relatively primitive. The room Spirou, Q. Wu, J. Yang, J. Stein, R. Mohan, Z. Fuks, and C. Ling “Plan- of improvements in both the speed and the accuracy of ning, delivery, and quality assurance of intensity-modulated radiotherapy using dynamic multileaf collimator: A strategy for large-scale implemen- registration is significant. As the need for speed and ac- tation for the treatment of carcinoma of the prostate,” Int. J. Radiat. On- curacy continue to rise, innovative solutions will con- col., Biol., Phys., 39͑4͒, 863–873 ͑1997͒. tinue to emerge. It will be possible within the next 5M. Carol, “Integrated 3D conformal planning/multivane intensity modu- 5 years for a deformable image registration to be per- lating delivery system for radiotherapy,” in 3D Radiation Treatment Plan- ning and Conformal Therapy, edited by J. A. Purdy and B. Emami ͑Medi- formed in less than a minute. With fast deformable im- cal Physics, Madison, WI, 1995͒, pp. 435–445. age registration, the accumulation of doses to different 6T. Mackie, T. Holmes, and S. Swerdloff “Tomotherapy: A new concept parts of the target and to critical structures will be perfor the delivery of dynamic conformal radiotherapy,” Med. Phys. 20͑6͒, formed more accurately. 1709–1719 ͑1993͒. 7S. Webb “Optimizing the planning of intensity-modulated radiotherapy,” Phys. Med. Biol. 39͑12͒, 2229–2246 ͑1994͒. 8Q. Wu, M. Manning, R. Schmidt-Ullrich, and R. Mohan “The potential for sparing of parotids and escalation of biologically effective dose with IV.D. Dose painting with molecular and functional intensity-modulated radiation treatments of head and neck cancers: A imaging guidance treatment design study,” Int. J. Radiat. Oncol., Biol., Phys. 46͑1͒,195– 205 ͑2000͒. The integration of molecular and functional imaging with 9S. Y. Woo et al., “A comparison of intensity modulated conformal therapy radiation therapy will shift the current image guidance from with a conventional external beam stereotactic radiosurgery system for the treatment of single and multiple intracranial lesions,” Int. J. Radiat. merely geometrical to biological. The scenario of “dose Oncol., Biol., Phys. 35, 593–597 ͑1996͒. 112 painting” will become reality. Presently, our goals are gen- 10D. J. Convery and M. E. Rosenbloom “The generation of intensity- erally to deliver a high uniform dose to the target while spar- modulated fields for conformal radiotherapy by dynamic collimation,” ing surrounding critical structures. With the knowledge of Phys. Med. Biol. 37͑6͒, 1359–1374 ͑1992͒. 11P. Xia and L. J. Verhey “Mutileaf collimation leaf sequencing algorithm molecular signatures of the tumor and its microenvironment for intensity modulated beams with multiple static segments,” Med. Phys. revealed by the new imaging modalities, it will be more de- 25͑8͒, 1424–1434 ͑1998͒. sirable to paint a nonuniform dose distribution to best attack 12C. X. Yu et al., “A method for implementing dynamic photon beam in- the tumor while protecting its surrounding structures. Being tensity modulation using independent jaws and multileaf collimator,” Phys. Med. Biol. 40, 769–787 ͑1995͒. able to use computer optimization to take advantage of the 13C. X. Yu “Intensity-modulated arc therapy with dynamic multileaf colli- angular and positional preferences, IMRT will be well posi- mation: An alternative to tomotherapy,” Phys. Med. Biol., 40, 1435–1449 tioned in molecular and functional image guided dose paint- ͑1995͒. 14 ing. C. X. Yu, X. A. Li, L. Ma, D. J. Chen, S. Naqvi, D. Shepard, M. Sarfaraz, T. W. Holmes, M. Suntharalingam, and C. M. Mansfield “Clinical Imple- mentation of intensity-modulated arc therapy,” Int. J. Radiat. Oncol., Biol., Phys. 53͑2͒, 453–463 ͑2002͒. 15 V. CONCLUSION L. K. Mell, A. K. Mehrotra, and A. J. Mundt “Intensity-modulated radiation therapy use in the U. S., 2004,” Cancer ͑N.Y.͒, 104͑6͒, 1296–1303 We have reviewed and described the current state of ͑2005͒. IMRT and identified that IMRT is a well established technol- 16A. Pollack et al., “Prostate cancer radiation dose response: Results of the ogy offering dosimetric advantages for target coverage and MD Anderson phase III randomized trial,” Int. J. Radiat. Oncol., Biol., Phys. 53͑5͒, 1097–1105 ͑2002͒. normal tissue avoidance. We believe that the treatment plan 17M. J. Zelefsky et al., “High-dose intensity modulated radiation therapy quality has reached a limit imposed by the physics of photon for prostate cancer: early toxicity and biochemical outcome in 772 patients,” Int. J. Radiat. Oncol., Biol., Phys. 53͑5͒, 1111–1116 ͑2002͒. dose deposition and the room for further improvement in 18 plan quality is small. We also noticed that this intrinsic limit C. M. Nutting et al., “Reduction of small and large bowel irradiation using an optimized intensity-modulated pelvic radiotherapy technique in is also not difficult to approach with different IMRT patients with prostate cancer,” Int. J. Radiat. Oncol., Biol., Phys. 48, schemes. This fact has allowed efficiency improvements 649–656 ͑2000͒.

Medical Physics, Vol. 35, No. 12, December 2008 5239 Yu, Amies, and Svatos: IMRT planning and delivery 5239

19A. A. Martinez et al., “Improvement in dose escalation using the process 40J. C. Landry et al., “Treatment of pancreatic cancer tumors with intensity- of adaptive radiotherapy combined with three-dimensional conformal or modulated radiation therapy ͑IMRT͒ using the volume at risk approach intensity-modulated beams for prostate cancer,” Int. J. Radiat. Oncol., ͑VARA͒: Employing dose-volume histogram ͑DVH͒ and normal tissue Biol., Phys. 50, 1226–1234 ͑2001͒. complication probability ͑NTCP͒ to evaluate small bowel toxicity,” Med. 20K. S. C. Chao et al., “A prospective study of salivary function sparing in Dosim. 27, 121–129 ͑2002͒. patients with head-and-neck cancers receiving intensity-modulated or 41C. M. Nutting et al., “A comparison of conformal and intensity- three-dimensional radiation therapy: initial results,” Int. J. Radiat. Oncol., modulated techniques for esophageal radiotherapy,” Radiother. Oncol. 61, Biol., Phys. 49͑4͒, 907–916 ͑2001͒. 157–163 ͑2001͒. 21A. Eisbruch et al., “Dose, volume, and function relationships in parotid 42R. B. Kuppersmith et al., “The use of intensity modulated radiotherapy salivary glands following conformal and intensity modulated irradiation for the treatment of extensive and recurrent juvenile angiofibroma,” Int. J. of head and neck cancer,” Int. J. Radiat. Oncol., Biol., Phys. 45, 577–587 Pediatr. Otorhinolaryngol. 52, 261–268 ͑2000͒. 43 ͑1999͒. A. C. Paulino and M. Skwarchuk “Intensity-modulated radiation therapy 22C. M. Nutting et al., “Improvements in target coverage and reduced spinal in the treatment of children,” Med. Dosim. 27, 115–120 ͑2002͒. 44 cord irradiation using intensity-modulated radiotherapy ͑IMRT͒ in pa- E. Huang et al., “Intensity-modulated radiation therapy for pediatric tients with carcinoma of the thyroid gland,” Radiother. Oncol. 60, 163– medulloblastoma: Early report on the reduction of ototoxicity,” Int. J. 172 ͑2001͒. Radiat. Oncol., Biol., Phys. 52, 599–605 ͑2002͒. 45 23K. Sultanem, H. K. Shu, P. Xia, C. Akazawa, J. M. Quivey, L. J. Verhey, L. Hong, K. M. Alektiar, M. Hunt, E. Venkatraman, and S. A. Leibel, and K. K. Fu “Three-dimensional intensity-modulated radiotherapy in the “Intensity-modulated radiotherapy for soft tissue sarcoma of the thigh,” treatment of nasopharyngeal carcinoma: The University of California-San Int. J. Radiat. Oncol., Biol., Phys. 59͑3͒,752–975 ͑2004͒. 46 Francisco experience,” Int. J. Radiat. Oncol., Biol., Phys. 48͑3͒, 711–722 D. M. Shepard, G. Olivera, L. Angelos, O. Sauer, P. Reckwerdt, and T. R. ͑2000͒. Mackie, “A simple model for examining issues in radiotherapy optimiza- 24J. C. Roeske, A. Lujan, J. Rotmensch, S. E. Waggoner, D. Yamada, and tion,” Med. Phys. 26͑7͒, 1212–1221 ͑1999͒. 47 A. J. Mundt “Intensity-modulated whole pelvic radiation therapy in pa- E. J. Hall and C. Wuu, “Radiation-induced second cancers: The impact of 3D-CRT and IMRT,” Int. J. Radiat. Oncol., Biol., Phys. 56,83–88͑2003͒. tients with gynecologic malignancies,” Int. J. Radiat. Oncol., Biol., Phys. 48 48͑5͒, 1613–1621 ͑2000͒. D. B. Mansur, E. E. Klein, and B. P. Maserang, “Measured peripheral 25A. J. Mundt et al., “Intensity-modulated whole pelvic radiotherapy in dose in pediatric radiation therapy: A comparison of intensity-modulated and conformal techniques,” Radiother. Oncol. 82͑2͒, 179–184 ͑2007͒. women with gynecologic malignancies,” Int. J. Radiat. Oncol., Biol., 49 Phys. 52, 1330–1337 ͑2002͒. A. M. Allen et al., “Fatal pneumonitis associated with intensity- 26L. Portelance et al., “Intensity-modulated radiation therapy ͑IMRT͒ re- modulated radiation therapy for mesothelioma,” Int. J. Radiat. Oncol., Biol., Phys. 65, 640–645 ͑2006͒. duces small bowel, rectum, and bladder doses in patients with cervical 50 cancer receiving pelvic and para-aortic irradiation,” Int. J. Radiat. Oncol., D. C. Rice, W. R. Smythe, Z. Liao, T. Guerrero, J. Y. Chang, M. F. McAleer, M. D. Jeter, A. Correa, A. A. Vaporciyan, H. H. Liu, R. Ko- Biol., Phys. 51, 261–266 ͑2001͒. maki, K. M. Forster, and C. W. Stevens, “Dose-dependent pulmonary 27B. D. Kavanagh et al., “Clinical application of intensity-modulated radio- toxicity after postoperative intensity-modulated radiotherapy for malig- therapy for locally advanced cervical cancer,” Semin. Radiat. Oncol. 12, nant pleural mesothelioma,” Int. J. Radiat. Oncol., Biol., Phys. 69͑2͒, 260–271 ͑2002͒. 350–357 ͑2007͒. 28C. Brixey et al., “Impact of intensity modulated whole pelvic radiation 51C. X. Yu, D. A. Jaffray, and J. W. Wong, “Effects of intra-fraction organ therapy on acute hematologic toxicity in patients with gynecologic ma- ͑ ͒ motion on the delivery of dynamic intensity modulation,” Phys. Med. lignancies,” Int. J. Radiat. Oncol., Biol., Phys. 54, 1388–1396 2002 . ͑ ͒ 29 Biol. 43, 91–104 1998 . et al. 52 L. Hong , “Intensity-modulated tangential beam irradiation of the H. D. Kubo and B. C. Hill, “Respiration-gated radiotherapy treatment: A intact breast,” Int. J. Radiat. Oncol., Biol., Phys. 44, 1155–1164 ͑1999͒. ͑ ͒ 30 technical study,” Phys. Med. Biol. 41, 83–91 1996 . Y. C. Lo et al., “Intensity modulation for breast treatment using static 53P. J. Keall, V. R. Kini, S. S. Vedam, and R. Mohan, “Motion adaptive multileaf collimators,” Int. J. Radiat. Oncol., Biol., Phys. 46, 187–194 x-ray therapy: A feasibility study,” Phys. Med. Biol. 46, 1–10 ͑2001͒. ͑2000͒. 54 31 W. D. D’Souza, S. A. Naqvi, and C. X. Yu, “Real-time intra-fraction B. van Asselen et al., “An improved breast irradiation technique using motion tracking using the treatment couch: A feasibility study,” Phys. three-dimensional geometrical information and intensity modulation,” Med. Biol. 50, 4021–4033 ͑2005͒. Radiother. Oncol. 58, 341–347 ͑2001͒. 55 32 D. A. Kuban, S. L. Tucker, L. Dong, G. Starkschall, E. H. Huang, M. R. L. L. Kestin et al., “Intensity modulation to improve dose uniformity with Cheung, A. K. Lee, and A. Pollack, “Long-term results of the M. D. tangential breast radiotherapy: Initial clinical experience,” Int. J. Radiat. Anderson randomized dose-escalation trial for prostate cancer,” Int. J. ͑ ͒ Oncol., Biol., Phys. 48, 1559–1568 2000 . Radiat. Oncol., Biol., Phys. 70͑1͒, 67–74 ͑2008͒. 33 A. Harsolia, L. Kestin, I. Grills, M. Wallace, S. Jolly, C. Jones, M. Lala, 56A. Pollack, A. Hanlon, E. M. Horwitz, S. Feigenberg, R. G. Uzzo, and R. A. Martinez, S. Schell, and F. A. Vicini “Intensity-modulated radio- A. Price, “Radiation therapy dose escalation for prostate cancer: A ratio- therapy results in significant decrease in clinical toxicities compared with nale for IMRT,” World J. Urol. 4, 200–208 ͑2003͒. conventional wedge-based breast radiotherapy,” Int. J. Radiat. Oncol., 57M. J. Zelefsky, Z. Fuks, and S. A. Leibel, “Intensity-modulated radiation Biol., Phys. 68͑5͒, 1375–1380 ͑2007͒. therapy for prostate cancer,” Semin. Radiat. Oncol. 3, 229–237 ͑2002͒. 34 R. M. Cardinale et al., “A comparison of three stereotactic radiotherapy 58S. Junius, K. Haustermans, B. Bussels, R. Oyen, B. Vanstraelen, T. techniques: ARCS vs. noncoplanar fixed fields vs. intensity modulation,” Depuydt, J. Verstraete, S. Joniau, and H. Van Poppel, “Hypofractionated Int. J. Radiat. Oncol., Biol., Phys. 42, 431–436 ͑1998͒. intensity modulated irradiation for localized prostate cancer, results from 35 D. D. Leavitt et al., “Intensity-modulated radiosurgery/radiotherapy using a phase I/II feasibility study,” Radiother. Oncol. 2,29͑2007͒. a micromultileaf collimator,” Med. Dosim. 26, 143–150 ͑2001͒. 59K. K. Fu et al., “A Radiation Therapy Oncology Group ͑RTOG͒ phase III 36 S. Derycke et al.,“Conformal radiotherapy of stage III non-small cell lung randomized study to compare hyperfractionation and two variants of ac- cancer: a class solution involving non-coplanar intensity-modulated celerated fractionation to standard fractionation radiotherapy for head and beams,” Int. J. Radiat. Oncol., Biol., Phys. 41, 771–777 ͑1998͒. neck squamous cell carcinomas: First report of RTOG 9003,” Int. J. Ra- 37J. van Sornsen de Koste et al., “An evaluation of two techniques for beam diat. Oncol., Biol., Phys. 48, 7–16 ͑2000͒. intensity modulation in patients irradiated for stage III non-small cell lung 60G. M. Freedman, N. J. Meropol, E. R. Sigurdson, J. Hoffman, E. Calla- cancer,” Lung Cancer 32, 145–153 ͑2001͒. han, R. Price, J. Cheng, S. Cohen, N. Lewis, D. Watkins-Bruner, A. 38S. Sura, V. Gupta, E. Yorke, A. Jackson, H. Amols, and K. E. Rosenzweig Rogatko, and A. Konski, “Phase I trial of preoperative hypofractionated “Intensity-modulated radiation therapy͑IMRT͒ for inoperable non-small intensity-modulated radiotherapy with incorporated boost and oral cell lung cancer: the Memorial Sloan-Kettering Cancer Center ͑MSKCC͒ capecitabine in locally advanced rectal cancer,” Int. J. Radiat. Oncol., experience,” Radiother. Oncol. 87͑1͒, 17–23 ͑2008͒. Biol., Phys. 67͑5͒, 1389–1393 ͑2007͒. 39M. T. Milano et al., “Intensity-modulated radiotherapy in treatment of 61T. Iuchi, K. Hatano, Y. Narita, T. Kodama, T. Yamaki, and K. Osato, pancreatic and bile duct malignancies: Toxicity and clinical outcome,” “Hypofractionated high-dose irradiation for the treatment of malignant Int. J. Radiat. Oncol., Biol., Phys. 59͑2͒, 445–453 ͑2004͒. astrocytomas using simultaneous integrated boost technique by IMRT,”

Medical Physics, Vol. 35, No. 12, December 2008 5240 Yu, Amies, and Svatos: IMRT planning and delivery 5240

Int. J. Radiat. Oncol., Biol., Phys. 64͑5͒, 1317–1324 ͑2006͒. 86J. Muzik, M. Soukup, and M. Alber “Comparison of fixed beam IMRT, 62A. J. Mundt and J. C. Roeske, Intensity Modulated Radiation Therapy-A helical tomotherapy, and IMPT for selected cases,” Med. Phys. 35͑4͒ Clinical Perspective ͑Decker, Toronto, 2005͒. 1580–1592 ͑2008͒. 63K. S. C. Chao, S. Apisarnthanarax, Go. Ozyigit, Practical Essentials of 87D. Cao, T. W. Holmes, M. Afghan, and D. M. Shepard “Comparison of Intensity Modulated Radiation Therapy ͑Lippincott Williams & Wilkins, plan quality provide by intensity modulated arc therapy ͑IMAT͒ and he- New York, 2004͒. lical tomotherapy,” Int. J. Radiat. Oncol., Biol., Phys., 69͑1͒, 240–250 64L. Veldeman, I. Madani, F. Hulstaert, G. De Meerleer, M. Mareel, and W. ͑2007͒. Neve De, “Evidence behind use of intensity-modulated radiotherapy: A 88G. Zhang, Z. Jiang, D. Shepard, M. Earl, and C. Yu, “Effect of beamlet systematic review of comparative clinical studies,” Lancet Oncol. 9͑4͒, step-size on IMRT plan quality,” Med. Phys. 32͑11͒, 3448–3454 ͑2005͒. 367–375 ͑2008͒. 89J. M. Galvin, G. Ezzell, A. Eisbrauch, C. Yu, B. Butler, Y. Xiao, I. Rosen, 65 K. Hatano, H. Araki, M. Sakai, T. Kodama, N. Tohyama, T. Kawachi, M. J. Rosenman, M. Sharpe, L. Xing, P. Xia, T. Lomax, D. A. Low, and J. Imazeki, T. Shimizu, T. Iwase, M. Shinozuka, and H. Ishigaki, “Current Palta, “Implementing IMRT in clinical practice: A joint document of the status of intensity-modulated radiation therapy ͑IMRT͒,” J. Clin. Oncol. American Society for Therapeutic Radiology and Oncology and the 12͑6͒, 408–415 ͑2007͒. American Association of Physicists in Medicine,” Int. J. Radiat. Oncol., 66 C. Yu, D. Shepard, M. Earl, D. Cao, S. Luan, C. Wang, and D. Z. Chen, Biol., Phys. 58͑5͒, 1616–1634 ͑2004͒. “New developments in intensity modulated radiation therapy,” Technol. 90S. Luan, C. Wang, D. Cao, D. Z. Chen, D. M. Shepard, and C. X. Yu, Cancer Res. Treat. 5͑5͒, 451–464 ͑2006͒. “Leaf-sequencing for intensity-modulated arc therapy using graph algo- 67 T. Bortfeld, “IMRT: A review and preview,” Phys. Med. Biol. 51͑13͒, rithms,” Med. Phys. 35͑1͒, 61–69 ͑2008͒. R363–R379 ͑2006͒. 91Y. Kamino, K. Takayama, M. Kokubo, Y. Narita, E. Hira, N. Kawawda, T. 68 A. Olafsson, R. Jeraj, and S. J. Wright, “Optimization of intensity- Mizowaki, Y. Nagata, T. Nishidai, and M. Hiraoka, “Development of a modulated radiation therapy with biological objectives,” Phys. Med. Biol. four-dimensional image-guided radiotherapy system with a gimble x-ray 50͑22͒, 5357–5379 ͑2005͒. head,” Int. J. Radiat. Oncol., Biol., Phys. 66͑1͒, 271–278 ͑2006͒. 69 X. Zhang, H. Liu, X. Wang, L. Dong, Q. Wu, and R. Mohan, “Speed and 92C. M. Ma, T. Pawlicki, M. C. Lee, S. B. Jiang, J. S. Li, J. Deng, B. Yi, E. convergence properties of gradient algorithms for optimization of IMRT,” Mok, and A. L. Boyer, “Energy- and intensity-modulated electron beams Med. Phys. 31͑5͒, 1141–1152 ͑2004͒. ͑ ͒ ͑ ͒ 70 for radiotherapy,” Phys. Med. Biol. 45 8 , 2293–2311 2000 . C. Cotrutz and L. Xing, “Segment-based dose optimization using a ge- 93J. J. Wilkens and U. Oelfke, “Optimization of radiobiological effects in netic algorithm,” Phys. Med. Biol. 48͑18͒, 2987–2998 ͑2003͒. ͑ ͒ ͑ ͒ 71 intensity modulated proton therapy,” Med. Phys. 32 2 , 455–465 2005 . Y. Li, J. Yao, and D. Yao, “Automatic beam angle selection in IMRT 94A. J. Lomax, E. Pedroni, H. Rutz, and G. Goitein, “The clinical potential ͑ ͒ planning using genetic algorithm,” Phys. Med. Biol. 49 10 , 1915–1932 of intensity modulated proton therapy,” Z. Med. Phys. 14͑3͒, 147–152 ͑2004͒. ͑ ͒ 72 2004 . S. P. Goldman, J. Z. Chen, and J. J. Battista, “Feasibility of a fast inverse 95D. M. Shepard, M. A. Earl, X. A. Li, S. Naqvi, and C. X. Yu, “Direct dose optimization algorithm for IMRT via matrix inversion without nega- aperture optimization: A turnkey solution for step-and-shoot IMRT,” tive beamlet intensities,” Med. Phys. 32͑9͒, 3007–3016 ͑2005͒. Med. Phys. 29͑6͒, 1007–1018 ͑2002͒. 73E. K. Lee, T. Fox, and I. Crocker, “Simultaneous beam geometry and 96K. Otto, “Volumetric modulated arc therapy: IMRT in a single gantry intensity map optimization in intensity-modulated radiation therapy,” Int. arc,” Med. Phys. 35͑1͒, 310–317 ͑2008͒. J. Radiat. Oncol., Biol., Phys. 64͑1͒,301–320 ͑2006͒. 97S. Ulrich, S. Nill, and U. Oelfke, “Development of an optimization con- 74H. E. Romeijn, R. K. Ahuja, J. F. Dempsey, A. Kumar and J. G, Li, “A cept for arc-modulated cone beam therapy,” Phys. Med. Biol. 52͑14͒, novel linear programming approach to fluence map optimization for in- 4099–4119 ͑2007͒. tensity modulated radiation therapy treatment planning,” Phys. Med. Biol. 98 48͑21͒, 3521–3542 ͑2003͒. C. Cameron, “Sweeping-window arc therapy: an implementation of rota- 75T. Bortfeld, “Optimized planning using physical objectives and con- tional IMRT with automatic beam-weight calculation,” Phys. Med. Biol. ͑ ͒ ͑ ͒ 50, 4317–4336 ͑2005͒. straints,” Semin. Radiat. Oncol. 9 1 , 20–34 1999 . 99 76Q. Wu, D. Djajaputra, Y. Wu, J. Zhou, H. H. Liu, and R. Mohan, G. Tang, M. Earl, S. Luan, S. Naqvi, and C. X. Yu, “Converting multiple- “Intensity-modulated radiotherapy optimization with gEUD-guided dose- arc Intensity-modulated arc therapy into a single arc for efficient deliv- ͑ ͒ ͑ ͒ ery,” Int. J. Radiat. Oncol., Biol., Phys. 69͑3͒, S673 ͑2007͒. volume objectives,” Phys. Med. Biol. 48 3 , 279–291 2003 . 100 77J. Lian, C. Cotrutz, and L. Xing, “Therapeutic treatment plan optimization C. Wang, S. Luan, G. Tang, D. Z. Chen, M. Earl, and C. Yu, “Arc- ͑ ͒ with probability density-based dose prescription,” Med. Phys. 30͑4͒, 655– modulated radiation therapy AMRT : A single-arc form of intensity- ͑ ͒ ͑ ͒ 666 ͑2003͒. modulated arc therapy,” Phys. Med. Biol. 53 22 , 6291–6303 2008 . 101 78D. Craft, T. Halabi, H. A. Shih, and T. Bortfeld, “An approach for prac- M. A. Earl, M. K. N. Afghan, C. X. Yu, Z. Jiang, and D. M. Shepard, ͑ ͒ tical multiobjective IMRT treatment planning,” Int. J. Radiat. Oncol., “Jaws-only IMRT using direct aperture optimization,” Med. Phys. 34 1 , Biol., Phys. 69͑5͒, 1600–1607 ͑2007͒. 307–314 ͑2007͒. 102 79L. C. O. Haas, K. J. Burnham, and J. A. Mills, “Optimization of beam Y. Kim, L. J. Verhey, and P. Xia, “A feasibility study of using conven- orientation in radiotherapy using planar geometry,” Phys. Med. Biol. 43, tional jaws to deliver IMRT plans in the treatment of prostate cancer,” 2179–2193 ͑1998͒. Phys. Med. Biol. 52͑8͒, 2147–2156 ͑2007͒. 103 80C. G. Rowbottom, S. Webb, and M. Oldham, “Beam orientation customi- M. A. Earl et al., “Inverse planning for intensity-modulated arc therapy zation using an artificial neural network,” Phys. Med. Biol., 44, 2251– using direct aperture optimization,” Phys. Med. Biol. 48, 1075–1089 2262 ͑1999͒. ͑2003͒. 104 ® 81J. Stein, R. Mohan, X. Wang, T. Bortfeld, Q. Wu, K. Preiser, C. Ling, and W. Hara, S. G. Soltys, and I. C. Gibbs, “CyberKnife robotic radiosurgery W. Schlegel, “Number and orientations of beams in intensity-modulated system for tumor treatment,” Expert Review Anticancer Therapy 7͑11͒, radiation treatments,” Med. Phys. 24͑2͒, 149–160 ͑1997͒. 1507–1515 ͑2007͒. 105 82A. Pugachev, A. Boyer, and L. Xing, “Beam orientation optimization in U. Titt, O. N. Vassiliev, F. Ponisch, L. Dong, H. Liu, and R. Mohan, “A intensity-modulated radiation treatment planning,” Med. Phys. 27͑6͒, flattening filter free photon treatment concept evaluation with Monte 1238–1245 ͑2000͒. Carlo,” Med. Phys. 33͑6͒, 1595–1602 ͑2006͒. 83E. Ludlum and P. Xia, “Comparison of IMRT planning with two-step and 106D. A. Jaffray, “Emergent technologies for 3-dimensional image-guided one-step optimization: A way to simplify IMRT,” Phys. Med. Biol. 53, radiation delivery,” Semin. Radiat. Oncol. 15͑3͒, 208–216 ͑2005͒. 807–821 ͑2008͒. 107R. Jeraj, C. Wu, G. H. Olivera, and T. R. Mackie, “Re-optimization in 84D. M. Shepard, D. Cao, M. K. Afghan, and M. A. Earl, “An arc- adaptive radiotherapy” Phys. Med. Biol. 47, 3181–3195 ͑2002͒. sequencing algorithm for intensity modulated arc therapy,” Med. Phys. 108R. Mohan, X. Zhang, H. Wang, Y. Kang, X. Wang, H. Liu, K. K. Ang, D. 34,464–470͑2007͒. Kuban, and L. Dong, “Use of deformed intensity distributions for on-line 85P. Mavroidis, B. C. Ferreira, C. Shi, B. K. Lind, and N. Papanikolaou, modification of image-guided IMRT to account for interfractional ana- “Treatment plan comparison between helical tomotherapy and MLC- tomic changes,” Int. J. Radiat. Oncol., Biol., Phys. 61͑4͒, 1258–1266 based IMRT using radiobiological measures,” Phys. Med. Biol. 52͑13͒, ͑2005͒. 3817–3836 ͑2007͒. 109Y. Feng, C. Castro-Pareja, R. Shekhar, and C. Yu, “Direct aperture

Medical Physics, Vol. 35, No. 12, December 2008 5241 Yu, Amies, and Svatos: IMRT planning and delivery 5241

deformation—An inter-fraction image guidance strategy,” Med. Phys. radiation dose calculation,” IEEE Symposium on Field-Programmable 33͑12͒, 4490–4498 ͑2006͒. custom Computing Machines ͑FCCM͒ April 2006. 110E. Ahunbay, G. Chen, C. Peng, C. Yu, S. Narayanan, X. A. Li, and C. 112C. C. Ling, J. Humm, S. Larson, H. Amols, Z. Fuks, S. Leibel, and J. A. Lawton, “An on-line adaptive planning strategy for inter-fraction image Koutcher, “Towards multidimensional radiotherapy ͑MD-CRT͒: Biologi- guidance” Med. Phys. 35͑8͒, 3607–3615 ͑2008͒. cal imaging and biological conformality,” Int. J. Radiat. Oncol., Biol., 111K. Whitton, X. Hu, C. Yu, and D. Z. Chan, “An FPGA solution for Phys. 47͑3͒, 551–560 ͑2000͒.

Medical Physics, Vol. 35, No. 12, December 2008 The future of heavy ion radiotherapy ͒ Oliver Jäkela Department of Medical Physics in Radiation Oncology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany and Heidelberg Ion Beam Therapy Center (HIT), Heidelberg, Germany Christian P. Karger Department of Medical Physics in Radiation Oncology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany Jürgen Debus Department of Radiation Oncology and Radiotherapy, University Clinic Heidelberg, Heidelberg, Germany and Heidelberg Ion Beam Therapy Center (HIT), Heidelberg, Germany ͑Received 5 February 2008; revised 19 September 2008; accepted for publication 22 September 2008; published 18 November 2008͒ Currently, there is an increasing interest in heavy ion radiotherapy ͑RT͒ and a number of new facilities are being installed in Europe and Japan. This development is accompanied by intensive technical, physical, and clinical research. The authors identify six research ﬁelds where progress is likely and propose a thesis on the expected achievements for each of the ﬁelds: ͑1͒ Synchrotrons with active energy variation and three-dimensional beam scanning will be the standard in ion beam RT. ͑2͒ Common standards for precise measurement, prescription, and reporting of dose will be available. ͑3͒ Intensity-modulated particle therapy will be state-of-the-art. ͑4͒ Time-adaptive treatments of moving targets will be feasible. ͑5͒ Therapeutic effectiveness of heavy ions will be known for the most important indications while cost effectiveness will remain to be shown. ͑6͒ The potential of high-linear energy transfer radiation will be known. The rationale for each of these theses is described. © 2008 American Association of Physicists in Medicine. ͓DOI: 10.1118/1.3002307͔

Key words: radiotherapy, heavy ions, heavy charged particles, relative biological effectiveness ͑RBE͒, high-LET

I. BACKGROUND To arrive at a biologically homogeneous dose distribution, a RBE model has to be included into the treatment planning The interest in heavy ion radiotherapy ͑RT͒ is currently in- 1–4 system. This model has to consider the rather complex decreasing worldwide. Similar to protons, heavy ions exhibit pendence of the RBE on LET, dose per fraction, the amount an inverted depth dose profile, the so-called Bragg curve, of projectile fragmentation, the cell or tissue type irradiated, which concentrates the dose at the end of the particle range. as well as on the selected biological endpoint. The depen- By superimposing several monoenergetic Bragg curves, the dence of the RBE on biological properties means that the Bragg peak can be spreadout to the extension of the tumor in therapeutic benefit may strongly depend on the combination depth, while still preserving an advantageous dose ratio be- of the normal- and tumor-tissue type and on the regarded tween tumor and normal tissue. The degree of conformality biological end point ͑e.g., early versus late effects͒. Experi- of charged particles was further enhanced by introducing active scanning techniques, which allow dose conformation not ence gained for one tumor entity may not be transferred to only at the distal but also at the proximal edge of the tumor another and the biological properties of heavy ions may even for each field.5 be disadvantageous for some tumors. As the linear energy transfer ͑LET͒ of heavy ions in- Pioneering work in heavy ion RT has been performed at ͑ ͒ creases significantly towards the end of their range, heavy the Lawrence Berkley Laboratory USA , where 2054 pa- ions are biologically more effective in the peak- than in the tients were treated with helium ions between 1957 and 6,7 plateau region, if the same dose is applied to the same tissue. 1992. Between 1975 and 1992, 433 patients have been 7,8 This behavior is considered by introducing the relative bio- treated with heavier ions ͑Ne, N, O, C, Si, Ar͒. Currently, logical effectiveness ͑RBE͒, which is defined as the ratio of a heavy ion RT is performed at three centers in Japan ͑HI- 9,10 11 photon dose to the corresponding iso-effective ion dose.5 MAC, Chiba and HIBMC, Hyogo ͒ and Germany ͑GSI, Therefore, dose has to be prescribed in terms of biologically Darmstadt͒. These centers all use carbon ions and have equivalent dose ͑=absorbed doseϫRBE͒ rather than ab- treated approximately 3500 patients ͑3000 patients at HI- sorbed dose. It is the difference of the increased RBE be- MAC until 12/2006, 430 at GSI until 8/2008, and 93 at tween the peak and the plateau regions which potentially HIBMC until 02/2007͒. The next heavy ion facilities, which increases the therapeutic effectiveness of heavy ion therapy will be brought into clinical operation, are the Heidelberg Ion relative to proton therapy. Therapy facility ͑HIT, Germany͒͑Fig. 1͒,12,13 the CNAO fa-

FIG. 1. Three-dimensional view of the new HIT facility at the University Hospital Heidelberg. The path of the ions is outlined by the red line from the two ion sources on the left ͑for protons and carbon ions͒, through the linac injector into the synchrotron ͑upper left part͒, following the high energy beam-lines towards the three treatment rooms equipped with two fixed horizontal beam lines and an isocentric gantry. ͑Courtesy by Stern, Gruner +Jahr AG & CO KG, Germany.͒ cility in Pavia ͑Italy͒,14,15 and the Gunma University Heavy Ion Medical Center ͑GHMC, Japan͒. ͓An experimental treatment facility at a research laboratory has also been set up in Lanzhou ͑China͒ and in November 2006 the treatment of patients with superficially-seated tumors has started ͑a maxi- FIG. 2. For passive beam delivery ͑a͒ the dose distribution is shaped by four ͑ mum energy of 100 MeV/u has been used16͔͒. Currently, components: the range shifter, the modulator wheel or alternatively a ridge filter͒, the collimator, and the compensator. The modulation depth is con- heavy ion RT is a matter of intensive technical, physical, and stant over the tumor cross section. For active beam delivery ͑b͒, a monoen- clinical research and our knowledge about feasibility, safety, ergetic pencil beam is scanned over the tumor cross section. After one slice and effectiveness will certainly increase within the next de- is irradiated the energy of the beam is switched actively ͑or passively, in ͒ ͑ cade. case of a range shifter to the next energy. Reprinted from Ref. 4 with permission of Springer.͒

II. CURRENT STATUS Currently, the only available sources for high energy ion It should be noted that a more flexible beam delivery sys- beams in radiotherapy are synchrotrons, which due to their tem based on the elements of passive systems has been de- size and complexity are the main reason for the large capital veloped and is explored at HIMAC. This so-called layer- investment necessary to build a clinical ion beam facility. stacking method10 uses a sequence of different modulators Another aspect of the currently used beam delivery systems each with only a small modulation depth, which are then is that they all rely on fixed beam lines: either horizontal stacked in depth to achieve the desired depth dose distribu- ͑HIMAC and GSI͒, vertical ͑HIMAC and HIBMC͒,orin- tion. A multileaf collimator is used to adapt the field size to clined by 45° ͑HIBMC͒, rather than gantry systems. the target in each layer. This method leads to a much better Both Japanese heavy ion beam facilities rely on a so- conformation of the dose to the target volume, similar to a called passive beam delivery system similar to the one de- scanning system. veloped in Berkeley ͓Fig. 2͑a͔͒. This system uses a beam To efficiently measure dose distributions generated with which is extracted from a synchrotron at a fixed energy and the dynamic beam scanning system, multichannel detector is then spread laterally as well as in depth, using passive systems are used rather than single ion chamber measure- beam shaping techniques: a wobbler magnet in combination ments, which are a standard for passive techniques. Although with a scattering system is used to produce a broad beam, the dosimetry of heavy ion beams was already harmonized which is then tailored to the target volume by a collimation by the introduction of the Code of Practice published by the system; the depth dose modulation ͑called the spread-out International Atomic Energy Agency ͑TRS-39817͒, the over- Bragg peak͒ is achieved by a ridge filter, variable range all uncertainty of dose determination in ion beams is still shifter plates, and a patient specific compensator. In contrast, considerably larger than in conventional radiotherapy. More- the newly designed European ion facilities all rely on the over, there is no common standard for the reporting of bio- method of active energy variation and pencil beam scanning, logical effective dose and RBE in ion beam therapy. which was developed in the 1990s at the GSI facility ͓Fig. For a passively modulated beam, the variation of the RBE 2͑b͔͒. with depth has to be taken into account in the design of the

Medical Physics, Vol. 35, No. 12, December 2008 5655 Jäkel, Karger, and Debus: The future of heavy ion radiotherapy 5655 ridge filters or modulators ͑i.e., the hardware͒. With the se- ning for ion beams the standard technique for all new lection of a certain modulator, the depth modulation, and clinical ion beam facilities. Furthermore, the develop- hence, the RBE profile is thus fixed. As the RBE profile ment of gantry systems for ions will continue and at depends not only on the treatment schedule ͑e.g., dose per least some new facilities will install gantries. fraction, number of daily applied fields͒ but also the type of ͑2͒ Dosimetry: Common standards for precise measure- tumor and normal tissue or the optimization technique ͑mul- ment, prescription, and reporting of dose will be tiple fields versus single field optimization͒, the flexibility of available. passive systems is limited. The realization of an intensity The overall uncertainty in determining the absorbed modulated particle beam therapy ͑IMPT͒ was also never re- dose to water in an ion beam will be at the same level as alized with a passive beam application system although in for megavoltage x rays today. The main improvements principle the above mentioned layer-stacking system offers will come from a better knowledge of the underlying this possibility. physical parameters. Water calorimetry will serve as ref- While it is the current standard in ion beam therapy to erence dosimetry and multichannel dosimetry systems detect interfractional movements of bony structures or metal will facilitate the measurement of two-dimensional ͑2D͒ markers by orthogonal x rays and to correct for thereafter, and 3D dose distribution. There will be standardized the management of intrafractional movement is more diffi- methods to report the biological effective dose and the cult. Due to the quasistatic treatment fields obtained with RBE. passive beam shaping techniques, the treatment of moving ͑3͒ Treatment planning: Intensity-modulated particle organs is not much different from that in conventional radiotherapy will be state-of-the-art. therapy with photons. It has been shown at HIMAC that The advancements of IMRT in conventional and pro- respiratory gating of the beam, e.g., by optical motion detec- ton radiotherapy will immediately be introduced in ion tion, can be used for ion beam therapy.18 The only additional beam therapy. The principles of IMPT based on the op- problem is the increased treatment time due to the pulsed timization of biological effective dose have been devel- beam. For the current beam scanning systems, however, the oped and, due to the rapid increase of computing power, treatment of moving organs is a much greater challenge due will be incorporated in any treatment planning system to interplay effects between organ motion and the scanned for ion beams. IMPT can and will further improve the beam ͑for a detailed discussion see Ref. 19͒. conformality of the applied dose distributions. Since The clinical experience gained with ion beams so far is beam delivery by active beam scanning is intrinsically very limited. The effectiveness of ion beams was demon- controlling and modulating the intensity, IMPT will be strated only for a limited number of tumors and with limited much more straightforward to be implemented as it was patient numbers ͑an overview of clinical data is found in for conventional RT with open fields and therefore re- Refs. 9 and 20–22͒. Moreover, the potential advantages of quires little to no additional effort for quality assurance. high LET radiation versus low LET could only be demon- ͑4͒ Moving organs: Time-adaptive treatments of moving tar- strated by comparison with historical clinical results and not gets will be feasible. by directly comparing proton and ion beams in the same Although the principal problem is the same for pho- setting. The available clinical data are mainly obtained using tons and ions, it has to be considered that organ move- carbon ions and are very scarce for other high LET ions.8 ments do not only change the lateral position of the target, but also its radiological depth, and hence, the III. WHERE WE WILL BE IN 10 YEARS required range of the ions. For heavy ions, changes in the depth modulation may also require a repeated opti- Although it is difficult to make predictions about the fu- mization of the biologically effective dose. In the future, ture, current research activities point to six fields, in which interfractional movements will be detected by on-board progress is likely on the one hand, but also mandatory on the imaging and will be compensated by setup corrections other hand to fully exploit the potential of heavy ion RT. In and if necessary also by adaptation of the treatment plan. the following, we start with a thesis related to each of the six Intrafractional organ movements will be monitored in fields accompanied by a brief description of what we think real time and will be compensated to some extent by the major achievements will be. using gating or tracking techniques. Improved imaging ͑1͒ Beam production and delivery: Synchrotrons with active technology ͓like on-board cone beam computed tomog- energy variation and three-dimensional ͑3D͒ beam scan- raphy ͑CT͔͒ will also allow direct visualization of the ning will be the standard in ion beam RT. tumor and soft tissue structures, rather than just bony Although different compact designs of ion beam ac- structures or markers. celerators are being investigated today, none of them ͑5͒ Clinical application: The therapeutic effectiveness of will be available for clinical use within the next decade. heavy ions will be known for the most important indi- The design of compact and maybe superconducting syn- cations. The cost effectiveness of heavy ion therapy, chrotrons will be optimized in terms of performance, however, will still have to be shown. stability, and costs. The techniques used to precisely With the upcoming of new heavy ion centers, the control the position and intensity of an ion beam will most important question is related to the safety and ef- advance strongly and will make 3D pencil beam scan- fectiveness of this new treatment modality. Both aspects

Medical Physics, Vol. 35, No. 12, December 2008 5656 Jäkel, Karger, and Debus: The future of heavy ion radiotherapy 5656

may depend on the RBE model used for optimization of ϳ10 nm͒. These beams are very intense ͑1012 protons per the biologically effective dose as well as on the treated pulse͒ and well collimated. In several research institutions, indications. Due to the uncertainties involved in the protons have been accelerated ͑up to 58 MeV in one institu- RBE models this especially includes the empirical deter- tion͒, when lasers with intensities of about 1020 Wcm−2 mination of the optimal biologically effective dose. Con- were applied.24 Probably the intensity has to be further in- siderable clinical experience in using heavy ion beams creased. The ion pulses are very short ͑in the picosecond has been gained in Berkeley and Chiba using passive range͒ and intense ͑several picocoulomb charge͒. The energy 6,8,9,11 beam delivery techniques, as well as for active sys- of the heavy charged particles, however, is distributed over a 20–23 tems at GSI. The number of patients treated with broad thermal spectrum with only a small intensity at high heavy ions will increase significantly within the next energies. decade and the indications for which heavy ion therapy Another concept that has recently been developed is based is most promising will be identified. on a new class of insulators called high gradient insulators The cost for a proton or an ion beam facility is con- ͑HGI͒, which feature significantly improved voltage holding siderably higher than for a conventional megavoltage ability over conventional insulators. Using these HGI, a new x-ray accelerator. This is due to the machine costs itself, type of induction linac was designed: the so-called dielectric but also due to the larger buildings, shielding require- wall accelerator ͑DWA͒. A conventional induction linac has ments as well as technical equipment, and additional an accelerating field only in the gap of the accelerating cells, manpower needed to operate such a facility. This raises which represent only a small fraction of the length. By re- the question if proton or ion beam therapy can ever be placing the conducting beam pipe by an insulating wall, ac- cost effective. This question is highly complex as its celerating fields can be applied uniformly over the entire answer requires reasonable input data on both, therapeu- length of the accelerator yielding a much higher gradient tic effectiveness as well as socioeconomic costs. ͑around 100 MeV/m͒ allowing the design of much more ͑6͒ Radiobiology: The potential of high-LET radiation will compact linear accelerators. The pulsed acceleration field is be known. developed by a series of so-called asymmetric Blumlein The simpler question of the effectiveness of heavy structures incorporated into the insulator.25,26 At the ion therapy has to be separated from the more difficult Lawrence Livermore National Lab, a prototype of a proton- question, if there is an increased effectiveness due to the DWA is currently being built and design studies for a high-LET component of heavy ions. Although the physi- 250 MeV proton accelerator with an overall length of less cal dose distributions are quite similar for heavy ions than 3 m have been presented.27 This DWA will produce a and protons, heavy ions are expected to be more effi- 100 mA beam current in a short pulse of 1 ns with variable cient in the Bragg peak than in the plateau region. Al- energy and focus. Such a compact accelerator mounted di- though there are radiobiological as well as some clinical 2,5,8,9 rectly on a gantry would allow the design of much more data supporting this assumption, this has to be validated in clinical trials and further experimental studies. compact treatment facilities. These investigations will lead to an improved under- Both systems lead to a much more compact design of the standing of the high-LET effect and the increased bio- treatment machines which would drastically reduce the over- logical effectiveness of heavy ions will be proven—or all costs of the facilities. Consequently, there is a strong fi- disproven—at least for some indications. Most likely, nancial interest, which might push the development of these these activities will be focused on the comparison of machines, so that these systems may become available for carbon ions and protons. Other ions such as helium or proton RT at the end of the next decade, for ion beams, oxygen will primarily be investigated within feasibility however, they will not be available within this time frame. studies. The first reason is that due to the higher energy needed, e.g., for a 12C beam, the DWA structure would be increased by at least a factor of 2 in length. Using laser induced accelerators, IV. THE DEVELOPMENTS IN THE NEXT DECADE even with much increased laser power, the intensities of the ion beam at these high energies will still be too small. An- IV.A. Beam production and delivery other unsolved problem is if and how beam scanning can be Two new designs of accelerators are currently being dis- realized with the very short and high intensity pulses from a cussed, which would be more compact, and hence, cheaper DWA or laser induction. than current solutions. Although a single DWA would probably be cheaper than a The first one uses laser induced acceleration of ions. Here, synchrotron, it can be used to operate only a single treatment a very high-intensity laser incidents on a thin metal target room, while a synchrotron can easily be operated with 3–5 and causes ionization. An electromagnetic shockwave causes treatment rooms. So unless the price of a DWA is signifi- electrons to be accelerated in the target, which then ionize cantly lower than for a synchrotron ͑around 20 M€, e.g., for the molecules on the backsurface of the target. The cloud of the synchrotron at the HIT facility͒, this will not be a cost electrons is then emitted from the backsurface, causing a effective solution. With this respect, laser induction may be very strong electrostatic field ͑ϳ1013 Vm−1͒ that accelerates more efficient, as a single laser could in principle be operated protons and ions from the backlayer of the target ͑thickness in combination with several treatment rooms.

Medical Physics, Vol. 35, No. 12, December 2008 5657 Jäkel, Karger, and Debus: The future of heavy ion radiotherapy 5657

The research needed to solve all the technical problems ticle spectra and the chamber specific correction factors. encountered in a compact ion accelerator based on a DWA or There are two major directions that will be followed here: laser induction are still enormous and it is very unlikely that one is the improvement of nuclear physics models to calcu- these will be solved within the next 1 or 2 decades. Rather, late fragmentation cross sections and secondary particle the existing accelerator designs will be optimized using, e.g., spectra and the other one is the inclusion of secondary elec- superconducting magnets to build more compact synchrotrons produced by this spectrum of charged particles and trons. For gantries also the use of superconducting fixed field which is important to understand the chamber specific cor- alternating gradient magnets is discussed to dramatically re- rections. duce the overall weight of a carbon gantry from around In combination with the broader introduction of dynamic 600 tons to only 1–2 tons ͑referring to the mass of the beam scanning systems, the development of efficient multi- beam-line only, the mass of the mechanical structure is pos- channel dosimetry systems will continue. There are already a sible in the same range͒.28 number of detector systems developed for particle physics Compact superconducting cyclotrons with diameters of applications that are currently investigated in view of their less than 6 m have also been proposed for ion beam use in proton and ion beam dosimetry. This includes so- therapy.29 Since cyclotrons do not allow for an active energy called gas electron multiplier ͑GEM͒ chambers, silicon pixel variation, it has yet to be shown, if these machines will be a detectors, or polycrystalline planar diamond detectors. serious alternative to synchrotrons. A more interesting devel- GEM chambers32 can be used as large area tracking de- opment is the combination of a commercial cyclotron ͑used, tectors with high temporal and spatial resolution ͑1 ms and e.g., for isotope production͒ as an injector for a compact 40 ␮m, respectively͒. In combination with a scintillator for linear accelerator of about 20 m length, acting as a booster. residual energy measurements they were used already for The new system is called cyclinac15 and has the advantage, time resolved radiography or as beam profile monitors.33 that no extraction or injection is needed. Thus, a continu- Silicon pixel detectors with pixel sizes around 50 ␮m al- ously extracted beam could be produced with a 1 ␮s pulse low measuring single particle events with little to no per millisecond and fast energy variation also within a mil- background.34,35 These so-called active nuclear emulsions lisecond. Especially this latter feature would be useful for the have been used for x ray and neutron tomography to resolve treatment of moving organs. tiny anatomical structures, e.g., in insects.36 The detector signal is proportional to the energy loss in the detector and may be used to discriminate particles and thus allow for a direct IV.B. Dosimetry dose determination. The Code of Practice for dosimetry ͑TRS-398͒17 is used Finally, extremely thin ͑less than 50 ␮m͒ polycrystalline in both, the Japanese and German ion beam facilities and can diamond detectors with millimeter resolution can yield a be considered a standard today. Accordingly, the dose in 100% efficiency for particle counting even at high count heavy ion fields can already be measured with an uncertainty rates, which makes them interesting for monitoring of the of 3% and further improvements will be rather small. Nev- beam position, intensity, and profile during application while ertheless, the basic quantities, like stopping powers for ions, minimizing the interaction with the beam.37 fragmentation spectra, and w values, but also the chamber Finally, the prescription, recording, and reporting of bio- specific correction factors have to be determined more pre- logical effective doses and RBE will be standardized when cisely to arrive at the same level of accuracy as for photon more clinical facilities become operational. This especially therapy. Moreover, the beam application using dynamic ras- includes specification of the applied RBE model, its version, ter scanning asks for multichannel detector systems that still the physical and biological parameters used for the RBE cal- have to be developed. culation in tumor and normal tissues as well as the biological Determination of absorbed dose to water currently relies end point to which the RBE-calculation refers to. This prob- of ionization chambers calibrated in a 60Co beam. In the long lem is currently being addressed by a new committee of the term, water calorimeters will allow a more direct measure- International Commission on Radiation Units.38 ment of absorbed dose to water.30 The only correction appearing in calorimetry is the so-called heat deficiency, which IV.C. Treatment planning quantifies the amount of radiation energy converted into chemical binding energies rather than into heat. This correc- The prototype system for radiotherapy planning for a tion typically is less than 1% and—according to current scanned carbon ion beam developed for the GSI facility al- knowledge—depends only little on the beam quality.31 If ready incorporates all features needed for intensity modu- these preliminary findings will be confirmed, it is very likely lated ion beam therapy. To achieve a homogenous biological that calorimetry can be used as primary standard for ion effect even for a single field, it is necessary to optimize and beams in the same way as already done for megavoltage control the number of ions at each scan spot. This intrinsi- x-rays today in some countries. cally implies a modulation of the intensity ͑or rather fluence͒ Another important gain of knowledge of physical param- of the ion beam at each beam spot. Since the depth dose eters will come from Monte Carlo simulations which are just modulation in that case is varying throughout the radiation being established as a new tool for dosimetry of ion beams. field, a detailed biological modeling of the RBE had to be This will affect especially the knowledge of secondary par- included in the treatment planning system.39

Medical Physics, Vol. 35, No. 12, December 2008 5658 Jäkel, Karger, and Debus: The future of heavy ion radiotherapy 5658

FIG. 3. Distribution of the biological effective dose for the irradiation of a skull base tumour, using two nearly opposing lateral ﬁelds of carbon ion ions. The treatment plans on the left and right side were generated with a separate and a simultaneous optimization of the dose distributions in both ﬁelds, respectively. The target volume ͑thick line͒ is shown together with the isodose lines at 90%, 80%, 70%, 50%, 30%, and 10% of the prescribed dose, respectively.

Simultaneous optimization of multiple fields is an impor- uncertainty may vary significantly for different beam angles, tant feature of IMPT and its technical realization is in prin- automatic optimization algorithms for the beam angles ciple just a numerical problem, since the particle numbers of should be designed to reduce these uncertainties to a mini- all beam spots of all fields have to be optimized at the same mum. time, rather than separately. Due to the large number of beam spots per field ͑typically 50 000 for a skull base tumor͒, the IV.D. Moving organs required computer memory and computing time is currently IV.D.1. Interfractional motion ͑ considerably typically 1.2 GB and 4000 s on a 1.2 GHz 15 ͒ In upcoming heavy ion facilities, on-board x-ray imag- Power4-CPU, respectively . With the expected increase in 12,13 computing power, however, this will not be a serious restric- ing devices will be state-of-the-art. These devices may be tion in the near future. IMPT has already been clinically used to detect translational or rotational setup errors between applied at GSI with the existing scanning technology and fractions by planar or cone-beam imaging. If no significant without additional efforts for the quality assurance.40,41 Start- deformations are present, translational setup corrections can ing from this basis, clinical application of IMPT will con- be automatically applied to the treatment couch. In case of a tinuously be developed. Figure 3 shows an example of an robotic couch, rotational corrections around three axes will IMPT plan including optimization of biological effective also be feasible. doses. If deformations are significant, however, an adaptive ap- Due to the sharp dose gradients especially at the distal end proach would need a quasi-instantaneous modification of of the Bragg peak, setup errors, organ movements, and range contours and reoptimization of the treatment plan. For heavy uncertainties may have significant impact on the quality of ion RT, however, reoptimization must also include the bio- the dose distributions. Resulting over- and undershooting has logically effective dose and for the near future, it seems not to be considered by adequate safety margins, which may be very likely that this can be realized in an acceptable time. As determined, e.g., by simulated target point displacements or an alternative, different treatment plans for different repre- modified CT-number/range-calibration curves. By introduc- sentative geometries may be prepared. In the actual treatment ing IMPT, it has been shown that setup errors do not lead to situation, the most suitable plan can then be selected. worse treatment plans than without IMPT and therefore, robustness against setup-related range uncertainties will be in- IV.D.2. Intrafractional motion cluded as an additional constraint in the dose optimization The most significant source of intrafractional movements process. is respiratory motion,42,43 although motion of heart44 or pros- Since the number of fields applied in ion beam therapy is tate ͑induced, e.g., by peristaltic motion and variation of or- generally smaller than in photon IMRT, the selection of gan filling͒45,46 may also be important. To compensate for proper beam angles becomes more important. As the range respiratory motion, several concepts have been developed.

Medical Physics, Vol. 35, No. 12, December 2008 5659 Jäkel, Karger, and Debus: The future of heavy ion radiotherapy 5659

Increasing margins as recommended for photon RT ͑Ref. be clinically implemented in the near future as this technique 47͒ may assure target coverage. In contrast to photon RT, solely requires reproducibility of a single breathing phase however, motion-related changes of the required particle rather than that of the complete breathing cycle. range may also lead to large margins in beam direction,48 and hence, to additional high dose contributions in normal tissue. IV.E. Clinical application If dose is delivered actively, target coverage may be dis- turbed by interplay effects between beam scanning and target IV.E.1. Therapeutic effectiveness movements, which may lead to hot or cold spots,50 and A relatively large number of indications has already been hence, cannot be considered by increased margins. To com- investigated in numerous clinical trials with carbon ion RT pensate for such effects, a rescanning technique was using the passive beam delivery and a lot of experience on suggested,50 which averages the effect of irradiations at dif- safety and effectiveness of this method has been gained.9 ferent breathing phases. Also for active scanning systems a number of clinical trials More advanced techniques attempt to compensate respira- have been performed but the experience is limited to very tory motion by gating on a stable breathing phase10,18 or by few indications, where organ motion is not important.20,21,23 tracking of the tumor motion.19 For passive beam delivery As the depth modulation for active techniques varies over the systems, gating is already clinically applied.10,18 For active tumor cross section, the RBE has to be calculated locally at systems, however, irradiation time may increase significantly each point in the treatment field rather than by using fixed due to the interplay between respiratory motion and duty RBE profiles. As compared to passive techniques, this may cycle of the synchrotron. This delivery time may be reduced introduce an additional source of uncertainty. to a certain extent by gating also the extraction of the beam With upcoming of the new hospital-based facilities with from the synchrotron. Remaining interplay effects due to reactive beam delivery systems additional indications will be sidual motion of the target may be compensated by investigated. These will include other malignant brain tu- rescanning.50 mors, prostate carcinomas, pancreatic tumors and, if motion Successful tracking of tumor motion would lead to opti- compensation techniques for scanned beams are better un- mal dose coverage of the target while minimizing the dose to derstood, also lung tumors. For some indications, the use of normal tissue. This approach is only feasible with a scanning ion beams only may be problematic due to the involved beam system and some developments have already been range uncertainties. For these indications, a combined treat- made.49,51,52 Here, the change of the lateral tumor position is ment with photon IMRT and an ion beam boost may be of compensated by the scanner magnets in real time. Changes significant impact. To find the optimal dose, the experience of radiological depth are additionally corrected by a obtained with passive beam delivery systems can be valu- computer-controlled range shifter consisting of opposing able. PMMA ͑polymethyl methacrylate͒ wedges.52 Depending on It is likely that initial studies will be performed with car- the actual breathing phase, the beam delivery system bon ions using relatively conservative fractionation regimes switches to one out of several treatment plans, each of them as they have been applied, e.g., with the scanned beam at optimized on a different phase of a four-dimensional GSI for most of the patients ͑with doses of 3–3.5 GyE per ͑4D͒-CT.51 fraction͒. For the new indications, dose escalation studies The necessity to calculate the range on a 4D-CT may have to be performed to maximize local control at acceptable involve additional uncertainties as 4D-CT protocols differ normal tissue toxicity rates. Hypofractionated treatment considerably from conventional CT protocols, and hence, the schedules may also be of interest. These, however, have to be relation between Hounsfield numbers and range may also be invented very carefully as the fractionation effect of heavy different. This aspect has to be investigated thoroughly prior ions in the plateau region is known to be similar as for pho- to clinical application 4D-CTs for ion beam therapy. tons, and hence, hypofractionation may lead to high biologi- Although technical aspects of tracking have already been cally effective doses in the normal tissue. Some experience developed and the potential benefit for the patient has been may be gained from the clinical trials at HIMAC, where demonstrated,51,52 the most severe obstacle is the real-time several hypofractionated schedules were investigated.9 determination of the actual tumor position. Using surrogate When scanned beams are applied to moving organs, the signals from external markers or breathing belts during treat- potential interplay between the scanned beam and organ moment planning CT and the actual treatment may not be suf- tion requires a new indication-related assessment of safety ficient as the correlation of these signals with the tumor po- and efficiency. To achieve this, additional clinical phase I/II sition is not always reproducible.53–55 Therefore, it seems trials have to be performed. Similarly, if new or modified likely that additional fluoroscopic images are required to as- RBE models are to be introduced in clinical routine, they sure that the tumor position is as expected. This, however, may lead to changes in the delivered biologically effective requires real-time image analysis and, in contrast to photon dose, which have to be evaluated in clinical studies. therapy, implantation of metallic fiducials as landmarks may Of special interest for ion beam therapy is the treatment of have a larger impact on the range of the particles and thus the radioresistant tumors. Therefore, a central issue is the inves- dose distribution ͑depending on the size and location of the tigation of the effectiveness for hypoxic tumors, which are marker͒. known to be highly radioresistant against low-LET radiation. In view of these problems, it is likely that only gating will The increase of the required dose for hypoxic tumors is de-

Medical Physics, Vol. 35, No. 12, December 2008 5660 Jäkel, Karger, and Debus: The future of heavy ion radiotherapy 5660

pediatric patients. For scanning techniques, the neutron dose is estimated to be 4.3 mSv/GyE,57 but further measurements as well as clinical long term follow-up of patients is needed to quantify the risk of the neutron component. Generally, a larger number of neutrons is produced in a carbon as compared to a proton beam. Even more important may be the fact, that the amount of neutrons produced in a passive beam delivery system is signiﬁcantly larger than for active beam delivery.57 Especially for pediatric patients, active techniques should be preferred.

IV.E.2. Cost effectiveness Reliable data on the costs as well as on the increased therapeutic effectiveness relative to conventional RT is already very limited for proton and even more for carbon ion RT. It has been shown in 2003 by Goitein and Jermann that the relative cost for proton therapy versus conventional therapy currently is around 2.5 times higher,58 if a recovery of the capital investments is required. It was estimated that until 2013 this ratio may decrease to 2.1–1.7. Without a recovery of investment costs, the ratio could be lowered to a

FIG. 4. Distribution of OER at 10% survival level for V79 and HSG cells value between 1.6 and 1.3. Concerning the costs of carbon exposed to helium ͑He: ᭡͒, carbon ͑12C: b͒, or neon ͑20Ne: ᭢͒ ions as a ion beam therapy, several European studies concluded that function of the dose-averaged LET. ͑Reprinted from Ref. 63 with permis- the costs for a single fraction of carbon beam therapy cur- ͒ sions of the author and Radiation Research. rently is around 1000 € ͑based on a 20 fraction treatment, see Ref. 59, and references therein͒. Interestingly, this is nearly identical to the costs per fraction given in Ref. 58 for proton scribed by the so-called oxygen enhancement ratio ͑OER͒, therapy. which has a value of 1 for well oxygenated tumors and val- A cost-effectiveness analysis for proton radiotherapy has ues of up to 3 for hypoxic tumors. There is some experimen- been performed for various tumors ͑breast, prostate, head & tal evidence that the OER decreases, if LET is increased neck, and childhood medulloblastoma͒ in Sweden,60 using a ͑Fig. 4͒. This would indicate that the increased radioresis- Markov simulation and calculating the gain in quality ad- tance of hypoxic tumors is significantly smaller for heavy ion justed life years. The results indicated that proton therapy for than for photon RT. This potential advantage, however, has these tumors was cost effective, if appropriate risk groups to be shown clinically and up to now, only very few data on were chosen. However, also the general lack of data and the comparison of the effectiveness of heavy ions for hy- large uncertainties in the analysis were mentioned. The study poxic and normoxic tumors are available.56 As the treatment can also be questioned, since many assumptions on the out- of hypoxic tumors is still a major challenge in radiotherapy, come of proton therapy had to be made without being based future studies with heavy ions have to focus on these tumor on solid clinical data ͑see Ref. 61 for a detailed discussion͒. types. Also recently a literature review on the cost effectiveness has To address the biological question, which ion type is clini- been published,61 but could not draw any firm conclusions on cally most effective, safety and efficiency has also to be the efficacy of proton or carbon beam therapy. proven also for other ion types ͑e.g., oxygen͒. Moreover, as The only published cost-effectiveness analysis for carbon local control is only one aspect of oncologic diseases, inter- ion beam therapy has been performed by our group59 for actions of heavy ion RT with additional chemotherapy, hor- chordoma patients. For a limited collective of ten patients, mone, or targeted therapies have to be investigated. This is the overall treatment costs have been calculated and were especially important in cases, where a significant improve- compared to the costs using conventional therapy. It has been ment in local control can be achieved with ion beams, but concluded, that carbon beam therapy is cost effective, if local where overall survival is still limited because of distant me- tumor control ͑used as indicator for therapy outcome͒ of tastases ͑like it was shown, e.g., for adenoidcystic carci- more than 70% can be achieved. The main cost driver in the noma, see Ref. 23͒. Also the possibility of synergistic effects treatment of skull base tumors that was identified here was between high LET radiation and other therapies has to be the neurosurgical resection of recurrent tumors. The results considered. can therefore not be generalized to other tumors and further Apart from therapeutic effectiveness, the possibility of investigations are needed. secondary malignancy due to neutrons produced by fragmen- Given the poor data base for costs and efficacy even for tations is an important issue, especially for the treatment of proton radiotherapy, it cannot be expected that sufficient data

Medical Physics, Vol. 35, No. 12, December 2008 5661 Jäkel, Karger, and Debus: The future of heavy ion radiotherapy 5661 on the cost effectiveness of ion beam therapy become avail- mal tissue studies have to investigate both, the Bragg peak as able before solid clinical data on the clinical effectiveness well as the plateau region. Especially, measurements in the are available. region proximal to the Bragg peak are highly important as combinations of high absorbed dose and increased RBE val- IV.F. Radiobiology ues may be found here. Since side effects in normal tissues typically occur near to the target volume, the key question is Although the clinical prove of safety and effectiveness of whether the related biologically effective dose is lower or heavy ion RT is highly important, this question has to be higher than that obtained with proton irradiations. clearly separated from the question, whether the high-LET Other relevant issues refer to the impact of hypofraction- component of heavy ion RT is of additional advantage for the ated treatments on normal tissue tolerance and the influence patient. To answer this question, thoroughly designed clinical of the oxygen status on tumor response. Although the toler- trials supplemented by systematic experimental studies are ance data obtained from animal studies cannot directly be required. transferred to patients, these studies offer the chance to principally prove a biological advantage of heavy ions. Apart IV.F.1. Clinical trials from dose response studies, additional investigations on a Preliminary results of carbon ion RT are impressive,9,20–23 molecular level are necessary to improve the understanding however, they do not allow definitive conclusion on superi- of the underlying mechanisms of high-LET irradiations. ority of heavy ions over protons. For skull-base chordomas, e.g., local control rates have been found to be comparable to V. CONCLUSIONS 21 those of protons or even better, if dose was escalated. This In the past decade, the fundamentals of heavy ion radio- comparison, however, may be biased since heavy ion treat- therapy have been developed and clinical application has ments were performed with scanning techniques, while most shown to be feasible and effective. Synchrotrons in combi- of the proton studies used passive beam delivery techniques. nation with 3D-scanning systems are and will continue to be Moreover, the base line characteristics of patients and tumors state-of-the-art. In the next decade the accuracy of absorbed may not be comparable between these studies. A quasiran- dose determination will be increased to the level of photon domized phase I/II trial comparing carbon ions versus pho- therapy and intensity modulated ion beam therapy will ad- ton IMRT showed significantly improved local control rates vance to a routinely applied treatment technique for selected for adenoidcystic carcinomas treated with a carbon ion 23 indications. The most challenging aspects of heavy ion boost. In this study, randomization was implicitly attained therapy in the future will be to identify these indications and by the temporal availability of this irradiation modality dur- to prove its safety and efficiency as well as of its additional ing the year. For definitive conclusions, however, prospective benefit with respect to proton therapy. Cost effectiveness of randomized-controlled phase III trials have to be performed, ion beam therapy has to be investigated further. It is, how- which compare local control rates at the same toxicity level ever, not likely that substantial data will be available before using identical beam delivery techniques for protons and its therapeutic benefit has been quantified. For some indica- heavy ions, respectively. For combined treatments of photon tions, effectiveness strongly relies on, successful compensa- IMRT and ion beam boosts, such comparisons must also in- tion of inter- and intrafractional motion. Form a strictly sci- clude comparisons against a pure photon treatment. In both entific view, the future role of heavy ion therapy in the cases, the already performed phase I/II trials will serve as a management of oncologic diseases is still unclear, from our basis for such investigations and adenoidcystic carcinoma, view today, however, it appears to be very promising. chordoma, and chondrosarcoma, as well as advanced pros- ͒ tate carcinomas are certainly good candidates for the inves- a Author to whom correspondence should be addressed. Present address: tigation of the potential benefit of heavy ions for patients. Dept. of Medical Physics in Radiation Oncology ͑E040͒, German Cancer While the direct comparison of proton and ion beams be- Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Ger- many. Telephone: ϩ49-6221-42-2596; ϩ49-6221-56-37668; Fax: ϩ49- came possible for the first time already at the HIBMC facil- 6221-42-2572. Electronic mail: [email protected] 11 ity in Hyogo ͑Japan͒, such trials will also be in the focus of 1O. Jäkel, D. Schulz-Ertner, C. P. Karger, A. Nikoghosyan, and J. Debus, the HIT facility,12,13 where a gantry will be available for the “Heavy ion therapy: Status and perspectives,” Technol. Cancer Res. Treat. 2, 377–387 ͑2003͒. first time, followed by other upcoming heavy ion centers. 2D. Schulz-Ertner, O. Jäkel, and W. Schlegel, “Radiation therapy with charged particles,” Semin. Radiat. Oncol. 16, 249–259 ͑2006͒. 3 IV.F.2. Experimental studies O. Jäkel, M. Krämer, D. Schulz-Ertner, P. Heeg, C. P. Karger, B. Didinger, A. Nikoghosyan, and J. Debus, “Treatment planning for carbon Clinical trials are strongly limited with respect to selec- ion radiotherapy in Germany: Review of clinical trials and treatment plan- ͑ ͒ tion of dose and toxicity level. They must therefore be ning studies,” Radiother. Oncol. 73, S86–S91 2004 . 4C. P. Karger and O. Jäkel, “Current status and new developments in ion supplemented by systematic studies in animals to investigate therapy,” Strahlenther. Onkol. 183, 295–300 ͑2007͒. the predictive power of the underlying RBE model. These 5G. Kraft, “Tumor therapy with heavy charged particles,” Prog. Part. Nucl. studies have to include measurements of RBE and ␣/␤ val- Phys. 45, S473–S544 ͑2000͒. 6 ues for normal tissue as well as tumor systems.62 J. R. Castro, D. E. Linstadt, J. P. Bahary, P. L. Petti, I. Daftari, J. M. Collier, P. H. Gutin, G. Gauger, and T. L. Phillips, “Experience in charged While the investigation of the tumor response must particle irradiation of tumors of the skull base: 1977–1992,” Int. J. Radiat. clearly be focused on the spreadout Bragg-peak region, nor- Oncol., Biol., Phys. 29, 647–655 ͑1994͒.

Medical Physics, Vol. 35, No. 12, December 2008 5662 Jäkel, Karger, and Debus: The future of heavy ion radiotherapy 5662

7Particle Newsletter 36, edited by J. Sisterson ͑Harvard Cyclotron Labo- Kluge, and D. Schardt, “Absorbed dose to water determination with ion- ratory, Harvard University, Boston, 2005͒, www.ptcog.com. ization chamber dosimetry and calorimetry in restricted neutron, photon, 8J. R. Castro, “Results of heavy ion radiotherapy,” Radiat. Environ. Bio- proton and heavy-ion radiation fields,” Phys. Med. Biol. 51, 3667–3682 phys. 34, 45–48 ͑1995͒. ͑2006͒. 9H. Tsujii et al., “Clinical results of carbon ion radiotherapy at NIRS,” J. 32F. Sauli, “GEM: A new concept for electron amplification in gas detec- Radiat. Res. ͑Tokyo͒ 48 Suppl A, A1–A13 ͑2007͒. tors,” Nucl. Instrum. Methods Phys. Res. A 386, 531–534 ͑1997͒. 10M. Torikoshi, S. Minohara, N. Kanematsu, M. Komori, M. Kanazawa, K. 33G. T. Y. Chen, S. Mori, A. Chu, and M. Folkert, Uncertainties in image Noda, N. Miyahara, H. Itoh, M. Endo, and T. Kanai, “Irradiation System guided radiotherapy of lung tumors, Proceedings of NIRS-CNAO Joint for HIMAC,” J. Radiat. Res. ͑Tokyo͒ 48 Suppl A, A15–A25 ͑2007͒. Symposium on Carbon Ion Radiotherapy, Milan, Italy, 2006, pp. 192–193 11Y. Hishikawa, Y. Oda, H. Mayahara, A. Kawaguchi, K. Kagawa, M. ͑2006͒. Murakami, and M. Abe, “Status of the clinical work at Hyogo,” Radio- 34C. Zhang, P. Lechner, G. Lutz, M. Porroe, R. Richter, J. Treisa, L. ther. Oncol. 73 Suppl 2, S38–S40 ͑2004͒. Strüder, and S. N. Hang, “Development of DEPFET Macropixel detec- 12P. Heeg, H. Eickhoff, and T. Haberer, “͓Conception of heavy ion beam tors,” Nucl. Instrum. Methods Phys. Res. A 568, 207–216 ͑2008͒. therapy at Heidelberg University ͑HICAT͔͒,” Z. Med. Phys. 14, 17–24 35J. Jakubek, T. Holy, E. Lehmann, S. Pospisil, J. Uher, D. Vacik, and D. ͑2004͒. Vavrik, “Spatial resolution of Medipix-2 device as neutron pixel detec- 13T. Haberer, J. Debus, H. Eickhoff, O. Jäkel, D. Schulz-Ertner, and U. tor,” Nucl. Instrum. Methods Phys. Res. A 546, 164–169 ͑2005͒. Weber, “The Heidelberg Ion Therapy Center,” Radiother. Oncol. 73 36J. Jakubek et al., “Neutron imaging and tomography with Medipix2 and Suppl 2, S186–S190 ͑2004͒. dental micro-roentgenography,” Nucl. Instrum. Methods Phys. Res. A 14U. Amaldi, “CNAO—The Italian Centre for Light-Ion Therapy,” Radio- 569, 205–209 ͑2006͒. ther. Oncol. 73 Suppl 2, S191–S201 ͑2004͒. 37M. Rebisz, B. Voss, A. Heinz, E. Usenko, and M. Pomorski, “CVD dia- 15U. Amaldi and G. Kraft, “European developments in radiotherapy with mond dosimeters for heavy ion beams,” Diamond Relat. Mater. 16, 1070– beams of large radiobiological effectiveness,” J. Radiat. Res. ͑Tokyo͒ 48 1073 ͑2007͒. Suppl A, A27–A41 ͑2007͒. 38A. Wambersie, J. H. Hendry, P. Andreo, P. M. DeLuca, R. Gahbauer, H. 16Q. Li, Z. Dai, Z. Yan, X. Jin, X. Liu, and G. Xiao, “Heavy-ion conformal Menzel, and G. Whitmore, “The RBE issues in ion-beam therapy: Con- irradiation in the shallow-seated tumor therapy terminal at HIRFL,” Med. clusions of a joint IAEA/ICRU working group regarding quantities and Biol. Eng. Comput. 45͑11͒, 1037–1043 ͑2007͒. units,” Radiat. Prot. Dosim. 122, 463–470 ͑2006͒. 17P. Andreo, D. T. Burns, K. Hohlfeld, M. S. Huq, T. Kanai, F. Laitano, V. 39M. Krämer and M. Scholz, “Rapid calculation of biological effects in ion Smyth, and S. Vynckier, “Absorbed dose determination in external beam radiotherapy,” Phys. Med. Biol. 51, 1959–1970 ͑2006͒. radiotherapy,” Technical Report Series No. 398 ͑2000͒. 40M. Ellerbrock, O. Jäkel, M. Krämer, A. Nikoghosyan, and D. Schulz- 18S. Minohara, T. Kanai, M. Endo, K. Noda, and M. Kanazawa, “Respira- Ertner, “Clinical implementation of intensity modulated heavy ion tory gated irradiation system for heavy-ion radiotherapy,” Int. J. Radiat. therapy,” Radiother. Oncol. 84, 129 ͑2007͒. Oncol., Biol., Phys. 47, 1097–1103 ͑2000͒. 41M. Ellerbrock, O. Jäkel, M. Krämer, A. Nikoghosyan, and D. Schulz- 19C. Bert, N. Saito, A. Schmidt, N. Chaudhri, D. Schardt, and E. Rietzel, Ertner, “Multiple field optimization in heavy ion treatment planning— “Target motion tracking with a scanned particle beam,” Med. Phys. 34, clinical aspects,” in Abstracts der Frühjahrstagung in Heidelberg ͑Deut- 4768–4771 ͑2007͒. sche Physikalische Gesellschaft ͑DPG͒ ST 6.4, Heidelberg, 2006͒. 20D. Schulz-Ertner, A. Nikoghosyan, H. Hof, B. Didinger, S. E. Combs, O. 42M. Engelsman, E. Rietzel, and H. M. Kooy, “Four-dimensional proton Jäkel, C. P. Karger, L. Edler, and J. Debus, “Carbon ion radiotherapy of treatment planning for lung tumors,” Int. J. Radiat. Oncol., Biol., Phys. skull base chondrosarcomas,” Int. J. Radiat. Oncol., Biol., Phys. 67, 171– 64, 1589–1595 ͑2006͒. 177 ͑2007͒. 43E. Rietzel, S. J. Rosenthal, D. P. Gierga, C. G. Willet, and G. T. Chen, 21D. Schulz-Ertner, C. P. Karger, A. Feuerhake, A. Nikoghosyan, S. E. “Moving targets: Detection and tracking of internal organ motion for Combs, O. Jäkel, L. Edler, M. Scholz, and J. Debus, “Effectiveness of treatment planning and patient set-up,” Radiother. Oncol. 73 Suppl 2, carbon ion radiotherapy in the treatment of skull-base chordomas,” Int. J. S68–S72 ͑2004͒. Radiat. Oncol., Biol., Phys. 68, 449–457 ͑2007͒. 44S. Mori, G. T. Chen, and M. Endo, “Effects of intrafractional motion on 22D. Schulz-Ertner and H. Tsujii, “Particle radiation therapy using proton water equivalent pathlength in respiratory-gated heavy charged particle and heavier ion beams,” J. Clin. Oncol. 25, 953–964 ͑2007͒. beam radiotherapy,” Int. J. Radiat. Oncol., Biol., Phys. 69, 308–317 23D. Schulz-Ertner, A. Nikoghosyan, B. Didinger, M. Munter, O. Jäkel, C. ͑2007͒. P. Karger, and J. Debus, “Therapy strategies for locally advanced adenoid 45P. Kupelian, T. Willoughby, A. Mahadevan, T. Djemil, G. Weinstein, S. cystic carcinomas using modern radiation therapy techniques,” Cancer Jani, C. Enke, T. Solberg, N. Flores, D. Liu, D. Beyer, and L. Levine, 104, 338–344 ͑2005͒. “Multi-institutional clinical experience with the Calypso System in local- 24K. W. Ledingham, W. Galster, and R. Sauerbrey, “Laser-driven proton ization and continuous, real-time monitoring of the prostate gland during oncology—A unique new cancer therapy?,” Br. J. Radiol. 80, 855–858 external radiotherapy,” Int. J. Radiat. Oncol., Biol., Phys. 67, 1088–1098 ͑2007͒. ͑2007͒. 25G. J. Caporaso, 1994 US-CERN-Japan Joint Accelerator School: Topical 46D. W. Litzenberg, J. M. Balter, S. W. Hadley, H. M. Sandler, T. R. Course: Frontiers Of Accelerator Technology, 3–9 Nov 1994, Maui, Ha- Willoughby, P. A. Kupelian, and L. Levine, “Influence of intrafraction waii, edited by M. M. S. T. S. I. Kurokawa ͑World Scientific, New Jersey, motion on margins for prostate radiotherapy,” Int. J. Radiat. Oncol., Biol., 1996͒, pp. 594–615. Phys. 65, 548–553 ͑2006͒. 26S. E. Sampayan, G. J. Caporaso, D. M. Sanders, R. D. Stoddard, D. O. 47ICRU Report 62, Prescribing, Recording and Reporting Photon Beam Trimble, J. Elizondo, M. L. Krogh, and T. F. Wieskamp, Particle Accel- Therapy ͑supplement to ICRU report 50͒͑International Commission on erator Conference, 1997. Proceedings of the 1997 ͑IEEE, Lawrence Liv- Radiation Units and Measurements, Washington, DC, 1999͒. ermore Nat. Lab., 1997͒, pp. 1308–1310. 48S. Minohara, M. Endo, T. Kanai, H. Kato, and H. Tsujii, “Estimating 27Y.-J. Chen and A. C. Paul, Proceedings of PAC07, Albuquerque, New uncertainties of the geometrical range of particle radiotherapy during res- Mexico, USA, edited by S. Hardage and C. Petit-Jean-Genaz ͑IEEE, Pis- piration,” Int. J. Radiat. Oncol., Biol., Phys. 56, 121–125 ͑2003͒. cataway, NJ, 2007͒, pp. 1787–1789. 49C. Bert, S. O. Grozinger, and E. Rietzel, “Quantification of interplay 28D. Trbojevic, D. Parker, E. Keil, and A. M. Sessler, “Carbon/proton effects of scanned particle beams and moving targets,” Phys. Med. Biol. therapy: A novel gantry design,” Phys. Rev. ST Accel. Beams 2007, 53, 2253–2265 ͑2008͒. 053503-1–053503-6 ͑2007͒. 50T. Furukawa, T. Inaniwa, S. Sato, T. Tomitani, S. Minohara, K. Noda, and 29Y. Jongen et al., Design Studies of the Compact Superconducting Cyclo- T. Kanai, “Design study of a raster scanning system for moving target tron for Hadron Therapy, Abstract TUPLS078, Proceedings of EPAC, irradiation in heavy-ion radiotherapy,” Med. Phys. 34, 1085–1097 ͑2007͒. Edinburgh, Scotland, 1678–1680 ͑2006͒. 51C. Bert and E. Rietzel, “4D treatment planning for scanned ion beams,” 30H. Palmans, J. Seuntjens, F. Verhaegen, J. M. Denis, S. Vynckier, and H. Radiother. Oncol. 2,24͑2007͒. Thierens, “Water calorimetry and ionization chamber dosimetry in an 52S. O. Grozinger, E. Rietzel, Q. Li, C. Bert, T. Haberer, and G. Kraft, 85-MeV clinical proton beam,” Med. Phys. 23, 643–650 ͑1996͒. “Simulations to design an online motion compensation system for 31H. J. Brede, K. D. Greif, O. Hecker, P. Heeg, J. Heese, D. T. Jones, H. scanned particle beams,” Phys. Med. Biol. 51, 3517–3531 ͑2006͒.

Medical Physics, Vol. 35, No. 12, December 2008 5663 Jäkel, Karger, and Debus: The future of heavy ion radiotherapy 5663

53C. Bert, K. G. Metheany, K. P. Doppke, A. G. Taghian, S. N. Powell, and radiation therapy,” Clin. Oncol. ͑R Coll. Radiol͒ 15, S37–S50 ͑2003͒. G. T. Chen, “Clinical experience with a 3D surface patient setup system 59O. Jäkel, B. Land, S. E. Combs, D. Schulz-Ertner, and J. Debus, “On the for alignment of partial-breast irradiation patients,” Int. J. Radiat. Oncol., cost-effectiveness of carbon ion radiation therapy for skull base chor- Biol., Phys. 64, 1265–1274 ͑2006͒. doma,” Radiother. Oncol. 83, 133–138 ͑2007͒. 54J. D. Hoisak, K. E. Sixel, R. Tirona, P. C. Cheung, and J. P. Pignol, 60J. Lundkvist, M. Ekman, S. R. Ericsson, B. Jonsson, and B. Glimelius, “Prediction of lung tumour position based on spirometry and on abdomi- “Proton therapy of cancer: Potential clinical advantages and cost- nal displacement: accuracy and reproducibility,” Radiother. Oncol. 78, effectiveness,” Acta Oncol. 44, 850–861 ͑2005͒. 339–346 ͑2006͒. 61M. Lodge, M. Pijls-Johannesma, L. Stirk, A. J. Munro, R. D. De, and T. 55J. D. Hoisak, K. E. Sixel, R. Tirona, P. C. Cheung, and J. P. Pignol, Jefferson, “A systematic literature review of the clinical and cost- “Correlation of lung tumor motion with external surrogate indicators of effectiveness of hadron therapy in cancer,” Radiother. Oncol. 83, 110–122 respiration,” Int. J. Radiat. Oncol., Biol., Phys. 60, 1298–1306 ͑2004͒. ͑2007͒. 56T. Nakano, Y. Suzuki, T. Ohno, S. Kato, M. Suzuki, S. Morita, S. Sato, K. 62C. P. Karger, P. Peschke, R. Sanchez-Brandelik, M. Scholz, and J. Debus, Oka, and H. Tsujii, “Carbon beam therapy overcomes the radiation resis- “Radiation tolerance of the rat spinal cord after 6 and 18 fractions of tance of uterine cervical cancer originating from hypoxia,” Clin. Cancer photons and carbon ions: Experimental results and clinical implications,” Res. 12, 2185–2190 ͑2006͒. Int. J. Radiat. Oncol., Biol., Phys. 66, 1488–1497 ͑2006͒. 57K. Gunzert-Marx, D. Schardt, and R. S. Simon, “The fast neutron com- 63Y. Furusawa, K. Fukutsu, M. Aoki, H. Itsukaichi, K. Eguchi-Kasai, H. ponent in treatment irradiations with 12C beam,” Radiother. Oncol. 73 Ohara, F. Yatagai, T. Kanai, and K. Ando, “Inactivation of aerobic and Suppl 2, S92–S95 ͑2004͒. hypoxic cells from three different cell lines by accelerated ͑3͒He-, ͑12͒C-, 58M. Goitein and M. Jermann, “The relative costs of proton and X-ray and ͑20͒Ne-ion beams,” Radiat. Res. 154, 485–496 ͑2000͒.

Medical Physics, Vol. 35, No. 12, December 2008 Locating and targeting moving tumors with radiation beams Sonja Dieterich Radiation Oncology, Stanford University, Stanford, California 94305 and Radiation Oncology, Georgetown University Hospital, Washington, DC 20007 Kevin Cleary Imaging Science and Information Systems, Georgetown University Hospital, Washington, DC 20007 Warren D’Souza Radiation Oncology, University of Maryland, College Park, Maryland 20742 Martin Murphy Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia 23284 Kenneth H. Wong Imaging Science and Information Systems, Georgetown University Hospital, Washington, DC 20007 ͒ Paul Kealla Radiation Oncology, Stanford University, Stanford, California 94305 ͑Received 18 March 2008; revised 17 October 2008; accepted for publication 17 October 2008; published 19 November 2008͒ The current climate of rapid technological evolution is reﬂected in newer and better methods to modulate and direct radiation beams for cancer therapy. This Vision 20/20 paper focuses on part of this evolution, locating and targeting moving tumors. The two processes are somewhat independent and in principle different implementations of the locating and targeting processes can be inter- changed. Advanced localization and targeting methods have an impact on treatment planning and also present new challenges for quality assurance ͑QA͒, that of verifying real-time delivery. Some methods to locate and target moving tumors with radiation beams are currently FDA approved for clinical use—and this availability and implementation will increase with time. Extensions of current capabilities will be the integration of higher order dimensionality, such as rotation and deformation in addition to translation, into the estimate of the patient pose and real-time reoptimization and adaption of delivery to the dynamically changing anatomy of cancer patients. © 2008 American Association of Physicists in Medicine. ͓DOI: 10.1118/1.3020593͔

Key words: respiratory motion, adaptive radiotherapy, tracking

I. INTRODUCTION physics-based advances in radiotherapy, the magnitude of / benefit may be hard to quantify in a series of site-specific This Vision 20 20 paper focuses on the evolution of locating 1 and targeting moving tumors. The rationale for using this randomized trials. However, the fundamental basis of radio- technology in the clinic is to significantly improve tumor therapy is that increased treatment accuracy improves tumor control while reducing critical organ damage for tumors control, and reduced normal tissue dose reduces treatment- that move with respiration, resulting in a better quality of related complications. Any improvements in this area will life, or beneficence for cancer patients. Beneficence is therefore improve the beneficence of radiation treatment. one of the three basic principles of the Belmont Beneficence applies to locating and targeting moving tu- report, ͑http://www.hhs.gov/ohrp/humansubjects/guidance/ mors with radiation beams. The concept of do no harm belmont.htm#xbenefit͒ one of the most important documents means that this technology should only be applied when mo- in the field of medical ethics. This report states “The term tion tracking—a change from traditional radiotherapy in sev- “beneficence” is often understood to cover acts of kindness eral aspects—is demonstrably safe and appropriate quality or charity that go beyond strict obligation. In this document, assurance is performed. The concept of maximizing possible beneficence is understood in a stronger sense, as an obliga- benefits and minimizing possible harm can be achieved by tion. Two general rules have been formulated as complemen- having the radiation beam aligned as closely as possible with tary expressions of beneficent actions in this sense: (1) Do not harm and (2) maximize possible benefits and minimize the moving tumor at all times during radiation delivery, ap- possible harms.” Beneficence, as it applies to image-guided propriately avoiding critical structures. Therefore the burden therapy, can be achieved by reducing the difference between of responsibility for systems that locate and target moving the planned and delivered dose, reducing treatment uncer- tumors is not necessarily the demonstration of a perfectly tainties and therefore margins, and improving dose confor- accurate system—it is sufficient to demonstrate safety and mation to the tumor. Our patients and the treatment team that the use of target tracking is an improvement over meth- should be demanding this beneficence. As with many ods without target tracking.

Real time motion correct ion component s Treatment unit Compute and actuate beam/ t arget alignment

Correct for Tr eat m en t reactiontime beam

Det ect motion Moving Tar get ( t u m o r )

FIG. 2. A generalized ﬂowchart showing the main components of a real-time motion correction system.

II. DESCRIPTION OF CURRENT STATUS The multitude of new technologies in radiation oncology has created a large amount of potentially confusing or contradictory terminology. Before we start discussing the state- of-the art, development, and future outlook on locating and

FIG. 1. Observed variation in lung tumor motion with time in three dimen- targeting moving tumors with radiation beams, we need to sions from Cyberknife Synchrony data. ͑Ref. 113͒ Notable is that there is clarify the general concepts and define the scope of the tech- significant motion in three dimensions, there are variations in the baseline nology. position of the tumor in all three dimensions and variations in the cycle-to- cycle period, respiratory cycle shape, and range of motion. II.A. Methods for real-time tumor localization The first task in a motion-adaptive radiotherapy system is spatial localization of the tumor. If we were to conceptualize Effectively treating a tumor that moves during respiration the ideal localization system, we can readily imagine certain has become the paradigm for motion-adaptive radiotherapy. capabilities. First, it would have real-time performance suf- This Vision 20/20 article will address issues of respiratory ficient to match any patient changes such as respiration. Sec- motion correction during treatment with emphasis on the two ond, it would be capable of imaging both structure and func- ͑ ͒ key components—locating the tumor and targeting the tu- tion e.g., cancer vs. inflammation . Third, it would have a mor. The complexity of the problem of targeting moving large field of view, enabling localization of both the planned treatment volume and surrounding body structures. Finally, it tumors is shown in Fig. 1, where there is tumor motion in all would be non-invasive and present only minimal additional three dimensions, varying baseline position and also varying risk to the patient, either during the course of radiation peak-to-trough motion, period, and trajectory shape within therapy or afterwards. Although this ideal localization sys- each motion cycle. A generalized schematic of real-time mo- tem has not yet been created, there are several localization tion correction is shown in Fig. 2. methods in current use or active development. Table I com- Respiratory gating is often seen as an alternative to mo- pares some methods for real-time tumor localization. Each of tion tracking. However, gating controls whether the beam is these methods emphasizes a particular property, such as tem- on or off. Tracking controls the alignment of the tumor and poral resolution or field-of-view, which in turn creates ad- the beam. Therefore, these two modalities are independent vantages and limitations. It is helpful to group these ap- and can coexist. The combination of both gating and tracking proaches into two broad classes ͑for the purpose of these will be at least as good as either modality alone. There are definitions, we will use “target” as a generic term for any also many other methods of respiratory motion management, object of interest in the body͒. such as motion inclusive methods, breath hold, and abdomi- Direct methods detect the target itself. Within this class nal compression. For a broader discussion on respiratory mo- are modalities such as x-ray imaging,3–9 MRI,10–13 tion management, readers are directed to the AAPM Task ultrasound,14–17 and electromagnetic tracking.18–20 Direct Group 76 report and references therein,2 as well as the Semi- methods can identify either artificially implanted points ͑fi- nars in Radiation Oncology special issue on intrafraction ducials͒ or anatomical landmarks. As a note of caution: organ motion and its management edited by Bortfeld and Some “direct” methods detect target surrogates, which al- Chen ͓14͑1͒, ͑2004͔͒. though placed within or near the target, may or may not

Medical Physics, Vol. 35, No. 12, December 2008 5686 Dieterich et al.: Locating and targeting moving tumors with radiation beams 5686

TABLE I. Some methods to locate moving targets.

Localization method Data dimensionality Invasive? Availability Imaging frequency

Electromagnetic ͑Refs. 18–20͒ Points Yes Commercially available for prostate 10 Hz Fluoroscopic ͑Refs. 3–7͒ Points Yes Translated to patient treatments 30 Hz Fluoroscopic/optical ͑Refs. 26–29͒ Points Noa and Yes Commercially available Before every beam/30 Hz Monoscopic/optical ͑Refs. 8,9͒ Points Yes Under development 30 Hz ͑theoretical͒ MRI ͑Ref. 10͒ Volume No Under development N/A Ultrasound ͑Ref. 14͒ Volumes No Under development 25 Hz aLung tumor projection method ͑Xsight Lung͒ available from Accuray. move or deform in a direct linear relationship with the target. with much less information than a full 4D CT. Finally, al- Indirect methods observe a surrogate quantity and infer though on-line target localization is appealing from the tech- localization information from the surrogate. The most com- nical point of view and may produce clinical benefits in mon example of this method is optical tracking to monitor some cases, the ultimate test of its value will be its impact on skin motion, although respiratory belts21,22 and airflow patient care. monitors23,24 also fall into this category. Indirect methods in the absence of internal imaging provide limited utility.25 II.B. Methods for target tracking Combining direct localization methods with indirect methods, either before or during the treatment, in order to model The heart of a real-time tumor tracking system is the con- the relationship between the surrogate and the target leads to trol loop that connects the tumor detection system with the hybrid tracking methods.8,9,26,27 targeting alignment system. The control loop must receive Clearly, if we are pursuing the ideal localization system, a target coordinate measurements, test that the target identifi- direct method is best. Using surrogates always introduces an cation is authentic ͑so as not to go off chasing false motion͒, extra source of error that can change quickly and is very filter the target data to avoid disruptive transients, and then difficult to characterize in advance, even though in some send the delivery system a prediction of where the tumor will patients this error may be small ͑see Table III in Ref. 2͒. be when the targeting adjustment has been completed. Tumor However, indirect methods do not require fiducial implanta- tracking requires motors that can guide the beam or couch tion, are nontoxic, and have excellent temporal resolution. faster than most respiratory motion and a fast secondary The challenge then is to develop direct methods which incor- feedback mechanism for each motor used to control the porate many of the benefits of indirect methods. Fortunately, beam ͑or patient͒ placement. Table II compares several mo- efforts toward this goal are well under way, e.g., in the on- tion tracking methods. going development of electromagnetic fiducial tracking The various motion adaptation systems in use and under methods and MRI techniques. consideration involve two fundamentally different types of It is important to note that all real-world systems involve control loop. The CyberKnife robotic treatment system,26–29 design compromises. Thus, localization systems need to be the multi-leaf collimator,30–42 gimbaled linac,43 and proton carefully matched to the capabilities of the other components and heavy ion treatment systems44,45 all use an open-loop of the radiation therapy system. For example, one might be control design. In an open loop system, the corrective re- able to continuously acquire four-dimensional ͑4D͒ CT data sponse has no effect on the target behavior that signaled the from the patient, but if the data cannot be analyzed fast response. In other words, there is no feedback between the enough to direct changes in the therapy delivery, then we corrective signal and the adaptive response. In contrast, a have a surfeit of information that produces little impact. couch compensation system46–49 has a closed-loop control Similarly, if the only response of the system is to gate the system. When the tumor moves within the patient, the detec- beam on or off, that determination could probably be made tion system triggers a compensating movement of the patient

TABLE II. Delivery methods designed to hit moving targets.

Motion capable of compensation Approximate system Tracking method ͑in principal͒ delay ͑ms͒ Availability

Block ͑Ref. 112͒ Translation N/A Translated to patient treatments at one center Couch ͑Refs. 46–48͒ Translation, Rotation 80 Under development DMLC ͑Refs. 30–40͒ Translation, Rotation, Deformation 160 Under development Gimbaled linac ͑Ref. 43͒ Translation, Rotation, Deformation N/A Under development Magnetic/mechanical particle beam ͑Refs. 44 and 45͒ Translation, Rotation, Deformation 80 Under development Robotic linac ͑Refs. 26–29͒ Translation, Rotation, Deformation 110 Commercially available

Medical Physics, Vol. 35, No. 12, December 2008 5687 Dieterich et al.: Locating and targeting moving tumors with radiation beams 5687

͑and thus the tumor͒ via the treatment couch. Thus, there is vances in treatment planning and 4D dose computation. The feedback through which the adaptive response may influence IM is typically defined by the excursion of the tumor on a 4D the target movement. CT. While this approach involves a patient-specific motion Real-time systems must react to change at least as fast as margin, it assumes that the tumor occupies the entire spatial it occurs. A system’s reaction time depends on a number of domain within the ITV. However, it does not consider the factors. Time is required to detect a change in the target variability in the respiration patterns spanning a single treat- position, process and filter the position data, communicate ment fraction duration or interfraction respiration variability. with the beam alignment system, and complete the reposi- This assumption results in a larger than necessary volume of tioning of either the beam or patient. If a single motion de- tissue being irradiated. As motion management assumes tection method ͑fluoroscopic imaging, for example͒ is used greater significance for highly conformal radiation delivery in a first order open loop system, then all of these time delays and stereotactic radiosurgery, and with advances in treatment combine linearly in series to give the total reaction time. On delivery technologies for real-time tumor tracking, more so- the other hand, if two different motion detection systems are phisticated planning approaches are warranted. used in parallel to provide partially redundant target position Broadly, three advanced approaches have been proposed data, then only the faster system’s delay adds into the reac- for 4D treatment planning: ͑1͒ Statistically based inverse tion time of an open loop system. For example, the Cy- planning approaches ͑“motion kernel” approach͒,56–63 ͑2͒ 4D berKnife uses an optical tracking system to provide fast, con- CT and dose registration based on deformable image tinuous estimates of a tumor’s respiratory induced motion, 64–68 ͑ ͒ 27 registration, and 3 inverse planning that explicitly con- with the estimate updated by periodic x-ray imaging. This siders organ-at-risk constraints during real-time tumor is an example of a hybrid detection method. The total system tracking.56,69 These approaches represent a significant in- reaction time includes the optical processing time while the crease in sophistication over conventional planning ap- time spent processing the x-ray images can be done outside proaches. 4D planning is computationally expensive and re- the duty cycle of the control loop. This allows the targeting quires additional resources such as 4D optimization as well system to invest more time in sophisticated image processing as image registration software. 4D planning also involves without a corresponding degradation of response time. additional sources of error, such as data sorting and image Closed loop systems such as a movable couch can have registration, and is only one short timespan of a patient’s higher order dynamics that involve multiple system response anatomy that can change during the course of treatment. Ad- time constants in addition to the dead time before the couch ditionally, in a 50-patient study artifacts of at least 4 mm begins its corrective response.46 In an open loop system the were observed in 90% of 50 4D CT scans.70 Therefore the total reaction time must be compensated by predicting the 4D data should be used with caution. future position of the target so that the beam reaches the In the motion kernel approach, the idealized pencil beam future target position at the same time as the tumor. A closed dose distribution in the presence of a moving target is calcu- control loop needs to predict the dead time before the system begins to respond to a change in the tumor position.46 lated either by time-averaging the dose matrices calculated The future displacement of a breathing motion can be for different instances of the anatomy corresponding to dif- predicted in several ways: ͑1͒ With a mathematical model of ferent parts of the respiration cycle, or by convolving the the breathing signal,50 ͑2͒ with a bio-mechanical model of pencil beam kernel with the probability density function ͑ ͒ 56 the breathing process,51 or ͑3͒ with heuristic learning algo- PDF that describes the 3D target trajectory. This approach rithms that mimic the breathing process as it is observed.52,53 results in a smeared out pencil beam dose distribution prior The last category includes neural network prediction algo- to dose optimization in comparison with the conventional rithms, which have been studied by several groups.52–55 Neu- pencil beam optimization approach in the absence of organ ral networks can adapt to changes in the breathing pattern as motion. Treatment plans generated with the motion kernel they occur, making them an attractive way to deal with the approach are less sensitive to the tumor motion compared nonstationary character of real breathing. with optimization approaches that do not account for motion. Current real-time motion correction strategies involve the tracking of the target volume without consideration of the II.C. Treatment planning organs-at-risk. As a result, while tracking considers adequate Conventional treatment planning has traditionally used a coverage of the tumor, it may result in unintended irradiation planning or “safety” margin around the clinical target vol- of organs-at-risk. This unintended irradiation occurs due to ume ͑CTV͒ that implicitly accommodates organ motion as differences in the trajectories of motion between the tumor well as setup uncertainties. However, the International Com- and the organs-at-risk. In an approach applied to robotic 69 mission on Radiation Units and Measurement ͑ICRU͒ Report radiosurgery, the motion path is discretized into steps ͑and 62 explicitly defines a margin to account for physiological the time-fraction of each step is determined͒. First, a set of changes ͓i.e., internal margin ͑IM͔͒. For tumors affected by beam orientations is chosen. For these beam orientations, the normal respiration, an internal target volume ͑ITV͒ is defined number of monitor units associated with this beam at a step such that it includes the addition of the IM to the CTV. The along the motion path is determined by considering its dose advent of 4D CT has enabled the delineation of the tumor contribution to tumor and organ-at-risk voxels. The total volume as a function of the respiration cycle leading to ad- dose is summed over all the discretized steps along the mo-

Medical Physics, Vol. 35, No. 12, December 2008 5688 Dieterich et al.: Locating and targeting moving tumors with radiation beams 5688 tion path of the tumor. The problem is formulated as a stan- The Radiological Physics Center ͑RPC͒͑http:// dard linear program and solved by minimizing the total rpc.mdanderson.org/rpc/͒ has responded to these study re- monitor units. quirements by developing phantoms for IMRT and SBRT The most widely reported 4D planning method involves treatments. The lung and thorax phantoms include motion the coregistration of dose distributions calculated on indi- platforms preprogrammed with sinusoidal and patient spe- vidual 3D CT data sets corresponding to various phases of ciﬁc motion patterns. The phantoms have been designed to the respiration cycle with a single ͑reference͒ 3D CT data set be used on a variety of treatment delivery platforms such as ͑typically end-inhale or end-exhale͒.64–68,71–77 This approach external beam machines and the Cyberknife. relies on the image registration algorithm to provide displacement vectors that show the trajectory of each voxel III. PROJECTION AHEAD from one image set to another. The dose distribution calculated on each CT data set is then weighted by the time- Today’s current technological status of locating and tar- weight of the CT phase in the respiration cycle and accumu- geting moving tumors clearly leads the clinical status, and lated in the reference image. In this way one can see therefore we can expect the controlled introduction of several differences between the 4D computed dose and the dose cal- promising technologies into the clinic. The commercial culated on individual 3D CT data. This method has been translation of technical developments into clinical tools is applied for 4D proton treatment planning as well.78,79 not guaranteed for any invention and involves a complex mix of variables including development costs, risk analysis, competitive advantage, priority, timing, and market demand.

II.D. Quality assurance III.A. Methods for real-time tumor localization Quality assurance is a methodical system to assess the Real-time tumor tracking will become more widespread quality of the product or service. In radiation therapy, the in the next 10 years. This growth will stimulate two further quality assurance responsibilities of the medical physicists areas of research and development. The first problem is how are the technical functionality and safety of the equipment to account for deformation. There is both tumor deformation under all clinical conditions, and the safety of information and motion with respect to the normal structures in a manner, workflow pertaining to treatment planning and accurate treat- which can change from day to day ͑and cycle to cycle for ment delivery. State regulations and AAPM task group re- thoracic and abdominal tumors͒. Multiple targets can move ports form the framework and basis of the quality assurance with different trajectories, such as in a lung treatment where program, which then has to be customized to the specific the primary gross tumor volume ͑GTV͒ and mediastinal work environment and technology. nodes can move independently from the spinal cord, esopha- The traditional QA approach has been to anticipate for gus, and heart. The second and somewhat related problem is equipment or procedure failure and establish safety proce- the integration of target tracking radiotherapy with online dures to prevent technical errors. Relatively simple tools and and even real-time plan adaptation. Major—but not phantoms were used for functionality testing. This approach insurmountable—barriers to implementation of volumetric has drawbacks in the age of rapidly developing, complex real-time adaptation include ͑1͒ methods to measure or esti- technology such as real-time motion adaptive radiation mate the position of the evolving volumetric anatomy with therapy. Recently, several nonstationary phantoms have been ͑ ͒ ͑ ͒ 80–83 time, 2 real-time deformable image registration, and 3 published as well as developed commercially, with more fast 4D optimization algorithms. Some solutions under de- becoming available, to measure the precision and accuracy velopment to measure the evolving volumetric anatomy with of respiratory motion compensation. Matching the complex- time are integrated MR-linacs or real-time ultrasound guid- ity of human respiration, driven by multiple muscle groups ance discussed under the “Direct” methods section. Com- and involving significant deformation, remains a challenge bined measurement/estimates of the evolving anatomy could for phantom development. involve generalizations of the internal/external correlation ͑ ͒ National Cancer Institute NCI sponsored protocols are models to estimate the entire anatomy as opposed to a single required to address respiratory motion when intensity modu- point. Graphical processing units ͑GPUs͒ can offer near real- ͑ ͒ lated radiation therapy IMRT is used for intra-thoracic tu- time speed for deformable algorithms.84–88 Fast 4D optimi- mors and other locations. Institutions participating in Radia- zation algorithms will also directly benefit from ongoing ad- ͑ ͒ tion Therapy Oncology Group RTOG studies are required vancements in processor technology. to demonstrate the capability to fulfill study requirements and must submit the data to the physics and image guidance III.B. Methods for target tracking committees. RTOG-0618, a stereotactic lung radiotherapy trial, states “Special considerations must be made to account Future developments in real-time control will aim to re- for the effect of internal organ motion ͑e.g., breathing͒ on duce system reaction time ͑Table II͒ while improving tempo- target positioning and reproducibility. Acceptable maneuvers ral prediction to compensate for delays. Reaction time can be include reliable abdominal compression, accelerator beam reduced by increasing the speed of each stage of target ac- gating with the respiratory cycle, tumor tracking and active quisition, signal processing, communication, and adaptive breath-holding techniques.” alignment response. It can also be reduced by developing

Medical Physics, Vol. 35, No. 12, December 2008 5689 Dieterich et al.: Locating and targeting moving tumors with radiation beams 5689 parallel control architectures in which those elements of the III.D. Quality assurance target localization process that are time-intensive are moved partly or completely out of the serial part of the control loop The complexity of these real-time motion adaptive tech- so that they do not add to the reaction time. Ideally the im- nologies has made it very difficult for a single person to proved predictors will not add computational cost that in- understand in detail where potential failures might occur. creases system response time. There will, however, always Current pathways to disseminate QA information are slow be some lag time left over. Future developments will corre- compared to the speed at which new products are imple- late the characteristics of each patient’s breathing with the mented in clinical practice. However, procedures and equip- performance of the prediction and tracking algorithms so that ment need to be evaluated thoroughly in a clinical setting to the algorithms can be customized to each patient for the best ensure that a comprehensive quality control ͑QC͒ and QA results. These developments will also provide resources to program can be developed. The knowledge of experts in the estimate a patient’s “trackability” before treatment, so that field of safety such as industrial process engineers has appropriate margins for the residual alignment uncertainty scarcely been tapped in the health care environment. can be tailored for the individual treatment plan. The traditional QA approach had drawbacks in the age of A challenge for target tracking systems that move the rapidly developing, complex technology such as real-time ͑ beam in response to respiratory motion the “open loop” sys- motion adaptive radiation therapy. As a first step, the use of ͒ tems described above is that the beam modifying devices nonstationary phantoms which simulate skin and tumor mo- need to be able to adjust the beam with sufficient acceleration separately is becoming a standard tool in the QA process tion and velocity to follow the motion for a reasonable frac- to measure the precision and accuracy of respiratory motion tion of the treatment to maintain high delivery efficiency. If compensation. The major limitation of these phantoms is the mechanically the motion cannot keep up, a beam hold should dependency of the measurement result on the simulated mo- be asserted. This is easiest for magnetic steering of particle tion pattern used. Because we still do not have “ground beams, but more difficult where mechanical motion is truth” data of real-time tumor motion and surrogate marker needed. A particular challenge is using the DMLC to shape for the time intervals required for treatment ͑maximum 150 s fields in real time, particularly in the presence of large mo- of data vs. 15–60 min treatment length͒, the results will not tion perpendicular to the leaf motion direction. Delivery ef- truly reflect patient treatment results. In addition, simulating ficiencies of lower than 25% for SMLC and DMLC IMRT rotation and deformation is still challenging. A minor, but fields in the presence of high frequency motion perpendicu- significant, issue may be the effects on the dose distribution lar to the leaf motion direction have been measured.41 For due to the change of the dose calculation parameters such situations, several mean position estimation algorithms throughout the respiratory cycle ͑e.g., SSD, surface correc- have been proposed to maintain high delivery efficiency, in tion, density changes of lung͒. This potential change of dose which the average position of the tumor motion is followed, and the respiratory variations about this average are distribution can only be simulated and measured in anthro- ignored.89–91 These methods all but eliminate systematic er- pomorphic phantoms or very sophisticated software which ror in tracking, with the remaining motion included as ran- takes into account the body deformation in correlation with dom error. With little systematic error a moderate random the timing of the respective beam delivery with the corre- error has little impact on margins,92 though there are of sponding respiratory phase. course other errors such as tumor delineation uncertainty, Accuracy measurements with this new generation of tumor rotation, and tumor deformation that may have a sig- phantoms will give the medical physicist the answer to the question of technical accuracy of the real-time motion adap- nificant impact on margins. 93 Extensions of current delivery capabilities will be the in- tive treatment delivery system. Indirect tracking methods tegration of higher order dimensionality, such as rotational such as hybrid skin/tumor tracking models and/or 4DCT and deformational information in addition to translation, into based simulations of the correlation between internal motion the estimate of the patient pose and real-time reoptimization and a surrogate respiratory marker do not provide real-time and adaption of delivery to the dynamically changing position information. This in turn introduces an additional anatomy of cancer patients. error, namely the uncertainly from the correlation model between external surrogate and tumor position.29 Phantoms are not sufficiently anthropomorphic, and real-time in vivo do- III.C. Treatment planning simetry can so far only provide a few checkpoints of the Future 4D treatment planning approaches will have to delivery accuracy of a 3D treatment plan. consider intra- and interfraction variations in tumor and As treatments move towards real-time feedback and real- organs-at-risk motion patterns. While 4D planning is cur- time adaptation, QA processes will need to account for the rently not routine from a clinical perspective, its adoption on increased delivery complexity and shorter timescales of a routine basis will become essential to complement techno- beam adjustment. This will involve the addition of real-time logical advances in 4D delivery techniques. Eventually, real- measurement as appropriate on the radiation delivery devices time volumetric imaging may also be incorporated in adap- themselves and synchronization of measured motion and tive planning strategies such that the optimal plan is dose delivery data streams to facilitate dose reconstruction to delivered to the temporally evolving anatomy of the patient. estimate the dose delivered to the patient. Also, phantoms

Medical Physics, Vol. 35, No. 12, December 2008 5690 Dieterich et al.: Locating and targeting moving tumors with radiation beams 5690

tion could allow for significantly reduced patient-treatment time, in addition to high treatment accuracy. Avoiding the need to reposition the patient prior to or during treatment and reducing the overall treatment time are hypothesized to reduce the post-couch-movement secondary skeletal motion induced by couch motion or fatigue. Clinical outcomes will improve: Anticipating improved clinical outcomes is always controversial in the absence and unlikely chance of a randomized trial comparing radiotherapy where in one arm real-time target information is not acquired or ignored, and a second arm where real-time locating and tumor targeting occurs, however it is the driving factor in the development of improved technology in radio- FIG. 3. The number of Medline-indexed articles published in the past 10 completed years with the search terms “tumor tracking radiotherapy.” therapy. The entire field of radiotherapy is based on the te- nets that increased tumor dose will increase local control and possibly survival, and that lowering normal tissue dose de- mimicking the complexity of multidimensional motion and creases toxicity. For lung cancer there is ample evidence of 94–100 daily anatomic changes observed during human treatments the benefits of dose escalation and toxicity 101–108 will form an integral part of system tests. reduction, which can be simultaneously achieved by more accurate and precise radiotherapy. Intrafraction motion is not just a concern in the thorax and IV. EVIDENCE AND RATIONALE FOR FUTURE … PROJECTION abdomen. For the prostate “ an on-line target motion monitoring and correction strategy is necessary to implement hy- The future projections for locating and targeting moving pofractionated SBRT with intensity modulated beams for tumors can be broadly summarized as follows. prostate cancer treatments” concludes a recent Medical Phys- 109 ͑1͒ Technology and methods will continue to be developed ics paper investigating the dosimetric concerns of in- and improve. trafraction motion for the prostate—where motion is present ͑2͒ Clinical availability and implementation will increase. but significantly smaller than for thoracic and abdominal ͑3͒ Efficiency of treatment delivery will increase. sites. Perhaps the most compelling, albeit indirect, clinical ͑4͒ Clinical outcomes will improve. evidence for image guided radiotherapy is in a retrospective review: “Rectal distension on the treatment-planning CT Evidence for these projections are given below. scan decreased the probability of biochemical control, local Technology and method will continue to be developed and control, and rectal toxicity in patients who were treated with- improve/Clinical availability and implementation will in- out daily image-guided prostate localization, presumably be- crease: Stating that radiotherapy technology will improve is cause of geographic misses.”41 The rectal distension was obvious, given funding from governments, philanthropic or- found to be a greater prognostic indicator than high risk dis- ganizations, individual departments, and intramural and ex- ease. tramural vendor research and development support. This projection is also based on the large increase in scientific interest in explicit motion management. The number of papers with V. STRATEGY FOR MOVING FROM THE PRESENT keywords “tumor tracking radiotherapy” has grown from a TO THE FUTURE few in the mid-to-late 1990s to over 50 in 2007. This growth Changing the practice of radiotherapy from predomi- is shown in Fig. 3. nantly static to real-time dynamic is a paradigm shift for the The number of available systems for locating and target- treatment team. As in many other areas of medical physics ing tumors has increased with time. When clinically avail- and particularly radiation oncology—many of these exciting able, tumor tracking is used. Cyberknife system users have areas are highlighted in the Vision 20/20 series—moving embraced the tumor tracking approach. Experimentally, the from the present to the future will involve continued innova- use of the MLC for tracking has been demonstrated on three tion and research and development in academia and small different vendor platforms, Varian,38,41,42 Siemens ͑personal and large companies. Medical physicists will play key roles communication, Martin Tacke, DKFZ, June 2008͒, and To- in the clinical practice and guidelines. Locating and targeting motherapy ͑Personal communication, Gustavo Olivera, To- moving tumors with radiation beams is currently available motherapy. July 2008͒, though none are clinically available from one vendor, Accuray, via the Cyberknife platform. Thus yet. there is a wealth of clinical and medical physics expertise Efficiency of treatment delivery will increase: Integrating and experience in this area, and this should be leveraged as tumor localization and targeting can not only improve accu- other real-time locating and targeting solutions are brought racy and precision, but also efficiency. The development of on line. It may well be that different vendors are used for the techniques to rapidly account for variations in the external locating and targeting tasks, with real-time software integra- pose of the patient and internal target and normal tissue motion. An example is electromagnetic localization ͑Calypso͒

Medical Physics, Vol. 35, No. 12, December 2008 5691 Dieterich et al.: Locating and targeting moving tumors with radiation beams 5691 integrated with an MLC tracking system ͑Varian͒ that has Lagendijk, “Integrating a MRI scanner with a 6 MV radiotherapy accel- been experimentally investigated in a phantom study.110,111 erator: Dose deposition in a transverse magnetic field,” Phys. Med. Biol. 49, 4109–4118 ͑2004͒. 11J. J. Lagendijk, B. W. Raaymakers, A. J. Raaijmakers, J. Overweg, K. J. VI. CONCLUSIONS Brown, E. M. Kerkhof, R. W. van der Put, B. Hardemark, M. van Vulpen, and U. A. van der Heide, “MRI/linac integration,” Radiother. Oncol. 86, In conclusion, we are seeing rapid progress in the devel- 25–29 ͑2008͒. opment and clinical implementation of active target tracking. 12A. J. Raaijmakers, B. W. Raaymakers, and J. J. Lagendijk, “Experimental These developments combine imaging, planning, and treat- verification of magnetic field dose effects for the MRI-accelerator,” Phys. Med. Biol. 52, 4283–4291 ͑2007͒. ment delivery with motion tracking. The authors anticipate in 13 C. Kirkby, T. Stanescu, S. Rathee, M. Carlone, B. Murray, and B. G. the future there will be a larger choice of real-time target Fallone, “Patient dosimetry for hybrid MRI-radiotherapy systems,” Med. localization systems, all of the major linear accelerator Phys. 35, 1019–1027 ͑2008͒. manufacturers will offer some form of motion tracking, and 14A. Hsu, N. R. Miller, P. M. Evans, J. C. Bamber, and S. Webb, “Feasi- the fraction of radiotherapy treatments using motion tracking bility of using ultrasound for real-time tracking during radiotherapy,” Med. Phys. 32, 1500–1512 ͑2005͒. will steadily increase. Given the dose-response relationship 15J. Wu, O. Dandekar, D. Nazareth, P. Lei, W. D’Souza, and R. Shekhar, for tumor and normal tissues that the field of radiation on- “Effect of ultrasound probe on dose delivery during real-time ultrasound- cology is founded upon, more accurate radiation therapy will guided tumor tracking,” Conf. Proc. IEEE Eng. Med. Biol. Soc. 1, 3799– hopefully improve tumor control and reduce treatment- 3802 ͑2006͒. 16A. Sawada, K. Yoda, M. Kokubo, T. Kunieda, Y. Nagata, and M. Hiraoka, related toxicity. “A technique for noninvasive respiratory gated radiation treatment system based on a real time 3D ultrasound image correlation: A phantom study,” ACKNOWLEDGMENTS Med. Phys. 31, 245–250 ͑2004͒. 17M. Fuss, J. Boda-Heggemann, N. Papanikolau, and B. J. Salter, “Image- The authors acknowledge the organizers and sponsors of guidance for stereotactic body radiation therapy,” Med. Dosim. 32,102– the Motion Adaptive Radiotherapy Workshop held at Geor- 110 ͑2007͒. 18 getown University in 2007 where many of the concepts de- T. R. Willoughby, P. A. Kupelian, J. Pouliot, K. Shinohara, M. Aubin, M. Roach, 3rd, L. L. Skrumeda, J. M. Balter, D. W. Litzenberg, S. W. Had- scribed above were discussed. The major sponsors were Si- ley, J. T. Wei, and H. M. Sandler, “Target localization and real-time emens Medical Solutions, Accuray Inc., Calypso Medical, tracking using the Calypso 4D localization system in patients with local- and Elekta Oncology Systems. ized prostate cancer,” Int. J. Radiat. Oncol., Biol., Phys. 65, 528–534 ͑2006͒. ͒ 19 a Author to whom correspondence should be addressed. Electronic mail: J. M. Balter, J. N. Wright, L. J. Newell, B. Friemel, S. Dimmer, Y. Cheng, [email protected] J. Wong, E. Vertatschitsch, and T. P. Mate, “Accuracy of a wireless lo- 1S. M. Bentzen, “Randomized controlled trials in health technology assess- calization system for radiotherapy,” Int. J. Radiat. Oncol., Biol., Phys. 61, ment: Overkill or overdue?,” Radiother. Oncol. 86, 142–147 ͑2008͒. 933–937 ͑2005͒. 2P. Keall, G. Mageras, J. Balter, R. Emery, K. Forster, S. Jiang, J. Kapa- 20P. Kupelian, T. Willoughby, A. Mahadevan, T. Djemil, G. Weinstein, S. toes, D. Low, M. Murphy, C. Ramsey, M. Van Herk, S. Vedam, J. Wong, Jani, C. Enke, T. Solberg, N. Flores, D. Liu, D. Beyer, and L. Levine, and E. Yorke, “The management of respiratory motion in radiation oncol- “Multi-institutional clinical experience with the Calypso System in local- ogy report of AAPM Task Group 76,” Med. Phys. 33, 3874–3900 ͑2006͒. ization and continuous, real-time monitoring of the prostate gland during 3S. Shimizu, H. Shirato, K. Kitamura, S. Ogura, H. Akita-Dosaka, U. external radiotherapy,” Int. J. Radiat. Oncol., Biol., Phys. 67, 1088–1098 Tateishi, Y. Watanabe, K. Fujita, T. Shimizu, and K. Miyasaka, “Fluoro- ͑2007͒. scopic real-time tumor-tracking radiation treatment ͑RTRT͒ can reduce 21L. Dietrich, S. Jetter, T. Tucking, S. Nill, and U. Oelfke, “Linac- internal margin ͑IM͒ and set-up margin ͑SM͒ of planning target volume integrated 4D cone beam CT: First experimental results,” Phys. Med. ͑PTV͒ for lung tumors,” Int. J. Radiat. Oncol., Biol., Phys. 48, 166–167 Biol. 51, 2939–2952 ͑2006͒. ͑ ͒ 22 2000 . N. Wink, C. Panknin, and T. D. Solberg, “Phase versus amplitude sorting 4 S. Shimizu, H. Shirato, K. Kitamura, N. Shinohara, T. Harabayashi, T. of 4D-CT data,” Med. Phys. 7,77–85͑2006͒. Tsukamoto, T. Koyanagi, and K. Miyasaka, “Use of an implanted marker 23J. W. Wong, M. B. Sharpe, D. A. Jaffray, V. R. Kini, J. M. Robertson, J. and real-time tracking of the marker for the positioning of prostate and S. Stromberg, and A. A. Martinez, “The use of active breathing control bladder cancers,” Int. J. Radiat. Oncol., Biol., Phys. 48, 1591–1597 ͑ABC͒ to reduce margin for breathing motion,” Int. J. Radiat. Oncol., ͑2000͒. ͑ ͒ 5 Biol., Phys. 44, 911–919 1999 . S. Shimizu, H. Shirato, S. Ogura, H. Akita-Dosaka, K. Kitamura, T. Nish- 24 J. Hanley, M. M. Debois, D. Mah, G. S. Mageras, A. Raben, K. Rosen- ioka, K. Kagei, M. Nishimura, and K. Miyasaka, “Detection of lung tu- zweig, B. Mychalczak, L. H. Schwartz, P. J. Gloeggler, W. Lutz, C. C. mor movement in real-time tumor-tracking radiotherapy,” Int. J. Radiat. Ling, S. A. Leibel, Z. Fuks, and G. J. Kutcher, “Deep inspiration breath- Oncol., Biol., Phys. 51, 304–310 ͑2001͒. hold technique for lung tumors: The potential value of target immobili- 6H. Shirato, S. Shimizu, T. Kunieda, K. Kitamura, M. van Herk, K. Kagei, zation and reduced lung density in dose escalation,” Int. J. Radiat. Oncol., T. Nishioka, S. Hashimoto, K. Fujita, H. Aoyama, K. Tsuchiya, K. Kudo, Biol., Phys. 45, 603–611 ͑1999͒. and K. Miyasaka, “Physical aspects of a real-time tumor-tracking system 25 for gated radiotherapy,” Int. J. Radiat. Oncol., Biol., Phys. 48, 1187–1195 S. S. Korreman, T. Juhler-Nottrup, and A. L. Boyer, “Respiratory gated ͑2000͒. beam delivery cannot facilitate margin reduction, unless combined with 7H. Shirato, S. Shimizu, T. Shimizu, T. Nishioka, and K. Miyasaka, “Real- respiratory correlated image guidance,” Radiother. Oncol. 86,61–68 ͑ ͒ time tumour-tracking radiotherapy,” Lancet 353, 1331–1332 ͑1999͒. 2008 . 26 8R. I. Berbeco, S. B. Jiang, G. C. Sharp, G. T. Chen, H. Mostafavi, and H. M. J. Murphy, “Tracking moving organs in real time,” Semin. Radiat. Shirato, “Integrated radiotherapy imaging system ͑IRIS͒: Design consid- Oncol. 14, 91–100 ͑2004͒. 27 erations of tumour tracking with linac gantry-mounted diagnostic x-ray A. Schweikard, H. Shiomi, and J. Adler, “Respiration tracking in radio- systems with flat-panel detectors,” Phys. Med. Biol. 49, 243–255 ͑2004͒. surgery,” Med. Phys. 31, 2738–2741 ͑2004͒. 28 9B. Cho, Y. Suh, S. Dieterich, and P. J. Keall, “A monoscopic method for C. Ozhasoglu, M. J. Murphy, G. Glosser, M. Bodduluri, A. Schweikard, real-time tumour tracking using combined occasional x-ray imaging and K. Forster, D. P. Martin, and J. R. Adler, “Real-time tracking of the tumor continuous respiratory monitoring,” Phys. Med. Biol. 53, 2837–2855 volume in precision radiotherapy and body radiosurgery—A novel ap- ͑2008͒. proach to compensate for respiratory motion,” presented at the Computer 10B. W. Raaymakers, A. J. Raaijmakers, A. N. Kotte, D. Jette, and J. J. Assisted Radiology and Surgery, San Francisco, 2000.

Medical Physics, Vol. 35, No. 12, December 2008 5692 Dieterich et al.: Locating and targeting moving tumors with radiation beams 5692

29Y. Seppenwoolde, R. I. Berbeco, S. Nishioka, H. Shirato, and B. Heijmen, radiotherapy,” Int. J. Radiat. Oncol., Biol., Phys. 53, 822–834 ͑2002͒. “Accuracy of tumor motion compensation algorithm from a robotic res- 51D. A. Low, P. J. Parikh, W. Lu, J. F. Dempsey, S. H. Wahab, J. P. Huben- piratory tracking system: A simulation study,” Med. Phys. 34, 2774–2784 schmidt, M. M. Nystrom, M. Handoko, and J. D. Bradley, “Novel breath- ͑2007͒. ing motion model for radiotherapy,” Int. J. Radiat. Oncol., Biol., Phys. 30 J. R. McClelland, S. Webb, D. McQuaid, D. M. Binnie, and D. J. Hawkes, 63, 921–929 ͑2005͒. “Tracking ‘differential organ motion’ with a ‘breathing’ multileaf colli- 52M. J. Murphy, J. Jalden, and M. Isaksson, “Adaptive filtering to predict mator: Magnitude of problem assessed using 4D CT data and a motion- lung tumor breathing motion during image-guided radiation therapy,” compensation strategy,” Phys. Med. Biol. 52, 4805–4826 ͑2007͒. Proceedings of the 16th International Congress on Computer-assisted Ra- 31D. McQuaid and S. Webb, “IMRT delivery to a moving target by dynamic diology and Surgery ͑2002͒, pp. 539–544. MLC tracking: Delivery for targets moving in two dimensions in the 53 beam’s eye view,” Phys. Med. Biol. 51, 4819–4839 ͑2006͒. S. S. Vedam, P. J. Keall, A. Docef, D. A. Todor, V. R. Kini, and R. 32S. Webb and D. M. Binnie, “A strategy to minimize errors from differen- Mohan, “Predicting respiratory motion for four-dimensional radio- tial intrafraction organ motion using a single configuration for a ‘breath- therapy,” Med. Phys. 31, 2274–2283 ͑2004͒. 54 ing’ multileaf collimator,” Phys. Med. Biol. 51, 4517–4531 ͑2006͒. M. Isaksson, J. Jalden, and M. J. Murphy, “On using an adaptive neural 33S. Webb, “Quantification of the fluence error in the motion-compensated network to predict lung tumor motion during respiration for radiotherapy dynamic MLC ͑DMLC͒ technique for delivering intensity-modulated ra- applications,” Med. Phys. 32, 3801–3809 ͑2005͒. diotherapy ͑IMRT͒,” Phys. Med. Biol. 51, L17-L21 ͑2006͒. 55G. C. Sharp, S. B. Jiang, S. Shimizu, and H. Shirato, “Prediction of 34 L. Papiez and D. Rangaraj, “DMLC leaf-pair optimal control for mobile, respiratory tumour motion for real-time image-guided radiotherapy,” deforming target,” Med. Phys. 32, 275–285 ͑2005͒. Phys. Med. Biol. 49, 425–440 ͑2004͒. 35 L. Papiez, D. Rangaraj, and P. Keall, “Real-time DMLC IMRT delivery 56A. Trofimov, E. Rietzel, H. M. Lu, B. Martin, S. Jiang, G. T. Chen, and T. ͑ ͒ for mobile and deforming targets,” Med. Phys. 32, 3037–3048 2005 . Bortfeld, “Temporo-spatial IMRT optimization: Concepts, implementa- 36D. Rangaraj and L. Papiez, “Synchronized delivery of DMLC intensity tion and initial results,” Phys. Med. Biol. 50, 2779–2798 ͑2005͒. modulated radiation therapy for stationary and moving targets,” Med. 57W. A. Beckham, P. J. Keall, and J. V. Siebers, “A fluence-convolution Phys. 32, 1802–1817 ͑2005͒. 37R. McMahon, L. Papiez, and D. Rangaraj, “Dynamic-MLC leaf control method to calculate radiation therapy dose distributions that incorporate ͑ ͒ utilizing on-flight intensity calculations: A robust method for real-time random set-up error,” Phys. Med. Biol. 47, 3465–3473 2002 . 58 IMRT delivery over moving rigid targets,” Med. Phys. 34, 3211–3223 I. J. Chetty, M. Rosu, N. Tyagi, L. H. Marsh, D. L. McShan, J. M. Balter, ͑2007͒. B. A. Fraass, and R. K. Ten Haken, “A fluence convolution method to 38P. J. Keall, H. Cattell, D. Pokhrel, S. Dieterich, K. H. Wong, M. J. Mur- account for respiratory motion in three-dimensional dose calculations of phy, S. S. Vedam, K. Wijesooriya, and R. Mohan, “Geometric accuracy of the liver: A Monte Carlo study,” Med. Phys. 30, 1776–1780 ͑2003͒. a real-time target tracking system with dynamic multileaf collimator 59J. Leong, “Implementation of random positioning error in computerised tracking system,” Int. J. Radiat. Oncol., Biol., Phys. 65, 1579–1584 radiation treatment planning systems as a result of fractionation,” Phys. ͑2006͒. ͑ ͒ 39 Med. Biol. 32, 327–334 1987 . P. J. Keall, V. R. Kini, S. S. Vedam, and R. Mohan, “Motion adaptive 60A. E. Lujan, E. W. Larsen, J. M. Balter, and R. K. Ten Haken, “A method x-ray therapy: A feasibility study,” Phys. Med. Biol. 46, 1–10 ͑2001͒. for incorporating organ motion due to breathing into 3D dose calcula- 40T. Neicu, H. Shirato, Y. Seppenwoolde, and S. B. Jiang, “Synchronized tions,” Med. Phys. 26, 715–720 ͑1999͒. moving aperture radiation therapy ͑SMART͒: average tumour trajectory 61P. J. Keall, W. A. Beckham, J. T. Booth, S. F. Zavgorodni, and M. Oppe- for lung patients,” Phys. Med. Biol. 48, 587–598 ͑2003͒. 41A. Sawant, R. Venkat, V. Srivastava, D. Carlson, S. Povzner, H. Cattell, laar, “A method to predict the effect of organ motion and set-up variations ͑ ͒ and P. Keall, “Management of three-dimensional intrafraction motion on treatment plans,” Australas. Phys. Eng. Sci. Med. 22,48–52 1999 . 62 through real-time DMLC tracking,” Med. Phys. 35, 2050–2061 ͑2008͒. T. Craig, J. Battista, and J. Van Dyk, “Limitations of a convolution 42J. Zimmerman, S. Korreman, G. Persson, H. Cattell, M. Svatos, A. method for modeling geometric uncertainties in radiation therapy. II. The Sawant, R. Venkat, D. Carlson, and P. Keall, “DMLC motion tracking of effect of a finite number of fractions,” Med. Phys. 30, 2012–2020 ͑2003͒. moving targets for intensity modulated arc therapy treatment—a feasibil- 63T. Craig, J. Battista, and J. Van Dyk, “Limitations of a convolution ity study,” Acta Oncol. 1–6 ͑2008͒. method for modeling geometric uncertainties in radiation therapy. I. The 43 Y. Kamino, K. Takayama, M. Kokubo, Y. Narita, E. Hirai, N. Kawawda, effect of shift invariance,” Med. Phys. 30, 2001–2011 ͑2003͒. T. Mizowaki, Y. Nagata, T. Nishidai, and M. Hiraoka, “Development of a 64G. T. Chen, J. H. Kung, and E. Rietzel, “Four-dimensional imaging and four-dimensional image-guided radiotherapy system with a gimbaled treatment planning of moving targets,” Front. Radiat. Ther. Oncol. 40, ͑ ͒ X-ray head,” Int. J. Radiat. Oncol., Biol., Phys. 66, 271–278 2006 . 59–71 ͑2007͒. 44C. Bert, N. Saito, A. Schmidt, N. Chaudhri, D. Schardt, and E. Rietzel, 65S. Flampouri, S. B. Jiang, G. C. Sharp, J. Wolfgang, A. A. Patel, and N. “Target motion tracking with a scanned particle beam,” Med. Phys. 34, C. Choi, “Estimation of the delivered patient dose in lung IMRT treatment 4768–4771 ͑2007͒. 45S. O. Grozinger, E. Rietzel, Q. Li, C. Bert, T. Haberer, and G. Kraft, based on deformable registration of 4D-CT data and Monte Carlo simu- ͑ ͒ “Simulations to design an online motion compensation system for lations,” Phys. Med. Biol. 51, 2763–2779 2006 . 66 scanned particle beams,” Phys. Med. Biol. 51, 3517–3531 ͑2006͒. M. Guckenberger, J. Wilbert, T. Krieger, A. Richter, K. Baier, J. Meyer 46W. D. D’Souza and T. J. McAvoy, “An analysis of the treatment couch and M. Flentje, “Four-dimensional treatment planning for stereotactic and control system dynamics for respiration-induced motion compensa- body radiotherapy,” Int. J. Radiat. Oncol., Biol., Phys. 69, 276–285 tion,” Med. Phys. 33, 4701–4709 ͑2006͒. ͑2007͒. 47W. D. D’Souza, S. A. Naqvi, and C. X. Yu, “Real-time intra-fraction- 67T. Guerrero, G. Zhang, W. Segars, T. C. Huang, S. Bilton, G. Ibbott, L. motion tracking using the treatment couch: A feasibility study,” Phys. Dong, K. Forster, and K. P. Lin, “Elastic image mapping for 4-D dose Med. Biol. 50, 4021–4033 ͑2005͒. estimation in thoracic radiotherapy,” Radiat. Prot. Dosim. 115, 497–502 48 P. Qiu, W. D. D’Souza, T. J. McAvoy, and K. J. Ray Liu, “Inferential ͑2005͒. modeling and predictive feedback control in real-time motion compensa- 68Y. Suh, E. Weiss, H. Zhong, M. Fatyga, J. V. Siebers, and P. J. Keall, “A tion using the treatment couch during radiotherapy,” Phys. Med. Biol. 52, deliverable four-dimensional intensity-modulated radiation therapy- 5831–5854 ͑2007͒. planning method for dynamic multileaf collimator tumor tracking deliv- 49J. Wilbert, J. Meyer, K. Baier, M. Guckenberger, C. Herrmann, R. Hess, ery,” Int. J. Radiat. Oncol., Biol., Phys. 71, 1526–1536 ͑2008͒. C. Janka, L. Ma, T. Mersebach, A. Richter, M. Roth, K. Schilling, and M. 69 Flentje, “Tumor tracking and motion compensation with an adaptive tu- A. Schlaefer, J. Fisseler, S. Dieterich, H. Shiomi, K. Cleary, and A. Sch- mor tracking system ͑ATTS͒: System description and prototype testing,” weikard, “Feasibility of four-dimensional conformal planning for robotic Med. Phys. 35, 3911–3921 ͑2008͒. radiosurgery,” Med. Phys. 32, 3786–3792 ͑2005͒. 70 50Y. Seppenwoolde, H. Shirato, K. Kitamura, S. Shimizu, M. van Herk, J. T. Yamamoto, U. W. Langner, and P. Keall, “Retrospective analysis of V. Lebesque, and K. Miyasaka, “Precise and real-time measurement of artifacts in the four-dimensional CT images of 50 patients,” Int. J. Radiat. 3D tumor motion in lung due to breathing and heartbeat, measured during Oncol., Biol., Phys. 72, 1250–1258 ͑2008͒.

Medical Physics, Vol. 35, No. 12, December 2008 5693 Dieterich et al.: Locating and targeting moving tumors with radiation beams 5693

71P. Keall, “4-dimensional computed tomography imaging and treatment 94N. C. Choi and J. A. Doucette, “Improved survival of patients with un- planning,” Semin. Radiat. Oncol. 14, 81–90 ͑2004͒. resectable non-small-cell bronchogenic carcinoma by an innovated high- 72 P. J. Keall, S. Joshi, G. Tracton, V. Kini, S. Vedam, and R. Mohan, dose en-bloc radiotherapeutic approach,” Cancer 48, 101–109 ͑1981͒. “4-Dimensional radiotherapy planning,” Int. J. Radiat. Oncol., Biol., 95M. K. Martel, R. K. Ten Haken, M. B. Hazuka, M. L. Kessler, M. Straw- Phys. 57, S233 ͑2003͒. derman, A. T. Turrisi, T. S. Lawrence, B. A. Fraass, and A. S. Lichter, 73 K. K. Brock, D. L. McShan, R. K. Ten Haken, S. J. Hollister, L. A. “Estimation of tumor control probability model parameters from 3-D dose Dawson, and J. M. Balter, “Inclusion of organ deformation in dose cal- distributions of non-small cell lung cancer patients,” Lung Cancer 24, culations,” Med. Phys. 30, 290–295 ͑2003͒. ͑ ͒ 74 31–37 1999 . M. Rosu, I. J. Chetty, J. M. Balter, M. L. Kessler, D. L. McShan, and R. 96P. Okunieff, D. Morgan, A. Niemierko, and H. D. Suit, “Radiation dose- K. Ten Haken, “Dose reconstruction in deforming lung anatomy: Dose response of human tumors,” Int. J. Radiat. Oncol., Biol., Phys. 32, 1227– grid size effects and clinical implications,” Med. Phys. 32, 2487–2495 ͑ ͒ ͑ ͒ 1237 1995 . 2005 . 97 75 C. A. Perez, M. Bauer, S. Edelstein, B. W. Gillespie, and R. Birch, “Im- E. Rietzel, G. T. Chen, N. C. Choi, and C. G. Willet, “Four-dimensional image-based treatment planning: Target volume segmentation and dose pact of tumor control on survival in carcinoma of the lung treated with irradiation,” Int. J. Radiat. Oncol., Biol., Phys. 12, 539–547 ͑1986͒. calculation in the presence of respiratory motion,” Int. J. Radiat. Oncol., 98 Biol., Phys. 61, 1535–1550 ͑2005͒. C. A. Perez, T. F. Pajak, P. Rubin, J. R. Simpson, M. Mohiuddin, L. W. 76E. Heath and J. Seuntjens, “A direct voxel tracking method for four- Brady, R. Perez-Tamayo, and M. Rotman, “Long-term observations of the dimensional Monte Carlo dose calculations in deforming anatomy,” Med. patterns of failure in patients with unresectable non-oat cell carcinoma of Phys. 33, 434–445 ͑2006͒. the lung treated with definitive radiotherapy. Report by the Radiation 77P. J. Keall, S. Joshi, S. S. Vedam, J. V. Siebers, V. R. Kini, and R. Mohan, Therapy Oncology Group,” Cancer 59, 1874–1881 ͑1987͒. “Four-dimensional radiotherapy planning for DMLC-based respiratory 99C. A. Perez, K. Stanley, P. Rubin, S. Kramer, L. Brady, R. Perez-Tamayo, motion tracking,” Med. Phys. 32, 942–951 ͑2005͒. G. S. Brown, J. Concannon, M. Rotman, and H. G. Seydel, “A prospec- 78 M. Engelsman, E. Rietzel, and H. M. Kooy, “Four-dimensional proton tive randomized study of various irradiation doses and fractionation treatment planning for lung tumors,” Int. J. Radiat. Oncol., Biol., Phys. schedules in the treatment of inoperable non-oat-cell carcinoma of the 64, 1589–1595 ͑2006͒. lung. Preliminary report by the Radiation Therapy Oncology Group,” 79 Y. Kang, X. Zhang, J. Y. Chang, H. Wang, X. Wei, Z. Liao, R. Komaki, J. Cancer 45, 2744–2753 ͑1980͒. D. Cox, P. A. Balter, H. Liu, X. R. Zhu, R. Mohan, and L. Dong, “4D 100J. Wulf, K. Baier, and M. P. Flentje, “Dose escalation in radiothreapy of proton treatment planning strategy for mobile lung tumors,” Int. J. Radiat. lung tumors by stereotactic irradiation: Is there a dose-response relation- Oncol., Biol., Phys. 67, 906–914 ͑2007͒. ship for local tumor control?” Int. J. Radiat. Oncol., Biol., Phys. 63, S52 80R. Kashani, M. Hub, M. L. Kessler, and J. M. Balter, “Technical note: A ͑2005͒. physical phantom for assessment of accuracy of deformable alignment 101 algorithms,” Med. Phys. 34, 2785–2788 ͑2007͒. J. Bradley, J. O. Deasy, S. Bentzen, and I. El-Naqa, “Dosimetric corre- 81R. Kashani, K. Lam, D. Litzenberg, and J. Balter, “Technical note: A lates for acute esophagitis in patients treated with radiotherapy for lung ͑ ͒ deformable phantom for dynamic modeling in radiation therapy,” Med. carcinoma,” Int. J. Radiat. Oncol., Biol., Phys. 58, 1106–1113 2004 . 102 Phys. 34, 199–201 ͑2007͒. J. Bradley, M. V. Graham, K. Winter, J. A. Purdy, R. Komaki, W. H. Roa, 82M. Serban, E. Heath, G. Stroian, D. L. Collins, and J. Seuntjens, “A J. K. Ryu, W. Bosch, and B. Emami, “Toxicity and outcome results of deformable phantom for 4D radiotherapy verification: Design and image RTOG 9311: A phase I-II dose-escalation study using three-dimensional registration evaluation,” Med. Phys. 35, 1094–1102 ͑2008͒. conformal radiotherapy in patients with inoperable non-small-cell lung 83E. Nioutsikou, N. S.-T. J. Richard, J. L. Bedford, and S. Webb, “Quanti- carcinoma,” Int. J. Radiat. Oncol., Biol., Phys. 61, 318–328 ͑2005͒. fying the effect of respiratory motion on lung tumour dosimetry with the 103M. V. Graham, J. A. Purdy, B. Emami, W. Harms, W. Bosch, M. A. aid of a breathing phantom with deforming lungs,” Phys. Med. Biol. 51, Lockett, and C. A. Perez, “Clinical dose-volume histogram analysis for ͑ ͒ 3359–3374 2006 . pneumonitis after 3D treatment for non-small cell lung cancer ͑NSCLC͒,” 84 J. E. Cates, A. E. Lefohn, and R. T. Whitaker, “GIST: An interactive, Int. J. Radiat. Oncol., Biol., Phys. 45, 323–329 ͑1999͒. GPU-based level set segmentation tool for 3D medical images,” Med. 104M. L. Hernando, L. B. Marks, G. C. Bentel, S. M. Zhou, D. Hollis, S. K. Image Anal. 8, 217–231 ͑2004͒. Das, M. Fan, M. T. Munley, T. D. Shafman, M. S. Anscher, and P. A. 85A. E. Lefohn, J. M. Kniss, C. D. Hansen, and R. T. Whitaker, “A stream- Lind, “Radiation-induced pulmonary toxicity: A dose-volume histogram ing narrow-band algorithm: Interactive computation and visualization of analysis in 201 patients with lung cancer,” Int. J. Radiat. Oncol., Biol., level sets,” IEEE Trans. Vis. Comput. Graph. 10, 422–433 ͑2004͒. 86 Phys. 51, 650–659 ͑2001͒. K. O. Noe, B. D. De Senneville, U. V. Elstrom, K. Tanderup, and T. S. 105 Sorensen, “Acceleration and validation of optical flow based deformable S. L. Kwa, J. V. Lebesque, J. C. Theuws, L. B. Marks, M. T. Munley, G. registration for image-guided radiotherapy,” Acta Oncol. 47, 1286–1293 Bentel, D. Oetzel, U. Spahn, M. V. Graham, R. E. Drzymala, J. A. Purdy, ͑2008͒. A. S. Lichter, M. K. Martel, and R. K. Ten Haken, “Radiation pneumoni- 87K. O. Noe, K. Tanderup, J. C. Lindegaard, C. Grau, and T. S. Sorensen, tis as a function of mean lung dose: An analysis of pooled data of 540 “GPU accelerated viscous-fluid deformable registration for radiotherapy,” patients,” Int. J. Radiat. Oncol., Biol., Phys. 42,1–9͑1998͒. Stud. Health Technol. Inform. 132, 327–332 ͑2008͒. 106D. Oetzel, P. Schraube, F. Hensley, G. Sroka-Perez, M. Menke, and M. 88G. C. Sharp, N. Kandasamy, H. Singh, and M. Folkert, “GPU-based Flentje, “Estimation of pneumonitis risk in three-dimensional treatment streaming architectures for fast cone-beam CT image reconstruction and planning using dose-volume histogram analysis,” Int. J. Radiat. Oncol., demons deformable registration,” Phys. Med. Biol. 52, 5771–5783 Biol., Phys. 33, 455–460 ͑1995͒. ͑ ͒ 107 2007 . Y. Seppenwoolde, J. V. Lebesque, K. de Jaeger, J. S. Belderbos, L. J. 89 D. Ruan, J. A. Fessler, and J. M. Balter, “Mean position tracking of Boersma, C. Schilstra, G. T. Henning, J. A. Hayman, M. K. Martel, and ͑ ͒ respiratory motion,” Med. Phys. 35, 782–792 2008 . R. K. Ten Haken, “Comparing different NTCP models that predict the 90R. George, Y. Suh, M. Murphy, J. Williamson, E. Weiss, and P. Keall, incidence of radiation pneumonitis,” Int. J. Radiat. Oncol., Biol., Phys. “On the accuracy of a moving average algorithm for target tracking dur- 55, 724–735 ͑2003͒. ing radiation therapy treatment delivery,” Med. Phys. 35, 2356–2365 108E. D. Yorke, A. Jackson, K. E. Rosenzweig, S. A. Merrick, D. Gabrys, E. ͑2008͒. 91A. Trofimov, C. Vrancic, T. C. Chan, G. C. Sharp, and T. Bortfeld, “Tu- S. Venkatraman, C. M. Burman, S. A. Leibel, and C. C. Ling, “Dose- mor trailing strategy for intensity-modulated radiation therapy of moving volume factors contributing to the incidence of radiation pneumonitis in targets,” Med. Phys. 35, 1718–1733 ͑2008͒. non-small-cell lung cancer patients treated with three-dimensional confor- 92M. van Herk, “Different styles of image-guided radiotherapy,” Semin. mal radiation therapy,” Int. J. Radiat. Oncol., Biol., Phys. 54, 329–339 Radiat. Oncol. 17, 258–267 ͑2007͒. ͑2002͒. 109 93K. H. Wong, S. Dieterich, J. Tang, and K. Cleary, “Quantitative measure- S. Hossain, P. Xia, C. Chuang, L. Verhey, A. Gottschalk, G. Mu, and L. ment of CyberKnife robotic arm steering,” Technol. Cancer Res. Treat. 6, Ma, “Simulated real time image guided intrafraction tracking-delivery for 589–594 ͑2007͒. hypofractionated prostate IMRT,” Med. Phys. 35, 4041–4048 ͑2008͒.

Medical Physics, Vol. 35, No. 12, December 2008 5694 Dieterich et al.: Locating and targeting moving tumors with radiation beams 5694

110A. Sawant, R. L. Smith, R. Venkat, L. Santaman, B. Cho, P. Poulsen, H. a dynamic multileaf collimator tracking system ͑abstract͒,” Int. J. Radiat. Cattell, J. Newell, P. Parikh, and P. Keall, “Geometric accuracy and la- Oncol., Biol., Phys. 72, S612–S613 ͑2008͒. tency of an integrated 4D IMRT delvery system using real-time internal 112M. Uematsu, CT-guided focal high dose radiotherapy, presented at the 4th position monitoring and dynamic MLC tracking ͑abstract͒,” Int. J. Radiat. S. Takahashi International Workshop on 3 Dimensional Conformal Radio- Oncol., Biol., Phys. 72, S27–S28 ͑2008͒. therapy, Nagoya, Japan, 2004. 111R. L. Smith, A. Sawant, L. Santaman, R. Venkat, J. Newell, B. Cho, P. 113Y. Suh, S. Dieterich, and P. J. Keall, “Geometric uncertainty of 2D pro- Poulsen, H. Cattell, P. Keall, and P. Parikh, “IMRT dosimetric measure- jection imaging in monitoring 3D tumor motion,” Phys. Med. Biol. 52, ments from a real-time internal position monitoring system coupled with 3439–3454 ͑2007͒.

Medical Physics, Vol. 35, No. 12, December 2008 Prospects of photoacoustic tomography ͒ Lihong V. Wanga Optical Imaging Laboratory, Department of Biomedical Engineering, Washington University in St. Louis, Campus Box 1097, One Brookings Drive, St. Louis, Missouri 63130-4899 ͑Received 8 August 2008; revised 10 October 2008; accepted for publication 15 October 2008; published 19 November 2008͒ Commercially available high-resolution three-dimensional optical imaging modalities—including confocal microscopy, two-photon microscopy, and optical coherence tomography—have fundamentally impacted biomedicine. Unfortunately, such tools cannot penetrate biological tissue deeper than the optical transport mean free path ͑ϳ1 mm in the skin͒. Photoacoustic tomography, which combines strong optical contrast and high ultrasonic resolution in a single modality, has broken through this fundamental depth limitation and achieved superdepth high-resolution optical imaging. In parallel, radio frequency-or microwave-induced thermoacoustic tomography is being actively developed to combine radio frequency or microwave contrast with ultrasonic resolution. In this Vision 20/20 article, the prospects of photoacoustic tomography are envisaged in the following aspects: ͑1͒ photoacoustic microscopy of optical absorption emerging as a mainstream technology, ͑2͒ melanoma detection using photoacoustic microscopy, ͑3͒ photoacoustic endoscopy, ͑4͒ simultaneous functional and molecular photoacoustic tomography, ͑5͒ photoacoustic tomography of gene expression, ͑6͒ Doppler photoacoustic tomography for ﬂow measurement, ͑7͒ photoacoustic tomography of metabolic rate of oxygen, ͑8͒ photoacoustic mapping of sentinel lymph nodes, ͑9͒ multiscale photoacoustic imaging in vivo with common signal origins, ͑10͒ simultaneous photoacoustic and thermoacoustic tomography of the breast, ͑11͒ photoacoustic and thermoacoustic tomography of the brain, and ͑12͒ low-background thermoacoustic molecular imaging. © 2008 American As- sociation of Physicists in Medicine. ͓DOI: 10.1118/1.3013698͔

Key words: microscopy, melanoma detection, endoscopy, functional imaging, molecular imaging, reporter gene imaging, Doppler effect, metabolic rate of oxygen, sentinel lymph nodes, multiscale imaging, thermoacoustic tomography, breast imaging, brain imaging

I. INTRODUCTION free path, where photons have sustained many scattering events and retain only a weak memory of the original inci- ͑ ͒ The field of photoacoustic tomography PAT has grown a dence direction. The diffusive regime is beyond ten times the great deal in the past few years. PAT is cross-sectional or transport mean free path, where photons have suffered many three-dimensional imaging based on the photoacoustic effect. scattering events that they have almost completely lost their Alexander Graham Bell first reported on the photoacoustic 4 effect in 1880. Only recently, however, was PAT developed memory of the original incidence direction. as an imaging technology.1–29 PAT combines high ultrasonic Two important depth limits exist for optical imaging. One resolution and strong optical contrast in a single modality, is near the optical transport mean free path, representing the capable of providing high-resolution structural, functional,19 depth of the quasiballistic regime in biological tissue. Ballis- and molecular30,31 imaging in vivo in optically scattering bio- tic light intensity attenuates exponentially with a decay con- logical tissue at new depths. stant equal to the mean free path. To reach one transport In biological tissues, light transfer is dominated by scat- mean free path deep, photons must undergo significant scattering. The mean free path is on the order of 0.1 mm, and the tering, making focusing ineffective.32 We refer to this barrier transport mean free path is on the order of 1 mm. While the as the soft depth limit for high-resolution optical imaging. former measures the frequency of predominantly anisotropic Another depth limit is around 50–70 mm, which equals scattering, the latter assesses the frequency of equivalent iso- roughly ten times the 1/e optical penetration depth ͑the re- tropic scattering. As a result of scattering, photon propaga- ciprocal of the effective attenuation coefficient͒. To reach tion transitions from the ballistic regime into the diffusive this depth, light must experience 43 dB or 20 000 times one- regime around one transport mean free path.4 Specifically, the ballistic regime is within the mean free path, where a way decay in intensity. Beyond this limit, even diffuse pho- significant number of photons have undergone no scattering. tons are too few for practical purposes. We refer to this limit The quasiballistic regime is from the mean free path to the as the hard depth limit for optical imaging. Nevertheless, if transport mean free path, where photons have sustained a the tissue is illuminated from opposite sides, a thickness few scattering events but retain a strong memory of the origi- greater than 10 cm can be potentially covered, which is ad- nal incidence direction. The quasidiffusive regime is from equate for many biomedical applications such as breast im- the transport mean free path to ten times the transport mean aging.

High-resolution optical imaging beyond the soft depth transducers placed outside the tissue, producing electric sig- limit, sometimes referred to as superdepth optical imaging, nals. The electric signals are then amplified, digitized, and remained a void until PAT was developed. None of the com- transferred to a computer, where an image is formed. PAT mercially available optical ballistic imaging modalities— depends on any absorbed photons, either unscattered or scat- including confocal microscopy, two-photon microscopy and tered, to produce photoacoustic signals as long as the photon optical coherence tomography—can penetrate into scattering excitation is relaxed thermally. Readers are referred to recent biological tissue beyond the soft depth limit. By contrast, review and tutorial articles for more details.1,4 diffuse optical tomography—based on multiple-scattered The formation of a photoacoustic image, mapping the photons—can provide rapid functional and molecular imag- photoacoustic source according to the detected sound sig- ing beyond the soft depth limit; however, it has poor spatial nals, can be exemplified with the simplest case of pinpoint- resolution. The motivation driving the development of PAT is ing a single sound source such as thunder in three- to overcome the poor spatial resolution of diffuse optical dimensional ͑3D͒ space. If the time delay between seeing tomography or the soft depth limit of existing high- lightening and hearing thunder is recorded, one can infer that resolution optical imaging. the thunder took place on a spherical surface of a radius An approach to overcome the optical hard depth limit is to determined by the product of the speed of sound and the time adopt radiofrequency or microwaves for photoacoustic 6,7 delay. If three such measurements are taken at different lo- excitation. In this case, the technology is referred to as cations, the sound source can be accurately triangulated. If radio frequency- or microwave-induced acoustic tomography produced by the photoacoustic effect, the sound source can ͑ ͒ or thermoacoustic tomography TAT . For simplicity here, be imaged by PAT. In most practical cases, the sound source radio frequency refers to microwaves as well. In TAT, a radio is spatially distributed rather than localized at a point. frequency generator instead of a laser is used. The radio PAT has been implemented in two major forms. One form frequency generator transmits radio frequency pulses into the is based on a scanning focused ultrasonic transducer. Acous- tissue to be imaged. Radio frequency absorption produces tic focusing in combination with time-resolved detection of heat and subsequent ultrasonic waves. The ultrasound detec- photoacoustic waves directly provides 3D spatial resolution. tion and image formation are similar to those in PAT. Scanning over the tissue produces tomographic images. Both PAT and TAT are designed to overcome the poor Dark-field confocal photoacoustic microscopy belongs to spatial resolution of pure optical or radio frequency imaging this category.33–35 Dark field means that the light illumination yet to retain the high electromagnetic contrasts. In terms of pattern on the tissue surface is donut shaped with a dark spatial resolution, pure optical imaging beyond the soft depth core; confocal means that the ultrasonic detection shares the limit suffers from strong diffusion due to tissue scattering, same focus as the light illumination. The other form is based whereas pure radio frequency imaging suffers from strong on an array of unfocused ultrasonic transducers. This diffraction due to the long wavelength. Ultrasonic scattering method, also referred to as photoacoustic computed tomog- coefficient in tissue is 2–3 orders of magnitude less than the ͑ raphy, requires the use of an inverse algorithm to reconstruct optical counterpart, and the acoustic diffraction or wave- 36 length͒ is 2–3 orders of magnitude weaker ͑or shorter͒ than a tomographic image. the radio frequency counterpart. As a result, PAT and TAT The dominant contrast of interest is based on the optical can provide high spatial resolution by detecting the induced absorption in the photoacoustic excitation phase. By using ultrasonic waves. Unlike ultrasonography or optical coher- multiwavelength measurement, one can simultaneously ence tomography, PAT and TAT produce speckle-free quantify concentrations of multiple chromophores of differ- images. ent colors, such as oxygenated and deoxygenated hemoglo- The subsequent sections are organized as follows. First, bin molecules in red blood cells. Such quantification of he- the basic principle of PAT is reviewed. Then, the future pros- moglobin can provide functional imaging of the pects of PAT and TAT are envisioned on twelve specific top- concentration and oxygen saturation of hemoglobin. Both ics. Finally, a summary is provided. parameters are related to hallmarks of cancer: the concentration of hemoglobin correlates with angiogenesis,27 whereas the oxygen saturation of hemoglobin correlates with II. BASICS OF PHOTOACOUSTIC TOMOGRAPHY hypermetabolism.31 Such parameters of hemoglobin can also 19 PAT involves optical irradiation, ultrasonic detection, and be used to image brain activity. In addition, extrinsic opti- image formation. The tissue is usually irradiated by a short- cal absorption contrast agents can be used to provide mo- 30,31 pulsed laser beam to produce thermal and acoustic impulse lecular imaging of biomarkers. responses. Locally absorbed light is converted into heat, PAT is highly sensitive to optical absorption. PAT works which is further converted to a pressure rise via thermoelas- on dark background—when no absorption exists, the back- tic expansion of the tissue. The initial pressure rise— ground signal is zero. Such dark background enables sensi- determined by the local optical energy deposition ͑also called tive detection. In the presence of absorption, the foreground specific optical absorption in the unit of J/m3͒ and other signal is proportional to the absorption coefficient. Any small thermal and mechanical properties—propagates in the tissue fractional change in optical absorption coefficient translates as an ultrasonic wave, which is referred to as a photoacoustic into an equal amount of fractional change in PAT signal, wave. The photoacoustic wave is detected by ultrasonic which means a relative sensitivity of 100%.2 When the frac-

Medical Physics, Vol. 35, No. 12, December 2008 5760 Lihong V. Wang: Prospects of photoacoustic tomography 5760 tional change is large, light transport modeling can be used to quantify the optical absorption coefﬁcient.37 The spatial resolution is derived from ultrasonic detection in the photoacoustic emission phase. Ultrasonic scattering is much weaker than optical scattering. The wavelength of the detected photoacoustic wave is sufﬁciently short. As a result, photoacoustic waves provide better resolution than optical waves beyond the soft depth limit. Among other parameters, the center frequency and the bandwidth of the ultrasonic detection system predominantly determine the spatial resolution of PAT. The greater the center frequency and the wider the bandwidth, the better the spatial resolution is.

III. PREDICTIONS III.A. Photoacoustic microscopy of optical absorption going mainstream

Prediction 1: Photoacoustic microscopy will join the suite FIG.1. ͑a͒ Photograph of a melanoma in a nude mouse; ͑b͒ image acquired with the 50-MHz photoacoustic microscope operating at 584 and 764 nm. of mainstream optical microscopy technologies. ͑ ͒ ͑ ͒ Composite of the two maximum amplitude projection MAP images pro- Photoacoustic microscopy PAM has shown the follow- jected along the z axis. Six orders of vessel branching ͑1–6͒ can be ob- ing capabilities. First, PAM has broken through the current served. ͑c͒ 3D rendering of the melanoma image acquired at 764 nm. Two fundamental depth limitation of high-resolution optical im- MAP images at this wavelength projected along the x and y axes are shown 33,34 on the sidewalls. The composite image in panel b is redrawn at the bottom. aging modalities. The commercially available micro- The top of the tumor is 0.32 mm below the skin surface, and the thickness of scopic optical imaging modalities—including confocal mi- the tumor is 0.3 mm. ͑d͒ Close-up two-dimensional image of the melanoma croscopy, two-photon microscopy, and optical coherence in a cross-section parallel with the z-x plane at the dashed line in panel b. ͑e͒ tomography—cannot provide penetration into scattering bio- HE-stained histological section at the same marked location. M: melanoma. Reproduced with permission ͑Fig.2ofRef.34͒. logical tissue beyond the soft depth limit ͑ϳ1mminthe skin͒ because they are based on ballistic and quasiballistic photons. Taking advantage of photons that have been scat- In light of its appealing capabilities, PAM is expected to tered an any number of times, PAM has filled the void of become commercially available and widely used in biomedi- penetration and reached superdepth optical imaging. As will cal research and clinical practice. be shown in Sec. III A, imaging depths of 3–30 mm have been experimentally demonstrated. Second, the depth-to- III.B. Melanoma detection using photoacoustic resolution ratio ͑maximum imaging depth divided by the microscopy axial resolution͒ can be approximately maintained at more than 100 while the imaging depth and spatial resolution are Prediction 2: Melanoma detection will become a high im- scaled. Third, PAM provides functional imaging based on pact application of photoacoustic microscopy. physiologically specific endogenous optical absorption con- While melanoma is the most deadly form of skin cancer, trasts. The red color in Fig. 1 shows a PAM image of blood it is curable if detected early. The diagnosis of melanoma is vasculature using endogenous contrast only, the contrast be- often based on its appearance. Abnormally appearing skin tween the blood and the background is as high as 13:1.34 In lesions are resected for biopsy. Because visual inspection is comparison, other imaging modalities such as x-ray com- inaccurate and biopsy is invasive, an accurate noninvasive puted tomography and magnetic resonance imaging usually method of melanoma detection is desirable. require the use of exogenous contrast agents to image blood PAM can acquire ͑1͒ structural images measuring tumor vessels clearly with high contrast. Further, magnetic reso- burden and depth, ͑2͒ functional images of hemoglobin con- nance imaging cannot measure the concentration of hemo- centration measuring tumor angiogenesis—a hallmark of globin and the absolute oxygenation of hemoglobin. Fourth, cancer, ͑3͒ functional images of hemoglobin oxygen satura- ͑ ͒ PAM can provide molecular or genetic imaging based on tion SO2 measuring tumor hypoxia or hypermetabolism— exogenous contrast mechanisms.30,31 Fifth, PAM can be con- another hallmark of cancer, and ͑4͒ images of melanin constructed to image in real time. A B-scan frame rate of 50 Hz centration measuring tumor pigmentation—a hallmark of has been achieved.38,39 Sixth, PAM images are free of melanotic melanoma, consisting of Ͼ90% of melanomas speckle artifacts. Finally, PAM is safe to human subjects and ͑note that even amelanotic melanoma contains a low concen- ready for clinical applications. tration of melanin͒.Anin vivo PAM image of a melanoma in The various high-resolution optical imaging modalities a small animal is shown in Fig. 1. The depth of melanoma, are compared in Table I. While PAM is sensitive to optical also an important prognostic parameter, was measured by absorption, it is insensitive to optical scattering or PAM. By contrast, other high-resolution optical microscopy fluorescence.2 The various modalities complement each other technologies cannot provide the required penetration. Be- in both penetration and contrast; they will therefore coexist. cause of biological variability in most biological problems, a

Medical Physics, Vol. 35, No. 12, December 2008 5761 Lihong V. Wang: Prospects of photoacoustic tomography 5761

TABLE I. Comparison of high-resolution optical imaging modalities.

Modality Penetration Primary contrast

Confocal microscopy ϳ0.5 mm Scattering, ﬂuorescence Two-photon microscopy ϳ0.5 mm Fluorescence Optical coherence tomography ϳ1 mm Scattering, polarization Photoacoustic microscopy Up to 30 mm, scalable Absorption

single biomarker is unlikely able to provide accurate diagno- ception of introducing exogenous contrast agent. By sis. However, the combination of four complementary mea- combining imaging physics with molecular and cell biology, sures can significantly enhance the likelihood of high accu- molecular imaging can potentially lead to better methods for racy. In addition, as Doppler photoacoustic microscopy preventing, diagnosing, and managing diseases. For ex- matures, blood flow measurement can add more diagnostic ample, tumor biology and angiogenesis can be characterized information. Therefore, it is expected that the combined rich with high specificity because molecular imaging probes can contrasts will provide the sensitivity and specificity needed be designed to target at specific molecular biomarkers ex- for the early detection of melanoma. pressed on neoendothelial-and tumor-cell surfaces. Such characterization will accelerate the development of III.C. Photoacoustic endoscopy molecular-targeted cancer therapeutics. Nevertheless, molecular imaging will not supplant functional imaging. The Prediction 3: Photoacoustic endoscopy will play a unique former requires the use of foreign contrast agent, whereas the role in diagnosing gastrointestinal cancer. latter depends on intrinsic contrast only. Therefore, the Incidence of gastrointestinal cancer is on the rise yet often former may involve some degree of toxicity and may not be diagnosed at an untreatable stage. Optical endoscopy is the universally applicable. In addition, functional imaging can current practice in identifying suspicious lesions for subse- measure some physiological parameters that cannot be easily quent biopsy. Operating in the mode of surface or ballistic measured by molecular imaging. imaging, existing optical endoscopy has severely limited Simultaneous functional and molecular PAT was demon- penetration. Ultrasound endoscopy is being introduced into strated in live mice ͑Fig. 2͒.31 One million human U87 glio- the clinic as well. Yet the mechanical contrast in ultrasound blastoma tumor cells were implanted stereotactically into images often cannot provide the required sensitivity and young adult immunocompromised nude mice in the head specificity. Other medical imaging modalities such as x-ray ϳ3 mm below the scalp surface. One week post inoculation, computed tomography and magnetic resonance imaging have 20 nmol of molecular imaging probe IRDye800-c͑KRGDf͒ not been implemented endoscopically because of diagnostic was administered through the tail vein while mannitol was insensitivity, technological difficulties or expenses. used to permeabilize the blood brain barrier. Approximately Light and sound are well suited for endoscopic applica- 20 h later, imaging with PAT was conducted. Four laser tions. Because both forms of energy have been used endo- wavelengths—764, 784, 804, and 824 nm—were used to scopically, PAM can naturally be implemented endoscopi- measure the spectral distribution of optical absorption due to cally. As PAM can provide a multitude of endogenous oxyhemoglobin, deoxyhemoglobin, and IRDye800- contrasts at new depths, it is likely to provide accurate diag- c͑KRGDf͒. Figure 2͑a͒ shows an in vivo pseudocolor func- nosis of superficial as well as deep lesions in the gastrointes- tional PAT image of the oxygen saturation of hemoglobin. A tinal tract. Similarly, intravascular photoacoustic imaging can focal region pointed by the arrow shows lower oxygen satu- also be implemented.40 Of course, adding molecular imaging capability to photoacoustic endoscopy can further enhance the diagnostic accuracy albeit at the inconvenience of using exogenous contrast agent.

III.D. Simultaneous functional and molecular photoacoustic tomography Prediction 4: Simultaneous functional and molecular photoacoustic tomography will provide unprecedented sensitivity and speciﬁcity to cancer diagnosis. While functional imaging is based on endogenous contrast, molecular imaging is based on exogenous contrast— which essentially stains invisible biomarkers in vivo. The FIG.2.͑a͒ In vivo functional PAT image of hemoglobin in a nude mouse former maps physiological activities at the tissue or organ brain with a U87 glioblastoma xenograft. The arrow indicates the hypoxic ͑ ͒ level, whereas the latter images biological and pathophysi- region. b In vivo molecular PAT image of tail-vein injected IRDye800- c͑KRGDf͒ in the same nude mouse brain. The circle indicates the region of ological processes at the molecular level. Both can be ac- integrin overexpression. Reproduced with permission ͑Figs.2and3of complished quantitatively and noninvasively—with the ex- Ref. 31͒.

Medical Physics, Vol. 35, No. 12, December 2008 5762 Lihong V. Wang: Prospects of photoacoustic tomography 5762 ration of hemoglobin than the surrounding area, indicating fusion in order to assay the activity of a particular promoter hypoxia characteristic of tumor due to hypermetabolism. in a cell. If the promoter is ubiquitous, a reporter gene can be Figure 2͑b͒ shows an in vivo pseudocolor molecular PAT used to tag cells. The most widely used conventional optical ␣ ␤ image of the molecular imaging probe. Integrin v 3 is imaging of reporter genes include fluorescence imaging of known to overexpress in U87 glioblastoma tumors while green fluorescence proteins or their mutants41 and biolumi- ͑ ͒ ␣ ␤ 42 IRDye800-c KRGDf is known to bind to v 3 integrin. The nescence imaging of luciferases. circled region indicates the overexpression of integrin in the Molecular PAT of reporter gene lacZ was demonstrated in U87 glioblastoma tumor. The focal regions of both the func- living rats.30 The lacZ gene encodes enzyme ␤-galactosidase. tional and molecular contrasts were corroborated to be the The enzyme can cleave an optically transparent substrate tumor region through postmortem fluorescence imaging and 5-bromo-4-chloro-3-indolyl-␤-D-galactoside ͑x-gal͒, yield- histological examination. ing a stable dark blue product. The blue product increases PAT is competitive in sensitivity compared with other ex- optical absorption and serves as a contrast agent for PAT. So isting molecular imaging technologies. In comparison to the far, x-gal was injected locally because systemic delivery nM–pM sensitivity of positron emission tomography at mm through the tail vein turned out to be inefficient. spatial resolution, PAT has poorer sensitivity ͑␮M–nM͒ but We hope to collaborate with developers of reporter genes better spatial resolution. While positron emission tomogra- to construct optical-absorption-based reporter gene systems phy uses ionizing radiation, PAT uses nonionizing light and that are more suitable for PAT. Because of its high spatial ultrasound. Even at its current level, the sensitivity of PAT is resolution at depths beyond the reach of pure high-resolution superior to that of magnetic resonance imaging ͑mM͒. Fur- optical imaging, PAT is expected to become a complemen- thermore, the sensitivity of PAT can be potentially improved tary tool to conventional optical imaging of reporter genes by increasing the local optical fluence, increasing the optical in vivo. absorption cross section of the contrast agent, increasing the photoacoustic conversion efficiency, increasing signal aver- III.F. Doppler photoacoustic tomography aging, and sacrificing the spatial resolution. In comparison to pure ultrasound imaging, which measures mechanical con- Prediction 6: Doppler photoacoustic tomography will pro- trast, PAT dominantly measures optical contrast and has vide imaging of blood flow in vivo with high spatial and many choices of contrast agents. Ultrasound molecular im- velocity resolution. aging, based on microbubbles, is confined to intravascular The photoacoustic Doppler effect was recently discovered space only. It is worth mentioning that x-ray imaging has not experimentally.43,44 While the optical Doppler effect involves yet been demonstrated to provide molecular imaging because light only, the acoustic Doppler effect involves sound only. of its low sensitivity. By contrast, the photoacoustic Doppler effect involves both In summary, PAT represents a new paradigm for func- light and sound, resulting from the combination of the pho- tional and molecular imaging. Translation to the clinic is toacoustic and Doppler effects. Here, the photoacoustic wave expected to follow the availability of molecular contrast undergoes a Doppler shift when the photoacoustic source— agents for human use. By combining functional and molecu- the part of the light absorbing medium generating the pho- lar imaging in PAT, unprecedentedly high sensitivity and toacoustic wave—has motion relative to the acoustic detec- specificity of cancer diagnosis are expected. tor. An important application is to image blood flow in vivo by measuring the photoacoustic Doppler effect due to mov- III.E. Photoacoustic tomography of gene expressions ing red blood cells. We coined photoacoustic Doppler flow- Prediction 5: Deep penetrating high-resolution photoa- metry ͑PADF͒ for this imaging technology. PADF has poten- coustic tomography will become a complementary tool to tial advantages over conventional Doppler flowmetry. First, conventional optical imaging of reporter genes. PAT can image blood vessels at a depth of a few millimeters Understanding the nature of genes during in vivo devel- with a spatial resolution of tens of micrometers, whereas opment and pathogenesis is of significant interest. Such un- Doppler optical coherence tomography can penetrate only derstanding can be enabled by gene expression imaging, a one optical transport mean free path. Second, PADF tracks form of molecular imaging based on reporter genes. A re- light absorbing particles instead of scattering particles. Be- porter gene is a segment of DNA fused to another gene of cause red blood cells have much higher optical absorption interest. Unlike the contrast-carrying molecular imaging than the background outside blood vessels, PADF should probe presented in the preceding section, reporter genes must have low background noise and high sensitivity. By contrast, express into protein products to provide contrast. The two acoustic flowmetry suffers from background scattering and fused genes, sharing the same promoter, are transcribed into consequently has difficulty measuring slow flows. Third, the a single mRNA molecule, which is then translated into fused Doppler shift in PADF is nearly independent of the excitation proteins. The protein encoded by the reporter gene carries light, enabling accurate measurement of both speed and di- contrast either directly or through enzymatic reactions. As a rection of flow even at large depths inside an optically scat- result, a positive contrast in a gene expression image indi- tering medium. In comparison, laser Doppler flowmetry suf- cates up-regulations of both the reporter gene and the fused fers from multiple light scattering, limiting the sensing depth gene. Alternatively, a reporter gene can be used without gene and obscuring the information of flow direction. Finally,

Medical Physics, Vol. 35, No. 12, December 2008 5763 Lihong V. Wang: Prospects of photoacoustic tomography 5763

PADF is free of speckle artifacts. Therefore, PADF is ex- For patients with breast cancer but clinically negative ax- pected to break fresh ground for in vivo flow measurement illae, biopsy of the sentinel lymph node ͑SLN͒—the first with high spatial resolution and high velocity sensitivity. draining nodes—for axillary staging has become a standard clinical practice. In this conventional method, both optical dye and radioactive Tc-99 colloids are injected into the breast III.G. Photoacoustic tomography of metabolic rate of tumor. Both contrast agents are accumulated by SLNs. Emis- oxygen sion from radioactivity is first detected to locate approxi- Prediction 7: Photoacoustic tomography will become the mately the SLNs. Then, the SLNs are located precisely first single modality that can independently image the meta- through an invasive surgical procedure by visually tracing bolic rate of oxygen in vivo using endogenous contrast. the accumulated optical dye such as methylene blue. The ͑ ͒ The metabolic rate of oxygen MRO2 quantifies metabo- identified SLNs are then resected for pathological examina- lism, which can potentially be directly used to measure hy- tion. Unfortunately, the surgical procedure has associated permetabolism, a hallmark of cancer. The MRO2 is defined morbidity. A noninvasive method for accurately locating the as the amount of oxygen consumed in a given tissue region SLN in vivo is sought-after because noninvasive diagnostic per unit time per 100 g of tissue or of the organ of interest. methods such as fine needle biopsy could be subsequently Because in typical physiological conditions, hemoglobin is utilized without surgery. the dominant carrier of oxygen the key measure of blood PAT can potentially map the SLN noninvasively with high ͑ ͒ oxygenation is oxygen saturation of hemoglobin SO2 . spatial resolution in real time, avoiding invasive surgery and PAT can simultaneously image cross sections of blood harmful radioactivity. Preliminary data demonstrated that vessels, the concentration and oxygenation of hemoglobin, as PAT has both the required penetration depth and spatial res- well as blood flow in vivo. These four parameters suffice to olution for SLN mapping.49 PAT can identify whether a node quantify oxygen metabolism in tissues and organs. For a is sentinel by detecting the accumulated dye because the dye single-vessel system, we have has high optical absorption contrast. The peak absorption ϰ ͑ in out͒ ␯ ͑ ͒ wavelength of methylene blue dye is 690 nm, which lies near MRO2 SO −SO · CHb · Ain · ¯in. 1 2 2 the optimal optical penetration window. Since the optical ␯ Here, Ain is the area of the incoming vessel, ¯in is the mean contrast agent has been used in clinical SLN biopsy already, flow velocity of blood in the incoming vessel, CHb is the total avoiding FDA approval for a new optical contrast agent can in concentration of hemoglobin, SO2 is the SO2 of the incom- significantly accelerate the translation of PAT into the out 50 ing vessel to the region of interest, and SO2 is the SO2 of clinic. While PAT has broad potential applications, imaging the outgoing vessel. While Ain is measured by structural PAT, the SLN is a perfect niche clinical application of PAT with CHb and SO2 are measured by multiwavelength functional anticipated high impact on breast axillary staging and man- ␯ PAT; further, ¯in is estimated using Doppler photoacoustic agement. flowmetry. It is extremely fortuitous that all independent parameters III.I. Multiscale photoacoustic imaging in vivo in Eq. ͑1͒ can be measured by PAT, a single hybrid imaging with common signal origins modality. By contrast, magnetic resonance imaging detects only temporal changes in deoxyhemoglobin concentration Prediction 9: Multiscale photoacoustic tomography of the instead of absolute values. Equation ͑1͒ can be extended to a same signal origins in vivo will enable research in multiscale multivessel system. Although positron emission tomography biology. can image MRO2, exogenous radioactive tracers are Multiscale biology, recognized as the future of biomedical required.45,46 Diffuse optical tomography has also been used sciences, needs multiscale imaging. To understand the work- to image MRO2 except that a theoretical model or another ings of a whole biological system, components spanning technique ͑diffuse correlation imaging͒ is needed to estimate multiple spatial scales must be integrated. The components the blood flow.47,48 Further, both positron emission tomogra- may range from subcellular organelles ͑sub-␮m scale͒, phy and diffuse optical tomography have low spatial reso- through cells ͑␮m͒, to organs ͑cm͒. To facilitate research in lution. Therefore, PAT will potentially become the first single multiscale biology, we must provide multiscale imaging in modality that can independently image the metabolic rate of vivo with common signal origins. If the contrast mechanisms oxygen in vivo at high spatial resolution without the use of were disconnected among the images of various length exogenous contrast agent. It is expected to play a critical role scales, integrating discoveries across the scales would be in metabolism-related biomedical research and clinical diag- challenging. nosis. PAT can provide multiscale imaging in vivo with the same contrast origins ͑Fig. 3͒. Our original 50-MHz photoacoustic microscope can penetrate 3 mm at tens of ␮m resolution. III.H. Sentinel lymph node mapping The image resolution and the penetration limit are scalable using photoacoustic tomography with the ultrasonic frequency within the reach of photons. Prediction 1: Sentinel lymph node mapping will become On the one hand, the penetration limit can be scaled up to one of the first niche applications of photoacoustic tomogra- centimeters, i.e., the hard depth limit. In this case, photoa- phy. coustic microscopy is scaled to macroscopy. For example,

Medical Physics, Vol. 35, No. 12, December 2008 5764 Lihong V. Wang: Prospects of photoacoustic tomography 5764

limited by the annihilation range of positrons, on the order of 1 mm. Although ultrasound can achieve microscopic imaging by increasing the frequency from the clinically used MHz range to GHz range, the contrast reﬂects mechanical rather than biochemical properties. Therefore, PAT is expected to be the ﬁrst imaging technology, if not the only one on the horizon, that can potentially span a length scale ranging from organelles to organs while providing consistent biochemical contrast.

III.J. Simultaneous photoacoustic and thermoacoustic FIG.3. ͑a͒ Image acquired with the 5-MHz photoacoustic imaging system tomography of the breast showing the 30 mm penetration limit in chicken breast tissue. Reproduced with permission ͑Fig. 2͒͑Ref. 51͒. ͑b͒ Photograph taken with transmission Prediction 10: Simultaneous photoacoustic and thermoa- optical microscopy showing the microvasculature in a nude mouse ear. ͑c͒ coustic tomography of the breast will supplement or supplant In vivo photoacoustic image of the vasculature acquired with optical- x-ray mammography. resolution photoacoustic microscopy. CL: capillary; SG: sebaceous gland. Reproduced with permission ͑Fig.3ofRef.52͒. While breast cancer remains the leading cause of cancer death among women, early diagnosis improves survival. X-ray mammography, the only mass screening tool for de- employing a 5-MHz ultrasonic transducer and an 804-nm tecting nonpalpable breast cancers, has been shown to reduce light source scaled the penetration to 3 cm as shown in Fig. breast cancer deaths. However, ionizing radiation is required, 3͑a͒.51 On the other hand, the spatial resolution can be scaled and detecting dense breasts and early-stage tumors is met down to Ͻ10 ␮m. Using a focused light beam resulted in with limited sensitivity. In addition, imaging tumors close to 5 ␮m lateral resolution, which is limited by the focal diam- the chest wall is difficult. Therefore, alternative nonionizing eter of the excitation light beam. This resolution allows in radiation-based screening technologies are needed. So far, vivo imaging of capillaries—the smallest blood vessels—as ultrasound imaging has been used as an adjunct to x-ray shown in Fig. 3͑c͒.52 Of course, optical focusing is effective mammography, especially in differentiating cystic from solid only within the soft depth limit. Theoretically, the ultimate breast masses. Magnetic resonance imaging has high sensi- spatial resolution is optically diffraction limited, potentially tivity but variable specificity. It is further limited by its high yielding sub-␮m resolution in PAT. Therefore, PAT can po- cost and use of exogenous contrast agent. tentially image as small as organelles and as large as organs PAT and TAT can be integrated into conventional ultra- with the same contrast mechanism. sound imaging to provide multiple complementary contrasts The multiscale or multiresolution capability of PAT is simultaneously. Three types of images of the breast can be analogous to that of conventional optical microscopy, where acquired: ͑1͒ structural ultrasound pulse-echo images, ͑2͒ a single microscope possesses multiple attached objectives, functional laser-induced PAT images of concentration and permitting users to select a magnification factor easily. Such oxygen saturation of hemoglobin, and ͑3͒ radio frequency- a capability allows one to image a large region of interest at induced TAT images of water and sodium concentrations. a relatively low resolution. Then, one may zoom into a Good optical contrast, related to hallmarks of cancer, be- smaller region of interest with higher resolution to visualize tween tumor and normal breast tissues has been observed.53 smaller features while the same contrast mechanism is main- In TAT, up to 5:1 contrast was observed between tumor and tained. This scalability is needed because of the tradeoff be- normal breast tissues.29 In comparison, x-ray contrast among tween the region of interest and the spatial resolution. Of soft tissues is typically only a few percent. Again, a single course, such scalability is not limited to a single imaging contrast is usually unable to provide accurate diagnosis be- system. On the contrary, multiple systems can potentially be cause of biological variability. However, the combination of used to image at various resolution scales. multiple complementary measures will likely improve the PAT is uniquely positioned for multiscale imaging in vivo. accuracy. Conventional optical microscopy in various forms is the tool While compatible with ultrasound imaging, PAT and TAT of choice for microscopic imaging of cells and tissues. It is are also compatible with each other, sharing the same ultra- capable of offering a wealth of optical contrasts. PAT extends sonic detection system and image reconstruction algorithm. the depth of conventional optical microscopy beyond the soft Integrating PAT with TAT adds significant contrast but does depth limit and provides a continuum for multiscale imaging. not add significant costs. PAT and TAT can potentially be In comparison, conventional clinical imaging modalities distributed to physicians as an add-on feature to existing such as x-ray computed tomography, magnetic resonance im- clinical ultrasound imaging systems. While PAT and TAT are aging, positron emission tomography, and single photon emerging technologies, ultrasonography is a mature clinical emission computed tomography have not been widely used technology. Incorporating PAT and TAT into conventional in microscopic form for various reasons. For example, the ultrasonography will facilitate physicians’ acceptance of the resolution of positron emission tomography is fundamentally new technologies.

Medical Physics, Vol. 35, No. 12, December 2008 5765 Lihong V. Wang: Prospects of photoacoustic tomography 5765

In summary, PAT and TAT use nonionizing radiation only PAT and TAT essentially involve a laser or radio frequency and can be implemented at relatively low cost. It can poten- source in addition to the detection components of an ultra- tially provide high-resolution, multicontrast imaging of the sound imaging system. Therefore, PAT and TAT can be breast. Depending on the clinical trial outcome, PAT and TAT implemented at relatively low cost. When ultrasound arrays could potentially serve as an adjunct or even replace x-ray are used as in ultrasonography, PAT and TAT can be per- mammography if its sensitivity and specificity are superior. formed in real time. A standard ultrasound imaging system is portable and can be used at bedside. With the addition of a laser or radio frequency source, the entire imaging system III.K. Photoacoustic and thermoacoustic tomography can still be made relatively portable for bedside or operating- of the brain room applications. Again, integrating PAT and TAT into ex- Prediction 11: Photoacoustic and thermoacoustic tomog- isting ultrasound imaging systems can potentially accelerate raphy will provide low-cost, high-resolution, real-time, and acceptance of the new technology by physicians. even bedside functional imaging of the brain. In summary, the major challenge to PAT and TAT of the Existing high-resolution human brain imaging human brain is the phase distortion due to the skull. Correct- modalities—including x-ray computed tomography, mag- ing the distortion is believed to be a tractable problem. netic resonance imaging, and ultrasonography—have limita- Therefore, PAT and TAT are expected to provide low-cost, tions. Both x-ray computed tomography and magnetic reso- high-resolution, real-time, and bedside functional imaging of nance imaging are expensive and bulky. Further, x-ray the brain. computed tomography uses ionizing radiation, and magnetic resonance imaging requires a strong magnetic field. There- III.L. Low-background thermoacoustic molecular fore, it is advantageous to develop an affordable, nonioniz- imaging ing, high-resolution, and real-time imaging modality that can Prediction 12: Radio frequency-induced thermoacoustic be used in operating rooms or at the bedside. Such a system tomography will provide high-resolution, high-sensitivity, can be used to monitor brain functions and conditions such and deep-penetrating molecular imaging with the aid of tar- as strokes, head injuries, tumors, and brain infections. In cer- geted radio frequency contrast agents. tain cases, ultrasound brain imaging comes close to meeting Molecular imaging based on TAT has immense potential. these objectives. Ultrasonography is an established pediatric PAT can provide molecular imaging within the hard depth brain imaging modality when used before the fontanels are limit for optical imaging. By contrast, radio frequency waves closed. After the closure of the fontanels, the image quality at sufficiently low frequency can penetrate beyond 10 cm as degrades significantly because the skull severely attenuates demonstrated in magnetic resonance imaging. Ultrasound at and distorts ultrasonic waves. an appropriate frequency can travel a similar depth. Conse- Fortunately, unlike pulse-echo ultrasound imaging, PAT quently, radio frequency-induced TAT can potentially pro- and TAT involve only one-way ultrasound attenuation and vide penetration greater than 10 cm. Because low-frequency distortion due to the skull. As demonstrated previously,19 ul- radiofrequency waves have low absorption, endogenous ther- trasound penetration through small animal skulls is feasible, moacoustic signals would be weak, providing a low back- and the associated distortions are relatively small. The au- ground. Such a low background enables highly sensitive de- thor’s group also demonstrated TAT through Rhesus monkey tection of any other radio frequency absorbers, which can be skulls.54 The extension of PAT and TAT to human brain im- targeted molecular contrast agents. While PAT boasts a aging is an area of research. The primary task is to correct myriad of contrast agents, TAT has none available yet except for the phase distortion due to the skull. The skull basically the recently tested carbon nanotubes.55 Molecular imaging functions as an irregular lens, whose aberration effect can be TAT is somewhat analogous to low-background positron compensated for if the phase distortion can be quantified. A emission tomography except that TAT uses nonionizing ra- potential solution is to use geometric measurements of the diation and provides high spatial resolution. The author’s skull from x-ray computed tomography or magnetic reso- group is actively seeking collaborations with chemists to nance imaging to predict the phase distortion. identify contrast agents for TAT. Once such contrast agents PAT and TAT can provide rich contrasts for high- become available, TAT is expected to avail a new paradigm resolution structural and functional imaging. As demon- of high-resolution, low-background, high-sensitivity, and strated by diffuse optical tomography, near-infrared light can deep-penetrating molecular imaging. penetrate through the skull to the cortex and has been used for functional brain imaging at low spatial resolution. PAT can potentially provide similar penetration but higher reso- IV. SUMMARY lution. At an appropriate frequency, radio frequency can pen- The author believes that PAT and TAT will find broad etrate deeper than light. Therefore, TAT can potentially im- applications in both basic research and clinical care. In gen- age deeper structures of the brain, while PAT will likely be eral, it can potentially be applied in tumor studies, where used to image cortical functions. angiogenesis and hypermetabolism are highly correlated PAT and TAT are also relatively low-cost, real-time, and with cancer aggressiveness; in neuroscience, where oxygen portable. In comparison to x-ray computed tomography and saturation and concentration of hemoglobin are related to magnetic resonance imaging, ultrasonography is low cost. neural activities; in radiotherapy and chemotherapy of can-

Medical Physics, Vol. 35, No. 12, December 2008 5766 Lihong V. Wang: Prospects of photoacoustic tomography 5766 cer, where hypoxia is responsible for resistance to therapy; 9G. Ku and L. V. Wang, “Scanning electromagnetic-induced thermoacous- and in trauma evaluation, where optical absorption is associ- tic tomography: Signal, resolution, and contrast,” Med. Phys. 28, 4–10 ͑2001͒. ated with both hemorrhage and edema. 10K. P. Kostli, D. Frauchiger, J. J. Niederhauser, G. Paltauf, H. P. Weber, The aforementioned predictions represent the author’s bi- and M. Frenz, “Optoacoustic imaging using a three-dimensional recon- ased opinions of the most promising prospects of PAT and struction algorithm,” IEEE J. Sel. Top. Quantum Electron. 7, 918–923 ͑2001͒. TAT. The topics of the 12 predictions are recapitulated as 11 ͑ ͒ M. H. Xu, G. Ku, and L. V. Wang, “Microwave-induced thermoacoustic follows: 1 photoacoustic microscopy of optical absorption tomography using multi-sector scanning,” Med. Phys. 28, 1958–1963 emerging as a mainstream technology, ͑2͒ melanoma detec- ͑2001͒. tion using photoacoustic microscopy, ͑3͒ photoacoustic en- 12G. Paltauf, J. A. Viator, S. A. Prahl, and S. L. Jacques, “Iterative recon- ͑ ͒ struction algorithm for optoacoustic imaging,” J. Acoust. Soc. Am. 112, doscopy, 4 simultaneous functional and molecular photoa- ͑ ͒ ͑ ͒ 1536–1544 2002 . coustic tomography, 5 photoacoustic tomography of gene 13M. H. Xu and L. V. Wang, “Time-domain reconstruction for thermoacous- expression, ͑6͒ Doppler photoacoustic tomography for flow tic tomography in a spherical geometry,” IEEE Trans. Med. Imaging 21, measurement, ͑7͒ photoacoustic tomography of metabolic 814–822 ͑2002͒. 14 rate of oxygen, ͑8͒ photoacoustic mapping of sentinel lymph Y. Xu, D. Z. Feng, and L. V. Wang, “Exact frequency-domain reconstruc- ͑ ͒ tion for thermoacoustic tomography-I: Planar geometry,” IEEE Trans. nodes, 9 multiscale photoacoustic imaging in vivo with Med. Imaging 21, 823–828 ͑2002͒. common signal origins, ͑10͒ simultaneous photoacoustic and 15Y. Xu, M. H. Xu, and L. V. Wang, “Exact frequency-domain reconstruc- thermoacoustic tomography of the breast, ͑11͒ photoacoustic tion for thermoacoustic tomography-II: Cylindrical geometry,” IEEE ͑ ͒ and thermoacoustic tomography of the brain, and ͑12͒ low- Trans. Med. Imaging 21, 829–833 2002 . 16V. G. Andreev, A. A. Karabutov, and A. A. Oraevsky, “Detection of background thermoacoustic molecular imaging. ultrawide-band ultrasound pulses in optoacoustic tomography,” IEEE The following specific clinical applications are also worth Trans. Ultrason. Ferroelectr. Freq. Control 50, 1383–1390 ͑2003͒. pursuing: Demarcation of cancer for Mohs surgery, treatment 17D. Finch, S. K. Patch, and Rakesh, “Determining a function from its mean planning, and monitoring for laser therapy of port-wine values over a family of spheres,” SIAM J. Math. Anal. 35, 1213–1240 ͑2003͒. stains, skin burn imaging to determine the need for skin 18K. P. Kostli and P. C. Beard, “Two-dimensional photoacoustic imaging by graft, intraoperative demarcation of brain tumors, and intra- use of Fourier-transform image reconstruction and a detector with an operative imaging of brain functions. Undoubtedly, many anisotropic response,” Appl. Opt. 42, 1899–1908 ͑2003͒. 19X. D. Wang, Y. J. Pang, G. Ku, X. Y. Xie, G. Stoica, and L. V. Wang, more applications will be identified. “Noninvasive laser-induced photoacoustic tomography for structural and While the photoacoustics research community continues functional in vivo imaging of the brain,” Nat. Biotechnol. 21, 803–806 to discover new phenomena and invent new technologies, ͑2003͒. 20 several companies are actively commercializing photoacous- X. D. Wang, Y. J. Pang, G. Ku, G. Stoica, and L. V. Wang, “Three- dimensional laser-induced photoacoustic tomography of mouse brain with tic tomography. We look forward to seeing the impact of PAT the skin and skull intact,” Opt. Lett. 28, 1739–1741 ͑2003͒. and TAT on biomedicine. 21M. H. Xu and L. V. Wang, “Analytic explanation of spatial resolution related to bandwidth and detector aperture size in thermoacoustic or photoacoustic reconstruction,” Phys. Rev. E 67, 056605 ͑2003͒. ACKNOWLEDGMENTS 22M. Haltmeier, O. Scherzer, P. Burgholzer, and G. Paltauf, “Thermoacous- tic computed tomography with large planar receivers,” Inverse Probl. 20, This work is sponsored in part by National Institutes of 1663–1673 ͑2004͒. Health Grant Nos. R01 EB000712 and R01 NS46214 23G. Ku, X. D. Wang, G. Stoica, and L. V. Wang, “Multiple-bandwidth ͑Bioengineering Research Partnership͒. L.W. has a financial photoacoustic tomography,” Phys. Med. Biol. 49, 1329–1338 ͑2004͒. 24Y. Xu and L. V. Wang, “Time reversal and its application to tomography interest in Endra, Inc., which, however, did not support this with diffracting sources,” Phys. Rev. Lett. 92, 033902 ͑2004͒. work. 25B. T. Cox and P. C. Beard, “Fast calculation of pulsed photoacoustic fields in fluids using k-space methods,” J. Acoust. Soc. Am. 117, 3616–3627 ͒ a Telephone: 314-935-6152; Fax: 314-935-7448. Electronic mail: ͑2005͒. [email protected] 26G. Ku and L. V. Wang, “Deeply penetrating photoacoustic tomography in 1M. H. Xu and L. V. Wang, “Photoacoustic imaging in biomedicine,” Rev. biological tissues enhanced with an optical contrast agent,” Opt. Lett. 30, Sci. Instrum. 77, 041101 ͑2006͒. 507–509 ͑2005͒. 2L. V. Wang, “Tutorial on photoacoustic microscopy and computed tomog- 27G. Ku, X. D. Wang, X. Y. Xie, G. Stoica, and L. V. Wang, “Imaging of raphy,” IEEE J. Sel. Top. Quantum Electron. 14, 171–179 ͑2008͒. tumor angiogenesis in rat brains in vivo by photoacoustic tomography,” 3A. A. Oraevsky and L. V. Wang, Photons Plus Ultrasound: Imaging and Appl. Opt. 44, 770–775 ͑2005͒. Sensing ͑SPIE, Bellingham, 2007͒, Vol. 643. 28J. Zhang, M. A. Anastasio, X. C. Pan, and L. V. Wang, “Weighted expec- 4L. V. Wang and H. Wu, Biomedical Optics: Principles and Imaging tation maximization reconstruction algorithms for thermoacoustic tomog- ͑Wiley, Hoboken, NJ, 2007͒. raphy,” IEEE Trans. Med. Imaging 24, 817–820 ͑2005͒. 5C. G. A. Hoelen, F. F. M. de Mul, R. Pongers, and A. Dekker, “Three- 29G. Ku, B. D. Fornage, X. Jin, M. H. Xu, K. K. Hunt, and L. V. Wang, dimensional photoacoustic imaging of blood vessels in tissue,” Opt. Lett. “Thermoacoustic and photoacoustic tomography of thick biological tis- 23, 648–650 ͑1998͒. sues toward breast imaging,” Technol. Cancer Res. Treat. 4, 559–565 6L. V. Wang, X. M. Zhao, H. T. Sun, and G. Ku, “Microwave-induced ͑2005͒. acoustic imaging of biological tissues,” Rev. Sci. Instrum. 70, 3744–3748 30L. Li, R. J. Zemp, G. Lungu, G. Stoica, and L. V. Wang, “Photoacoustic ͑1999͒. imaging of lacZ gene expression in vivo,” J. Biomed. Opt. 12, 020504- 7R. A. Kruger, D. R. Reinecke, and G. A. Kruger, “Thermoacoustic com- ͑1–3͒͑2007͒. puted tomography—technical considerations,” Med. Phys. 26, 1832–1837 31M. Li, J. Oh, X. Xie, G. Ku, W. Wang, C. Li, G. Lungu, G. Stoica, and L. ͑1999͒. V. Wang, “Simultaneous molecular and hypoxia imaging of brain tumors 8A. A. Karabutov, E. V. Savateeva, N. B. Podymova, and A. A. Oraevsky, in vivo using spectroscopic photoacoustic tomography,” Proc. IEEE 96, “Backward mode detection of laser-induced wide-band ultrasonic tran- 481–489 ͑2008͒. sients with optoacoustic transducer,” J. Appl. Phys. 87, 2003–2014 32L. V. Wang and G. Liang, “Absorption distribution of an optical beam ͑2000͒. focused into a turbid medium,” Appl. Opt. 38, 4951–4958 ͑1999͒.

Medical Physics, Vol. 35, No. 12, December 2008 5767 Lihong V. Wang: Prospects of photoacoustic tomography 5767

33K. Maslov, G. Stoica, and L. V. Wang, “In vivo dark-field reflection-mode 46S. H. Yee, K. Lee, P. A. Jerabek, and P. T. Fox, “Quantitative measure- photoacoustic microscopy,” Opt. Lett. 30, 625–627 ͑2005͒. ment of oxygen metabolic rate in the rat brain using microPET imaging of 34H. F. Zhang, K. Maslov, G. Stoica, and L. V. Wang, “Functional photoa- briefly inhaled O-15-labelled oxygen gas,” Nucl. Med. Commun. 27, coustic microscopy for high-resolution and noninvasive in vivo imaging,” 573–581 ͑2006͒. Nat. Biotechnol. 24, 848–851 ͑2006͒. 47D. A. Boas, G. Strangman, J. P. Culver, R. D. Hoge, G. Jasdzewski, R. A. 35H. F. Zhang, K. Maslov, and L. V. Wang, “In vivo imaging of subcutane- Poldrack, B. R. Rosen, and J. B. Mandeville, “Can the cerebral metabolic ous structures using functional photoacoustic microscopy,” Nature Proto- rate of oxygen be estimated with near-infrared spectroscopy?,” Phys. cols 2, 797–804 ͑2007͒. Med. Biol. 48, 2405–2418 ͑2003͒. 36M. H. Xu and L. V. Wang, “Universal back-projection algorithm for pho- 48J. P. Culver, T. Durduran, T. Furuya, C. Cheung, J. H. Greenberg, and A. toacoustic computed tomography,” Phys. Rev. E 71, 016706 ͑2005͒. G. Yodh, “Diffuse optical tomography of cerebral blood flow, oxygen- 37B. T. Cox, S. R. Arridge, K. P. Kostli, and P. C. Beard, “Two-dimensional ation, and metabolism in rat during focal ischemia,” Biopolymers 23, quantitative photoacoustic image reconstruction of absorption distribu- 911–924 ͑2003͒. tions in scattering media by use of a simple iterative method,” Appl. Opt. 49K. H. Song, E. W. Stein, J. A. Margenthaler, and L. V. Wang, “Noninva- 45, 1866–1875 ͑2006͒. sive photoacoustic identification of sentinel lymph nodes containing me- 38R. J. Zemp, R. Bitton, M. L. Li, K. K. Shung, G. Stoica, and L. V. Wang, thylene blue in vivo in a rat model,” J. Biomed. Opt. 13, 054033-͑1–6͒ “Photoacoustic imaging of the microvasculature with a high-frequency ͑2008͒. ultrasound array transducer,” J. Biomed. Opt. 12, 010501-͑1–3͒͑2007͒. 50E. M. Sevick-Muraca, R. Sharma, J. C. Rasmussen, M. V. Marshall, J. A. 39R. J. Zemp, L. Song, R. Bitton, K. K. Shung, and L. V. Wang, “Realtime Wendt, H. Q. Pham, E. Bonefas, J. P. Houston, L. Sampath, K. E. Adams, photoacoustic microscopy in vivo with a 30-MHz ultrasound array trans- D. K. Blanchard, R. E. Fisher, S. B. Chiang, R. Elledge, and M. E. ducer,” Opt. Express 16, 7915–7928 ͑2008͒. Mawad, “Imaging of lymph flow in breast cancer patients after microdose 40S. Sethuraman, J. H. Amirian, S. H. Litovsky, R. W. Smalling, and S. Y. administration of a near-infrared flurophore: Feasibility study,” Radiology Emelianov, “Ex vivo characterization of atherosclerosis using intravascu- 246, 734–741 ͑2008͒. lar photoacoustic imaging,” Opt. Express 15, 16657–16666 ͑2007͒. 51K. Song and L. V. Wang, “Deep reflection-mode photoacoustic imaging 41R. Y. Tsien, “The green fluorescent protein,” Annu. Rev. Biochem. 67, of biological tissue,” J. Biomed. Opt. 12, 060503 ͑2007͒. 509–544 ͑1998͒. 52K. Maslov, H. F. Zhang, S. Hu, and L. V. Wang, “Optical-resolution 42C. H. Contag and M. H. Bachmann, “Advances in vivo bioluminescence photoacoustic microscopy for in vivo imaging of single capillaries,” Opt. imaging of gene expression,” Annu. Rev. Biomed. Eng. 4, 235–260 Lett. 33, 929–931 ͑2008͒. ͑2002͒. 53Q. Zhu, C. Xu, P. Y. Guo, A. Aquirre, B. H. Yuan, F. Huang, D. Castilo, 43H. Fang, K. Maslov, and L. V. Wang, “Photoacoustic Doppler effect from J. Gamelin, S. Tannenbaum, M. Kane, P. Hedge, and S. Kurtzman, “Op- flowing small light-absorbing particles,” Phys. Rev. Lett. 99, 184501- timal probing of optical contrast of breast lesions of different size located ͑1–4͒͑2007͒. at different depths by US localization,” Technol. Cancer Res. Treat. 5, 44H. Fang, K. Maslov, and L. V. Wang, “Photoacoustic Doppler flow mea- 365–380 ͑2006͒. surement in optically scattering media,” Appl. Phys. Lett. 91, 264103– 54Y. Xu and L. V. Wang, “Rhesus monkey brain imaging through intact 264101 ͑2007͒. skull with thermoacoustic tomography,” IEEE Trans. Ultrason. Ferro- 45N. Kudomi, H. Watabe, T. Hayashi, and H. Iida, “Separation of input electr. Freq. Control 53, 542–548 ͑2006͒. function for rapid measurement of quantitative CMRO2 and CBF in a 55M. Pramanik, M. Swierczewska, D. Green, B. Sitharaman, and L. V. single PET scan with a dual tracer administration method,” Phys. Med. Wang, “Carbon nanotubes as a multimodal—thermoacoustic and Biol. 52, 1893–1908 ͑2007͒. photoacoustic—contrast agent” ͑unpublished͒.

Medical Physics, Vol. 35, No. 12, December 2008 Vision 20/20: Proton therapy ͒ Alfred R. Smitha Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030 ͑Received 6 August 2008; revised 5 December 2008; accepted for publication 8 December 2008; published 26 January 2009͒ The first patients were treated with proton beams in 1955 at the Lawrence Berkeley Laboratory in California. In 1970, proton beams began to be used in research facilities to treat cancer patients using fractionated treatment regimens. It was not until 1990 that proton treatments were carried out in hospital-based facilities using technology and techniques that were comparable to those for modern photon therapy. Clinical data strongly support the conclusion that proton therapy is superior to conventional radiation therapy in a number of disease sites. Treatment planning studies have shown that proton dose distributions are superior to those for photons in a wide range of disease sites indicating that additional clinical gains can be achieved if these treatment plans can be reliably delivered to patients. Optimum proton dose distributions can be achieved with intensity modulated protons ͑IMPT͒, but very few patients have received this advanced form of treatment. It is anticipated widespread implementation of IMPT would provide additional improvements in clinical outcomes. Advances in the last decade have led to an increased interest in proton therapy. Currently, proton therapy is undergoing transitions that will move it into the mainstream of cancer treatment. For example, proton therapy is now reimbursed, there has been rapid development in proton therapy technology, and many new options are available for equipment, facility configuration, and financ- ing. During the next decade, new developments will increase the efficiency and accuracy of proton therapy and enhance our ability to verify treatment planning calculations and perform quality assurance for proton therapy delivery. With the implementation of new multi-institution clinical studies and the routine availability of IMPT, it may be possible, within the next decade, to quantify the clinical gains obtained from optimized proton therapy. During this same period several new proton therapy facilities will be built and the cost of proton therapy is expected to decrease, making proton therapy routinely available to a larger population of cancer patients. © 2009 American Association of Physicists in Medicine. ͓DOI: 10.1118/1.3058485͔

Key words: proton therapy, particle therapy, hadron therapy, radiation oncology

I. ABBREVIATED HISTORY OF PROTON THERAPY Further progress in proton therapy was rather slow in the 35 years following the first patient treatments at LBL. Dur- 1 E. Rutherford proposed the existence of protons in 1919; ing this time, patients were treated in a few research facili- however, it was not until 1955 that the first patients were ties, notably in the United States, Sweden, and Russia, where treated with proton beams at the Lawrence Berkeley Labo- the methods and techniques for proton therapy were further ͑ ͒ 2 ratory LBL in California. In the years between 1919 and refined and new technology was developed. The clinical re- 1955, two events occurred that had an important impact on sults obtained in these research facilities demonstrated the proton therapy. First, in 1930, E. O. Lawrence built the first feasibility and efficacy of proton therapy. In 1990, the mod- cyclotron, paving the way for future particle accelerators ern era of particle therapy then began when the first hospital- with energies high enough for cancer treatment applications. based proton therapy facility was opened at the Loma Linda In 1946, Robert Wilson then proposed that because of their University Medical Center ͑LLUMC͒ in California.4 Now physical properties, beams of protons would be advanta- there are approximately 25 facilities around the world treat- geous for the treatment of deep-seated cancers stating, “It ing cancer patients with proton beams with more than 55,000 will be easy to produce well collimated narrow beams of fast patients treated.5 protons, and since the range of the beam is easily controllable, precision exposure of well defined small volumes within the body will soon be feasible.”3 Wilson also de- II. PROTON BEAM DELIVERY TECHNIQUES scribed the use of a rotating wheel of variable thickness, i.e., In order for the reader to understand the material in the a range modulation wheel ͑RMW͒, interposed in a proton following sections, it is necessary to understand the various beam as a method of adding together several Bragg peaks of methods used to deliver proton radiation therapy, which fall variable energies and weights in order to spread the proton into two general categories: passive scattering and spot scan- stopping region in depth to deliver a uniform dose to an ning ͑also called pencil beam scanning͒ techniques. A basic extended target volume. Figure 1 illustrates the concepts pro- overview of the techniques is given here; for further reading, posed by Wilson. good general descriptions can be found in the literature.6,7

15 MV Photons vs.

Photons Protons FIG. 1. Comparison between the depth dose curves for 15 MV photons and a proton spread-out-Bragg peak ͑SOBP͒. A “target volume” is shown in red. Shown also Ideal dose in red lines is an “ideal dose distribution” for the target volume, which provides uniform, maximum dose to the distribution target volume and zero dose outside the target volume. The proton dose distribution approaches the ideal case to a much greater extent than does the photon dose distribution. Notably, the proton dose stops abruptly distal to the target volume and delivers less dose to the region proximal to the target volume. Protons

The passive scattering technique uses scattering devices each directed from a different angle, this high dose pull back in the treatment delivery nozzle ͓usually double scatterers for into normal tissue is not additive over all fields. In principle, large fields and single scatterers for small ͑e.g., radiosurgery͒ the use of an RMW to obtain an SOBP in passive scattering fields͔ to spread the beam laterally and an RMW or ridge techniques modulates both energy and beam intensity. How- filter7 to create a spread-out-Bragg peak ͑SOBP͒ in the target ever, this should not be confused with intensity modulated volume. Between the nozzle exit and the patient surface, a proton treatment ͑IMPT͒ achieved with beam scanning tech- treatment field-specific collimator is used to shape the field niques as described below. laterally to conform to the maximum beams-eye-view extent The second type of beam delivery utilizes spot scanning of the target volume and a range compensator is used to techniques ͑also often called pencil beam scanning͒. Figure 3 correct for patient surface irregularities, density heterogene- illustrates how a target can be scanned by placing Bragg ities in the beam path, and changes in the shape of the distal peaks throughout the volume by the use of scanning magnets target volume surface. The size of the SOBP is chosen to and energy changes. Energy changes in scanning techniques cover the greatest extent in depth of the target volume. The can be carried out with various methods including: ͑1͒ en- SOBP size is constant over the entire target volume; there- ergy changes in the accelerator when a synchrotron is used; fore, in general, there is some pull back of the high dose ͑2͒ energy changes made with an energy selection system region into normal tissues proximal to the target volume when a cyclotron is used; or ͑3͒ either of the above methods ͑Fig. 2͒. Because several treatment fields are usually used, plus energy absorbers in the treatment nozzle.

FIG. 2. Diagram of a typical passive scattering system. The range modulation wheel ͑or ridge ﬁlter͒ creates the SOBP; the double scattering system spreads the beam laterally; and the collimator and range compensator shape the beam to the lateral extent and distal surface of the target volume. The size of the SOBP is chosen to cover the greatest extent of the target volume and, where the target volume is smaller, the high dose is pulled back into normal tissues proximal to the target volume.

Medical Physics, Vol. 36, No. 2, February 2009 558 Alfred R. Smith: Proton Therapy 558

High-density structure Target Volume Scanning Magnets FIG. 3. Diagram of a typical pencil beam scanning system. Two sets of scanning magnets scan the beam in a 2D pattern: the beam range is adjusted by changing the beam energy entering the nozzle. In the usual case, all spots for the deepest range are scanned, the energy is changed, and all spots with the new range are scanned, etc., until the entire target volume has been scanned. In pencil beam scanning, the high dose region can be con- Critical ﬁned to the target volume and no high dose spills over Scanning Magnets Structure into normal tissue.

Proton Pencil Body Beam Surface

Currently, no standard definitions exist for the various photon treatments that have been called IMRT but, which we techniques used to deliver scanned beam proton treatments. will call IMXT. IMPT is defined as the simultaneous optimi- For this paper, we will use the definitions given below. zation of all Bragg peaks from all fields with or without Scanning techniques can be used to spread the beam lat- additional dose constraints to organs at risk ͑OAR͒, such erally to generate large uniform treatment fields instead of that, when all fields are delivered to the patient, their com- using passive scattering techniques; this is designated as bination results in a desired dose distribution in the target “uniform field scanning.” This scanning technique is often volume and OARs. Figure 4 shows an IMPT treatment plan called “wobbling;” however, this name was originally ap- having four nonuniform fields optimized to deliver a uniform plied to a different technique developed at the Lawrence Ber- target dose when all fields are delivered. The desired dose keley Laboratory7 and it is misleading to apply the term here. distribution in the target volume may be uniform or nonuni- In uniform field scanning, collimators and range compensa- form, depending upon the treatment goals—for example, the tors are still required to shape the treatment beam laterally treatment goal may be to deliver a simultaneous boost dose and distally to the target volume. The primary advantages of in which case the resulting dose distribution would be nonuniform field scanning are that large field sizes ͑up to about uniform. Even when the treatment goal is to deliver a uni- 40 cmϫ40 cm or so͒ are feasible and, because of the ab- form dose distribution, there are usually low-level hot and/or sence of a double scattering system, protons are used more cold spots in the dose distribution. It should be noted that efficiently and fewer secondary neutrons are produced. An IMPT is characterized by variations in intensity and energy additional advantage is that the deliverable proton range is greater because there is no range loss in the scattering sys- 2 tem: the additional range is typically 1–3 gm/cm depend- Intensity Modulated Proton Therapy (IMPT) ing on the beam energy and field size. However, the disad- Composite dose from all fields vantages of uniform field scanning are that the resultant dose distributions in patients are essentially the same as those achieved with passive scattering techniques and a higher sensitivity is introduced to target motion errors than is present in passive scattering techniques. Additional techniques used in scanned beam treatment delivery are those that use the results of optimization techniques in treatment planning to achieve a desired dose distribution ͑usually uniform͒ in the target volume. Objective functions can be used to optimize spot patterns for single treatment fields. This technique would appropriately be called “single optimized uniform field” but it has become customary to define this as “single field uniform dose,” or SFUD, and this designation will be used throughout. An SFUD treatment plan consists of one or more individually FIG. 4. Illustration of intensity modulated proton therapy. Four nonuniform optimized fields. fields have been optimized to deliver a uniform dose to the target volume. The dose scale applies only to the central figure showing the composite dose Another technique for delivering scanned beam proton ͑courtesy of A. Trofimov and A. Chan, Massachusetts General Hospital, therapy is IMPT, which is analogous to intensity modulated Department of Radiation Oncology͒.

Medical Physics, Vol. 36, No. 2, February 2009 559 Alfred R. Smith: Proton Therapy 559 rather than variations in intensity alone as is the case for • Conformal photons vs. conformal, passively scattered IMXT. IMPT permits realization of the full potential of par- protons, ticle beams to provide highly localized dose distributions for • IMXT vs. conformal, passively scattered protons, and cancer treatment; however, as stated elsewhere in this paper, • IMXT vs. IMPT. more research and development is required in order to reduce Many treatment planning studies have been published10–14 treatment errors in IMPT, especially those related to uncer- all of which had the general conclusion that, when photon tainties in treatment planning calculations of proton ranges in and proton treatment plans with comparable complexity are tissues and errors arising from target motion during treatment compared, protons provided superior dose distributions. delivery. These results were obtained from the analysis of dose vol- Spot scanning is usually achieved by one of two methods: ume histograms ͑DVHs͒ for both target volumes and normal discrete spot scanning or dynamic raster spot scanning, tissues. In particular, the integral dose in the proton treatment which are described later in this paper. plans was two to three times less than the integral dose in the To be clear, passive scattering, “uniform ﬁeld scanning,” photon plans.14 These results obtained from treatment plan- and SFUD techniques, even though they may have compo- ning comparisons provided strong evidence of the potential nents of energy and/or intensity modulation, do not comply for proton beams to deliver dose distributions that could im- with the deﬁnition for IMPT used in this paper. prove clinical results if those dose distributions could be realized in actual cancer treatments.

III. REASONS FOR INTEREST IN PROTON III.B. Clinical results THERAPY Robert Wilson’s observations on the potential advantages Several published reports have confirmed that the use of of proton therapy for cancer treatment created interest among proton beams results in improvements in both local control clinical scientists and led to the hypothesis that highly local- and normal tissue complications over those achieved with photon beams; however, these comparisons were predomi- ized dose distributions achieved by proton beams would re- 15–17 sult in higher probabilities for local control and disease-free nantly made against historical photon controls. It should survival, and lower probabilities for normal tissue damage. be noted that many of these results were obtained from pro- This hypothesis remains the motivating force for clinical ton treatments carried out in research-based facilities with studies in proton therapy. It is important to note that the horizontal, passively scattered beams, limited energies, and advantages of a proton dose distribution hold true for every restricted flexibility in the complexity and types of treat- beam used in a treatment plan and, for treatments of equal ments that could be carried out. Further, the number of pa- complexity in terms of such factors as technique, number of tients treated in a given disease site was relatively small and, beams, and beam directions, etc., protons will almost always thus, the analysis of these studies often did not produce sta- have superior dose distributions to photons. An exception is tistically significant results. It should also be noted that dur- when skin sparing is clinically important as photons offer ing the mid to late 1990s, no patients had been treated with more skin-sparing benefits than protons. It is also important IMPT techniques; therefore, the best achievable dose local- to note that, in some clinical situations, the advantage of ization for proton beams had not been realized. protons may be reduced by errors caused by proton range Based on these preliminary results, it was reasonable to uncertainties in the treatment plan or by target motion during conclude that, should patients be treated with proton beams treatment delivery.8,9 in modern, hospital-based facilities with improved treatment Several developments occurred in the decade or so before technology and improved treatment techniques, additional the early 2000s that generated increased interest in proton clinical gains could be achieved. therapy. These events took place in a number of areas including medical physics, clinical results, reimbursement, technol- III.C. Reimbursement ogy, and changes in the proton therapy equipment market- Until the late 1990s, proton treatment delivery had not place. been assigned procedure codes by the American Medical As- sociation. Billing was carried out using special procedure codes, which were evaluated by Medicare and third-party III.A. Medical physics developments insurance carriers on a case-by-case basis. Therefore, reim- Between the mid-1980s and mid-1990s, medical physi- bursement for proton therapy could be, and often was, de- cists developed methods to fully utilize medical imaging and nied. With no assurance of reimbursement, there was no fi- to calculate three-dimensional ͑3D͒ treatment plans for ex- nancial incentive in the private sector for building new ternal beams of photons, electrons, protons, and light ions. In facilities. Both LLUMC and Massachusetts General Hospital addition, inverse planning and optimization techniques were ͑MGH͒ proton treatment facilities were financed with insti- developed that made it possible to calculate treatment plans tutional and government funding. for intensity modulated radiation therapy. These develop- In the late 1990s, MGH and LLUMC successfully applied ments led to a large number of treatment planning compari- to the American Medical Association ͑AMA͒ for proton- sons including those for: specific treatment delivery procedure codes. Medicare and

Medical Physics, Vol. 36, No. 2, February 2009 560 Alfred R. Smith: Proton Therapy 560 private insurance carriers then assigned payment rates to the early 2000s discussed above created a more favorable cli- new procedure codes. Moreover, when Medicare set rates for mate for vendors and there are currently several companies proton treatment delivery, they stated that proton treatments marketing proton therapy systems and offering systems that were not considered to be investigational. The achievement provide both protons and carbon ions for cancer therapy. of reimbursement provided financial incentives for the pri- New proton/carbon systems based on superconducting tech- vate sector to finance, build, and operate proton therapy fa- nology have been developed that will make it possible to cilities, with the expectation that they could realize a reason- build more compact isocentric gantries and accelerators for able return on investments. Current reimbursement rates for hospital-based systems. In addition, companies have been proton therapy delivery remain attractive; however, one formed to develop and operate proton therapy facilities and should not expect that these rates will persist in the long others offer various levels of consulting ͑e.g., feasibility term. studies, marketing studies, business plans, technology evaluation, staffing and operating plans, etc.͒. The success of new III.D. Advances in technology hospital-based proton therapy projects like those at the Uni- versity of Florida/Shands Cancer Center in Jacksonville, Research laboratories where proton therapy was being Florida and The University of Texas M. D. Anderson Cancer carried out have continued to improve proton therapy tech- Center in Houston, Texas has demonstrated that these com- niques and develop new technologies for the acceleration, plex, expensive facilities can be built on time and on budget, transport, and delivery of proton therapy. In the private sec- and can rapidly reach targeted patient treatment capacity in tor, manufacturers have developed isocentric gantries, com- order to satisfy ambitious clinical programs and business pact cyclotrons, medical synchrotrons, and advanced treat- plans. ment delivery systems.18 Superconducting technology has been used to develop smaller and higher energy cyclotrons19 and the efficiency of cyclotrons in terms of beam extraction III.F. Summary and power consumption has been substantially improved. All the factors discussed above have contributed to Robotics have been introduced into proton therapy systems greatly increased interest in proton therapy in the United resulting in improved efficiency in the management of pa- States and worldwide. In fact, there has been such an explo- tient transport, patient treatment positioning, treatment appli- sion of interest in proton therapy during the past 3 years that 20,21 ances, and imaging systems. In addition, proton capabili- one could argue that the current enthusiasm is overheated. ties have been developed for commercial treatment planning There is an indication that some institutions seeking proton and data management systems. therapy facilities are doing so without critical evaluation of Vendors have made major improvements in treatment de- the clinical role of proton therapy and the relatively large livery techniques during the past decade. New technologies financial, clinical, and personnel commitments required for include: ͑1͒ beam scanning techniques; ͑2͒ “universal” developing and operating these facilities. Moreover, there is nozzles that have the ability to deliver both passive scattering an acute shortage of trained proton therapy staff and few and spot-scanning treatments; ͑3͒ RMWs installed perma- training programs. Therefore, institutions that are building nently in the nozzle that produce variable SOBPs by a com- new proton therapy facilities may have a difficult time re- bination of beam gating and beam intensity variation; cruiting trained, proficient staff for clinical operations. ͑4͒ advanced treatment control and safety systems; ͑5͒ improved imaging systems; and ͑6͒ multileaf collimators. IV. FUTURE PROSPECTS A noteworthy technological achievement was made at the Paul Sherrer Institute in Switzerland where techniques for Based on the current trends, the events that may occur in proton pencil beam scanning were developed and imple- particle therapy during the next decade are listed below: mented. This technology was first used for SFUD treatments and then extended to IMPT treatments.22,23 Several vendors IV.A. Clinical studies now offer advanced proton therapy systems that have U.S. MGH and LLUMC have carried out dose escalation stud- Food and Drug Administration ͑FDA͒ 510͑k͒ clearance. ies for prostate cancer.24 Recently, the National Cancer Insti- These achievements have matured proton therapy into fully tute approved funding for a P01 grant application submitted integrated, modern radiation therapy systems that provide by MGH and M. D. Anderson Cancer Center ͑MCACC͒ to advanced cancer treatments in state-of-the-art hospital set- conduct clinical studies in proton therapy with the objective tings. of applying advanced proton radiation planning and delivery techniques to improve outcomes for patients with nonsmall- III.E. Increased vendor options cell lung cancer ͑proton dose escalation and proton vs. pho- Until 1990, all proton therapy took place in research- ton randomized trials͒, liver tumors, pediatric medulloblas- based facilities with equipment developed by the clinical re- toma and rhabdomyosarcoma, spine/skull base sarcomas, searchers and engineers who worked in those facilities. The and paranasal sinus malignancies. It is expected that the Uni- lack of a sizable market was a disincentive for manufacturers versity of Florida and University of Pennsylvania facilities to spend large sums of money to develop proton therapy will also be participating in multi-institutional clinical equipment. The confluence of factors during the 1990s and studies.

Medical Physics, Vol. 36, No. 2, February 2009 561 Alfred R. Smith: Proton Therapy 561

There is an ongoing discussion in the radiation oncology • Using IMPT techniques, which have the potential to community regarding the appropriateness of prospective, decrease treatment times as fewer patient appliances randomized clinical trails comparing protons with photons. ͑field-shaping collimators and range compensators͒ will The basic argument is that the dose distributions of protons need to be manually inserted and removed for each will always be superior to those for photons when both mo- treatment field. It will also be possible after the treat- dalities are optimized and one cannot justify randomized ment setup procedure for the first treatment field to treat clinical trials of protons vs. photons because there would not all subsequent fields in a treatment session containing be equipoise between the two arms of the trial.25,26 Whether coplanar fields without re-entering the treatment room; or not one supports the concept of randomized clinical trials • Potentially using larger and fewer fractions ͑hypofrac- for protons, it is difficult to argue against the need for addi- tionation͒ in proton therapy than are currently used in tional clinical data; it is not feasible to draw statistically photon therapy. Proton therapy spares normal tissues to meaningful comparisons between photon and proton treat- a much greater extent than is possible with photon ment techniques without data acquired through carefully beams, making hypofractionation potentially effective. controlled clinical studies in an expanded range of disease With reduced numbers of treatment fractions, the cost to sites. patients for a course of therapy will decrease; and Research programs will also be directed toward the reduc- • As the demand for proton therapy increases, more fa- tion of treatment errors in proton therapy treatment planning cilities will be built and more equipment manufacturers and treatment delivery, especially those related to uncertain- will enter the market. Competition between manufactur- ties in the calculation of proton ranges in inhomogeneous ers should drive down the cost of particle therapy sys- tissues and errors arising from target motion during treatment tems. Further, rapid growth of proton therapy facilities, delivery. spurred by strong market acceptance, will allow manufacturers to sell more systems ͑i.e., high business star- IV.B. Lower costs for proton therapy tup and technology development costs for proton therapy systems can be spread among larger numbers of Currently, proton therapy is more expensive than photon systems͒. therapy. In 2003, Goitein and Jermann estimated the relative costs of proton and photon therapy, concluding that, with some foreseeable improvements, the ratio of costs ͑protons/ IV.C. Advances in technology ͒ 27 photons was likely to be about 1.7. However, these esti- New developments, many already underway, will have an mates are probably outdated. Reimbursement rates currently impact on proton therapy. make it possible to develop and operate proton therapy facilities with a reasonable profit margin. In the future, it is likely that reimbursement rates for proton therapy treatment IV.C.1. Single-room proton therapy systems delivery will decrease as capital costs of current facilities There is an increasing interest in smaller proton therapy will be spread among more patients as these facilities reach facilities that are better suited for community hospitals and full-capacity operations. large private practices. Several vendors are developing the In addition, the overall costs of proton therapy will be technologies necessary for “single-room solutions” for pro- reduced as proton therapy procedures become more efficient ton therapy systems. Single-room proton therapy systems and patient throughput increases. Increased patient through- have been stated to have the following advantages: put will make it possible to spread the capital costs of proton therapy among a larger number of patients and the cost per • They provide a lower-cost option for implementing pro- patient will decrease. Improved efficiencies can be realized ton therapy. ͑ in the following ways: • All or most components accelerator, beam transport, energy selection, and beam delivery͒ can be mounted • Using treatment setup rooms outside the treatment room on a rotating gantry or very near the gantry, thus, reduc- will increase patient throughput, especially for pediatric ing the size of the complete proton therapy system patients who require anesthesia, which currently re- enough that it can be installed in its entirety ͑or nearly quires these patients to spend more time in the treat- so͒ in a single treatment room. ment room than patients who do not require anesthesia; • There is no competition with other treatment rooms for • Using faster, automated imaging techniques for patient proton beams because each room has its own accelera- positioning both outside and inside the treatment room; tor. • Using robotics both outside and inside the treatment • If multiple rooms are used, the entire proton treatment room for transferring and positioning patients, for mov- capability is not lost if the accelerator goes down, as is ing imaging devices, and for handling treatment appli- the case when one large accelerator generates beams for ances; several treatment rooms. • Using improved accelerator, beam transport, and treat- Single-room systems may have the following disadvan- ment delivery technologies, which will reduce the time tages, however: currently required to change energies and to switch the beam from one room to another; • The costs of these systems may not necessarily be

Medical Physics, Vol. 36, No. 2, February 2009 562 Alfred R. Smith: Proton Therapy 562

cheaper per treatment room as compared to large sys- 250 tems using single accelerators to feed several treatment rooms. IBA 230 • Additional rooms may have to be installed if demand 200 for proton therapy increases in a location with a single- room system. If several treatment rooms are eventually needed, the cost effectiveness of the single-room con- 150 cept may be lost; for example, an additional accelerator ons will be needed for each treatment room. Maintaining T 100 multiple accelerators will also increase maintenance ACCEL K250 costs. • Because of the pulse structure of some accelerators ͑e.g., synchrocyclotrons͒ chosen for the proposed sys- 50 tems, it may be difficult to use spot scanning techniques to deliver IMPT treatments.28 IMPT could be delivered New 0 using a multileaf collimator; however, this method may 1995IBA 230 1999 ACCEL 2003 K250 2006 New 2010 have problems such as poor efficiency in the use of Date protons and increased neutron production. • These systems are new, and, thus, their operability, re- FIG. 5. This graph indicates how the weight ͑and, therefore, the size͒ of liability, and maintainability are not known. clinical cyclotrons has decreased since 1995. The IBA 230 room temperature cyclotron was the first cyclotron to be installed in a hospital-based proton therapy facility. More recently, the ACCEL K250 ͑now the Varian/ IV.C.2. Accelerator development ACCEL K250͒ has been installed in two European facilities. “New” superconducting cyclotrons will weigh about 10% of the IBA 230. Advances in accelerator technology are also expected. Several developments already underway show considerable potential to provide a new generation of more compact, more ͑RF͒ modulation. Higher duty factors will permit higher efficient, and less expensive accelerators for proton therapy. average beam currents and high repetition rates for spot Some developments will improve upon current technologies, scanning. Fixed fields require simpler and cheaper while others will provide entirely new types of accelerators, power supplies and are more easily operated than syn- 29 some of which are highlighted here. Flanz has provided an chrotrons. excellent overview of new accelerator technologies. • With respect to fixed field cyclotrons, nonscaling FFAG IV.C.2.a. Superconducting cyclotrons and synchrocyclo- accelerators allow strong focusing and, hence, smaller trons. Cyclotron and synchrocyclotron development has re- aperture requirements, which leads to low beam losses sulted in more compact systems with increased energy. These and better control over the beam. gains have been achieved by the use of new accelerator de- • FFAG accelerators ͑like synchrotrons͒ have a magnetic signs and the application of superconducting technology. ring that allows beam extraction at variable energies Figure 5 illustrates how the weight of cyclotrons/ rather than just a single energy, as in a cyclotron. synchrocyclotrons has deceased since 1995. Notably, the ac- • Their superconducting magnets and compact size make celerator energy has increased while the weight/size of the FFAG accelerators attractive for proton therapy applica- accelerators has decreased. At the current reduced weights of tions. approximately 20 tons, accelerators can be installed on iso- • Because of the possibility of changing energy and loca- centric gantries and rotated around patients, eliminating large tion with each spot and having a repetition rate of about 19,30 and expensive beam transport systems. There is at least 100 Hz, spot scanning with FFAG proton beams can be one vendor marketing a one-room proton therapy system carefully controlled in three dimensions. based on this concept. Such systems will be particularly at- The FFAG concept was developed in the 1950s in Japan, tractive to small community hospitals and large radiation on- Russia, and the United States.31 The first electron FFAG ac- cology private practices. celerator as developed in the late 1950s and several others IV.C.2.b. Fixed field alternating gradient (FFAG) accel were built in the early 1960s. In the 1980s, proposals for erators. To date, most particle therapy facilities have used FFAG-based neutron spallation sources were unsuccessful isochronous cyclotrons, and synchrotrons for particle accel- due to the perceived complexity of the magnets. In scaling- eration. However, FFAG accelerators may be able to replace type FFAG accelerators, the magnetic field has to be nonlin- both cyclotrons and synchrotrons for hadron therapy. FFAG ear with zero chromatic beam optics. Because the magnets accelerators combine many of the positive features of cyclo- are complex and expensive to manufacture, the resulting cost trons and synchrotrons with fixed magnetic fields as in cy- has limited their use in medicine. However, new magnet de- clotrons and pulsed acceleration as in synchrotrons. FFAG signs have been made possible by 3D magnetic field simula- accelerators have the following potential advantages: tion codes and large-scale computers. In addition, for a pro- • FFAG accelerators can be cycled faster than synchro- ton FFAG, a broad band and high gradient RF cavity is trons, limited only by the rate of the radiofrequency required. A new type of RF cavity developed at the High

Medical Physics, Vol. 36, No. 2, February 2009 563 Alfred R. Smith: Proton Therapy 563

Energy Accelerator Research Organization ͑KEK͒ in Japan32 yielding a much higher accelerating gradient. The DWA uses made it possible to overcome these problems, and in 1999, fast-switched high-voltage transmission lines to generate the first proton FFAG, was built at KEK in Japan.33 This pulsed electric fields on the inside of a high gradient insulat- machine was the proof of principle ͑POP͒ for proton FFAG ing ͑HGI͒ acceleration tube. High electric field gradients are accelerators and was named POP-FFAG. After the success of achieved by the use of alternating insulators and conductors POP-FFAG, a 150 MeV FFAG accelerator was developed at and short pulse times. An electric field propagates down the KEK. To date, several FFAG accelerators have been built in bore of the accelerator, pushing the proton “packet” in front the energy range 150–250 MeV and others have been of it. The system will produce individual pulses that can be proposed. varied in intensity, energy, and spot width and, therefore, The nonscaling FFAG accelerator was invented in 1999.34 should be suitable for IMPT applications. This accelerator’s magnet design provides a variation of orbit The enabling technologies for DWA are the high gradient length with energy, which can be arranged to greatly com- insulator, fast SiC switching, and new dielectric materials. press the range of the orbit radii and, thus, the magnet aper- The DWA technology is being developed at the Lawrence 39 ture, while maintaining linear magnetic field dependence. In Livermore Laboratory, with a full scale prototype proton addition, the small apertures and linear fields allow simplifi- therapy system expected to be operational in approximately 4 or 5 years. The private sector partner for this development cation and cost reduction compared with scaling FFAG ac- 40 celerators. Keil et al. have proposed a hadron cancer therapy is TomoTherapy and the first prototype is expected to be system using a nonscaling FFAG accelerator and gantry installed at the University of California Davis Cancer Center. composed of nonscaling FFAG cells.35 This accelerator will accelerate carbon ions up to 400 MeV/␮ and protons up to IV.C.3. Pencil beam „spot… scanning techniques 250 MeV. IV.C.2.c. Laser acceleration. Proton laser acceleration is Most patients who have been treated with proton beams have been treated with passive scattering techniques. Modern achieved by focusing a high-power ͑approximately 1015 W͒ passive scattering systems are much more efficient and ver- laser on a thin target such as a 5 ␮m-thick titanium foil, or satile than the systems used before hospital-based facilities multilayer targets, such as 100 nm-thick aluminum hydro- were developed, and additional advances have continued to gen. To achieve proton energies of 200–250 MeV with ad- the present time. Recently, there has been an effort to de- equate intensities, focused short laser pulses to intensities of velop multileaf collimators ͑MLCs͒ for passive scattering ap- 1022 W/cm2 or higher are required.36 The short plications; however, to date, proton MLCs have been less ͑ϳ30–80ϫ10−15 sec͒ laser pulse width produces a high than optimal ͑e.g., they have small field sizes, and, for some, peak power intensity that causes massive ionization in the their size does not permit positioning the MLC close to the target, expelling a large number of relativistic electrons. The patient surface, resulting in large air gaps that degrade the sudden loss of electrons gives the target a high positive lateral penumbra of the treatment beam͒. charge and this transient positive field accelerates protons to To date, only a handful of facilities are using beam scan- high energies. The resultant proton beams have a broad en- ning techniques for particle therapy. During the next decade, ergy spectrum; therefore, a magnetic spectrometer must be the development and refinement of beam scanning systems used to select a narrow energy band for patient treatment. will continue. Importantly, pencil beam scanning makes it This selection process throws away about 99.5% of the possible to deliver IMPT treatments, which provide a sub- beam, and, thus, the energy selection system must be heavily stantial dosimetric improvement over passive-scattering shielded against neutrons resulting from proton losses in the techniques. Analogous to IMXT, IMPT enables further opti- spectrometer. mization of dose distributions for proton therapy. Achieving the energy and beam intensity required for pro- Scientists at the PSI in Switzerland developed a spot- ton therapy is a major challenge. Groups in several countries scanning system where an energy selection system, one set 36–38 are working on proton laser acceleration; however, be- of scanning magnets ͑for 1D scanning͒, and couch shifts are cause of the technical difficulties, it is not expected that the used together to deliver pencil beam Bragg peaks to a target current development efforts will be able to achieve the re- volume.22 The magnet and energy selection system are used quired beams even for treatment of ocular melanomas to scan a section of the target volume, the couch is shifted, ͑ϳ70 MeV at a dose rate of approximately 10–12 Gy/min͒ then another section is scanned. In this way, the target vol- over the next 5–7 years. ume can be scanned in three dimensions. This scanning sys- IV.C.2.d. Dielectric wall accelerators. Conventional ac- tem has been used to deliver both SFUD and IMPT treat- celerator cavities have an accelerating field only in their ments. gaps, which occupy only a small fraction of the cavity More recent scanning systems use two sets of scanning length, and have an accelerating gradient of approximately magnets to scan the beam in a plane perpendicular to the 1–2 MeV/m. In contrast, dielectric wall accelerators nozzle axis ͑for 2D scanning͒. The target volume is divided ͑DWAs͒ have the potential of producing gradients of ap- into energy layers ͑highest to lowest energy͒, and each layer proximately 100 MeV/m. In a DWA, the beam pipe is re- is sequentially scanned with pencil beams. placed by an insulating wall so that protons can be acceler- The treatment is carried out by moving the beam spot ated uniformly over the entire length of the accelerator, throughout each of several energy layers in a target volume.

Medical Physics, Vol. 36, No. 2, February 2009 564 Alfred R. Smith: Proton Therapy 564

The spot can be moved dynamically ͑i.e., continuously͒ in a also been quite useful in calculating data used in commis- raster or line pattern or by a discrete spot scanning method, sioning proton treatment planning systems47,48 MC calcula- where the beam is cut off between spots and the dose at each tions can decrease the time required to commission a treat- spot is varied to achieve the prescribed dose pattern. In dy- ment planning system by eliminating a large number of namic raster scanning, either the scan speed or beam inten- measurements, especially in the case of spot beam scanning sity, or both, are varied to produce the intensity distribution where approximately 100 energies need to be commissioned. prescribed by the treatment plan. It is reasonable to expect that, with future developments, A fundamental challenge for proton therapy using scan- particularly in the area of increasing the speed of MC calcu- ning techniques will be to develop methods to reduce or lations, MC will play an increasing role in proton treatment eliminate treatment uncertainties caused by range errors or planning. target motions. Errors due to target motion during the deliv- IV.C.4.b. Optimization for IMPT treatment planning. Pro- ery of scanned treatment fields are a problem for several tons are much more sensitive to tissue inhomogeneities in the treatment situations, particularly, for the treatment of lung beam path than photons and current optimization algorithms tumors. Currently there are two primary ways to reduce mo- do not accurately account for the errors resulting from range tion errors: ͑1͒ beam gating, where the beam is turned off uncertainties and changes in scattering conditions caused by when the target has moved out of the target position for such inhomogeneities. For passive-scattering techniques, which the treatment plan was calculated;41 or ͑2͒ repainting such uncertainties are partially offset by expanding the mar- spots, repainting layers, or repainting the entire treatment gins around the clinical target volume or by using internal volume ͑in this context, repainting means to scan a particular target volumes determined from 4D CT treatment planning spot position, layer, or volume two or more times͒. Errors in scans. In IMPT, the dose distribution is sensitive to the un- target motion can be reduced in proportion to the number of certainties in each individual beam of the potentially several repaintings. In addition, repainting of spots and layers can be thousand Bragg peaks used in the treatment plan, and uncer- done in a straightforward manner using treatment planning tainties in the spot placements can result in unacceptable hot and beam delivery methods that have already been devel- and cold regions in the target volume. One approach to im- oped. However, rapid repainting of the entire volume will proving IMPT treatment planning is to include errors in the require a considerable amount of new technology to be de- optimization calculations in such a way as to ensure that the veloped for beam delivery, primarily in the area of very rapid treatment plan predicts actual dose distributions more reli- scanning and energy changes. When combined with repaint- ably. Work in this area is underway and these approaches ing, beam gating increases the complexity of treatment de- have the potential to improve the accuracy and robustness of livery. Furukawa et al. have proposed a design for a heavy- IMPT treatment plans.49 ion radiotherapy system that addresses this problem.42 Bert et al. have proposed a system in which pencil beam positions, as well as the beam energy, are changed according to IV.C.5. Positron emission tomography „PET… the tracked target motion to reduce motion errors.43 A confor treatment verification siderable amount of development effort is currently being Ideally, one would have a method available to measure directed toward decreasing the errors due to range uncertain- proton dose distributions delivered to patients either online ties and target motion errors when spot scanning techniques during treatment or offline immediately or soon after treat- are used and one can expect that good solutions will be ment. Such treatment verification would make it possible to found to reduce these errors during the next decade. correct the treatment plan after the first treatment session or to make corrections during the course of treatment. Such IV.C.4. Treatment planning calculations adjustments may be necessitated by changes in the patient’s IV.C.4.a. Monte Carlo treatment planning. Conventional weight or changes in the tumor’s size, shape, or position proton treatment planning using pencil beam algorithms has during treatment. Positron emission tomography ͑PET͒ is a been the mainstay of treatment planning using passive- potentially useful tool for validating the fidelity of the treat- scattering techniques. However, calculations by pencil beam ment plan delivery. algorithms can have appreciable errors in some situations, PET can verify treatment delivery by detecting annihila- notably when there are tissue interfaces or inhomogeneities tion ␥-rays arising from the decay of small amounts of ␤+ in the beam path or when metallic implants are present ad- emitters such as 11C, 15O, and 10C produced by nuclear frag- jacent to or in the target volume. Monte Carlo ͑MC͒ calcu- mentation reactions between the primary charged particle lations have the potential to increase the accuracy of dose and the target nuclei in the irradiated tissue. Particle treat- calculations in those instances where pencil beam algorithms ment delivery verification can be achieved by comparing the have difficulty. MC treatment planning has been developed measured ␤+ activity distribution with an expected pattern for proton therapy applications.44–46 However, MC calcula- calculated by treatment planning or by MC calculations of tions are time intensive and are not used routinely, although the expected ␤+ activity. In particular, PET techniques offer they can be useful in benchmarking pencil beam calcula- the potential to detect and quantify range uncertainties in tions. Within the next few years, MC calculations may be- treatment planning calculations. come faster and more efficient and, therefore, can be used Physicists at MGH and elsewhere50–53 have been explor- more routinely in treatment planning. MC calculations have ing the use of PET imaging, both offline and online, for

Medical Physics, Vol. 36, No. 2, February 2009 565 Alfred R. Smith: Proton Therapy 565 treatment verification. The preliminary results look promis- which can be achieved with proton doses of 10 mGy or less, ing and it is expected that with further development, this comparable to or better than doses stated for cone beam CT technique will become an important tool for verifying par- with kilovoltage x-ray beams.64 ticle treatment plan delivery. With the widespread use of isocentric gantries in proton treatment facilities, further development and study of proton CT and cone-beam CT are anticipated. Development of new IV.C.6. Proton CT high-bandwidth silicon strip detector systems will also make The idea of using proton beams for imaging has been proton-by-proton data collection feasible. Individual proton around for some time. In his seminal papers on the applica- tracking techniques will make it possible to measure the po- tion of photon absorption in radiology, Cormack pointed out sition of each particle’s track and each particle’s energy the possibility of using heavy charged particles in CT deposition,65,66 which will greatly increase the spatial and applications.54,55 In 1968, Koehler demonstrated that energy resolution of proton CT measurements. 160 MeV protons could produce images on radiographic films that had much better contrast than those produced with photons.56 Cormack and Koehler published a study on proton IV.C.7. QA systems for scanned proton beams CT in 1976.57 In the late 1970s and early 1980s, Hanson et Implementing scanned proton beams for cancer treatment al. published a series of papers on proton CT including one has generated the need for a new class of quality assurance of the earliest studies of human specimens.58 In addition, ͑QA͒ systems that permit rapid and accurate 2D and 3D data Schneider et al. conducted studies on the use of proton radi- acquisition. QA systems for scanned proton beams must also ography as a quality assurance tool for proton treatment be adaptable to the timing structure and energy stacking of planning.59,60 These studies, including measurements taken pencil beam scanning beam treatment delivery. In contrast to on an animal patient, concluded that inaccuracies in treat- dosimetric measurements for passive scattering methods, ment planning as a result of incomplete modeling of multiple when pencil beam scanning techniques are employed, the Coulomb scattering effects and errors in proton stopping dose measured at a point in the phantom can be obtained powers derived from photon CT scans could result in size- only by collecting the detector signal during the entire scan able deviations in predicted versus measured proton dose sequence. In many cases, it is also necessary to characterize distributions. Zygmanski et al. demonstrated the feasibility a single pencil beam, which places additional requirements of using proton cone-beam CT to determine proton stopping on the measuring system. powers for materials of various densities.61 In 2004, Schulte In 2000, Jäkel et al. described QA procedures and meth- et al. at the LLUMC proton therapy center reported on a ods for a treatment planning system used for scanned ion conceptual design for a proton CT system for applications in beam therapy.67 In 2005, Pedroni et al. reported on aspects of proton radiation therapy.62 dosimetric methods used to characterize the scanned proton Currently, most proton treatment planning dose calcula- beams at PSI in Switzerland68 including ionization chambers, tions use a pencil beam algorithm that accounts for tissue films, and a charged-coupled-device ͑CCD͒ camera coupled inhomogeneities by means of pathlength ͑water equivalent with a scintillating screen. In addition, Pedroni et al. have depth͒ scaling based on relative stopping powers. Hounsfield used a linear array of 26 ionization chambers and the CCD numbers obtained from x-ray treatment planning CT scans system to verify scanned dose distributions. In 1999, Karger are converted to proton stopping powers using measured re- et al. described a 24 ionization chamber planar array used for lationships between Hounsfield numbers and the relative the QA of heavy ion beams.69 More recently, Nichiporov and stopping powers for materials closely matched to human tis- Solberg reported on two ionization chamber array systems: a sues such as soft tissue, fat, lung tissue, soft bone, and hard 128-chamber planar array designed to measure beam profiles bone.63 These conversions are frequently inexact, which can in fields up to 38 cm in diam and an array of 122 small- lead to errors in the calculation of proton ranges in patients volume multilayer ionization chambers used for depth-dose of approximately 3% or more of the proton range. These measurements in clinical proton beams.70 Users of these ion- errors could be substantially reduced by the direct measure- ization chamber array systems have agreed that these sys- ment of relative proton stopping powers using proton CT tems provide considerable time savings in dosimetry mea- techniques. surements. Unfortunately, the ionization chamber arrays There are, however, also errors in proton CT data. For described above were developed in house at research facili- instance, limitations in the spatial and density resolution of ties and are not commercially available. As more proton proton CT arise from various sources: multiple Coulomb treatment facilities implement scanning techniques and the scattering in the patient leads to spatial uncertainties in the demand for appropriate dosimetry systems increases, ven- CT image and energy loss straggling due to momentum dors may be encouraged to develop similar commercial de- spread of the beam entering the patient and proton range vices. straggling in the patient can cause errors in density reso- A dosimetry system utilizing a CCD camera plus scintil- lution. In addition, secondary protons arising from nonelastic lating screen71 has been shown to be useful for measuring nuclear interactions can lead to noise in the proton CT im- proton fluences in air, and by placing absorbers in front of ages. Recent studies have demonstrated that density resolu- the screen, relative dose delivered at depth. Pedroni et al. tions of 1%–2% are possible with proton CT techniques, stated that the CCD system works well for conducting rela-

Medical Physics, Vol. 36, No. 2, February 2009 566 Alfred R. Smith: Proton Therapy 566 tive dosimetry measurements to compare treatment planning V. CONCLUSIONS calculations with the dose distributions delivered by the proton scanning system.68 A similar CCD system has also been Proton therapy is in the midst of a remarkable transition. used at the M. D. Anderson Proton Therapy Center to mea- During the next decade, important advances in proton sure fluence patterns in air at the isocenter for single spots, therapy treatment delivery, treatment planning, and quality uniform spot patterns, and for spot patterns calculated for a assurance systems will be made that will improve proton SFUD prostate treatment delivery. However, CCD camera- therapy’s efficiency, robustness, and accuracy. It is also ex- based proton dosimetry systems are not readily available, but pected that the cost to patients will decrease, making proton they can be made in house without undue difficulty. therapy more financially competitive with photon therapy. Other dosimetric systems such as radiochromic films,72,73 IMPT treatments will become available for routine use in alanine detectors,73 and polymer gels74 can be used for QA an increasing number of facilities, and methods will be de- measurements. However, the use of these systems is limited veloped to improve the accuracy and precision of this treat- because of saturation effects in the proton stopping region ment modality. With the availability of advanced IMPT tech- and because they are not real-time instruments. These sys- niques, it may be possible to quantify the clinical gains tems continue to be investigated, and it is expected that they obtained from optimized proton therapy and to compare the will, in time, become more widely used. clinical outcomes of photons and protons using the best dose distributions for both modalities. It will be necessary to develop methods to make proton treatment plan calculations more accurate and to verify that IV.C.8. Carbon ions treatment plans are actually realized in the delivery of proton There is a growing interest in using carbon ions for cancer treatments. It is not meaningful to compare protons with therapy. The rationale for using carbon ions is that in addi- photons unless we can demonstrate that the superior dose tion to their highly localized physical dose distributions, distributions of proton treatment plans can actually be deliv- 78 which are quite similar to those for proton beams, carbon ion ered to patients. beams are high linear energy transfer ͑LET͒ in their interac- More hospital-based, state-of-the-art proton therapy facili- tions in tissues. High LET provides increased relative bio- ties will be built and increasing numbers of patients will be logical effectiveness ͑RBE͒ and a low oxygen enhancement treated. As stated by Schultz-Ertner and Tsujii, “The poten- ratio ͑OER͒; therefore, carbon ions may be more effective tial of particle therapy can only be exploited if a full integra- than protons in treatment situations where cancer cells are tion of particle therapy into clinical environments and inter- anoxic or hypoxic.75–77 Carbon ion facilities in Japan disciplinary treatment strategies is sought and if new medical ͑HIMAC-Chiba and HIMC-Hyogo͒ and Germany ͑GSI, and technologic advances are properly incorporated into the 15 Darmstadt͒ have treated approximately 5,000 patients to total treatment process.” 5 date and a hospital-based facility is being constructed at the ͒ a Author to whom all correspondence should be addressed. Electronic DKFZ/German Cancer Research Center/University of mail: [email protected] Heidelberg, which will commence patient treatments in 1E. Rutherford, “Collisions of alpha particles with light atoms. III. Nitro- 2009. New facilities are being built in Japan, Italy, and Ger- gen and oxygen atoms,” Philos. Mag. 37, 571–580 ͑1919͒. 2 many and are in an advanced stage of planning in Austria C. A. Tobias, J. H. Lawrence, J. L. Born, R. K. McCombs, J. E. Roberts, H. O. Anger, V. V. A. Low-Beer, and C. B. Huggins, “Pituitary irradiation and France. Most of these carbon ion facilities will also have with high-energy proton beams: a preliminary report,” Cancer Res. 18, the ability to treat patients with proton beams. There are at 121–134 ͑1958͒. least three institutions in the United States that are contem- 3R. R. Wilson, “Radiological use of fast protons,” Radiology 47,487–491 ͑1946͒. plating proton/carbon ion facilities—at this time they are all 4 J. M. Slater, J. O. Archambeau, D. W. Miller, M. I. Notarus, W. Preston, planning to start with protons only and, at a later date, add and J. D. Slater, “The proton treatment center at Loma Linda University carbon ion capabilities, but there are several impediments to Medical Center,” Int. J. Radiat. Oncol., Biol., Phys. 22, 383–389 ͑1991͒. 5 the development of carbon ion facilities in the United States: “Particles” newsletter. Available from: http://ptcog.web.psi.ch/ ͑ ͒ ͑ ͒ ptcentres.html 1 carbon ion systems do not have FDA clearance; 2 there 6B. Gottschalk and E. Pedroni, “Treatment delivery systems,” Proton and are no procedure codes or reimbursement rates for carbon Charged Particle Radiotherapy, T. F. DeLaney and H. M. Kooy, eds. ion treatments; and ͑3͒ carbon ion facilities are much more ͑Lippincott Williams and Wilkins, Philadelphia, 2008͒, pp. 33–49. 7 expensive than proton facilities. The current financial cli- W. T. Chu, B. A. Ludewigt, and T. R. Renner, “Instrumentation for treatment of cancer using proton and light-ion beams,” Rev. Sci. Instrum. 64, mate, high costs of construction, and unfavorable foreign 2055–2122 ͑1993͒. exchange rates are also strong financial disincentives for 8A. J. Lomax, “Intensity modulated proton therapy and its sensitivity to building carbon ion facilities. treatment uncertainties. 1. The potential effects of calculational uncertain- ͑ ͒ In addition, the clinical value of carbon ions has not been ties,” Phys. Med. Biol. 53, 1027–1042 2008 . 9A. J. Lomax, “Intensity modulated proton therapy and its sensitivity to sufficiently demonstrated; however, clinical results are treatment uncertainties. 2. The potential effects of inter-fraction and inter- 15 promising. It is certain that investigations of both protons field motions,” Phys. Med. Biol. 53, 1043–1056 ͑2008͒. and carbon ions, and clinical comparisons between the two 10B. Glimelius, U. Isacsson, E. Blomquist, E. Grusell, B. Jung, and A. particles will be carried out during the next decade as more Montelius, “Potential gains using high-energy protons for therapy of malignant tumors,” Acta Oncol. 38, 137–145 ͑1999͒. facilities are opened that have the capability of treating pa- 11B. Glimelius et al., “Number of patients potentially eligible for proton tients with both types of particles. therapy,” Acta Oncol. 44, 836–849 ͑2005͒.

Medical Physics, Vol. 36, No. 2, February 2009 567 Alfred R. Smith: Proton Therapy 567

12R. Flynn, D. Barbee, T. Mackie, and R. Jeraj, “Comparison of intensity 37E. Fourkal, B. Shahine, M. Ding, J.-S. Li, T. Tajima, and C.-M. Ma, modulated x-ray therapy and intensity modulated proton therapy for se- “Particle in cell simulation of laser-accelerated proton beams for radiation lective subvolume boosting: A phantom study,” Phys. Med. Biol. 52, therapy,” Med. Phys. 29, 2788–2798 ͑2002͒. 6073–6091 ͑2007͒. 38S. S. Bulanov et al., “Accelerating protons to therapeutic energies with 13L. Haisen, H. Romeijn, H. Fox, J. Palta, and J. Dempsey, “A computa- ultraintense, ultraclean, and ultrashort laser pulses,” Med. Phys. 35, tional implementation and comparison of several intensity modulated pro- 1770–1776 ͑2008͒. ton therapy treatment planning algorithms,” Med. Phys. 35, 1103–1112 39G. J. Caporaso et al., “A compact linac for intensity modulated proton ͑2008͒. therapy based on a dielectric wall accelerator,” Phys. Medica 24, 98–101 14A. J. Lomax et al., “A treatment planning inter-comparison of protons and ͑2008͒. intensity-modulated photon therapy,” Radiother. Oncol. 51, 257–271 40T. R. Mackie et al., “A proposal for a novel compact intensity modulated ͑1999͒. proton therapy system using a dielectric wall accelerator,” Med. Phys. 34, 15D. Schultz-Ertner and H. Tsujii, “Particle radiation therapy using proton 2628 ͑2007͒. and heavier ion beams,” J. Clin. Oncol. 25, 953–964 ͑2007͒. 41H. M. Lu, R. Brett, G. Shapr, S. Safai, S. Jiang, J. Flanz, and H. Kooy, “A 16H. Tsujii, et al. “Clinical results of fractionated proton therapy,” Int. J. respiratory-gated treatment system for proton therapy,” Med. Phys. 34, Radiat. Oncol., Biol., Phys. 25, 49–60 ͑1993͒. 3273–3278 ͑2007͒. 17H. Suit et al., “Proton beams to replace photon beams in radical dose 42T. Furukawa, T. Inaniwa, S. Sato, T. Tomitani, S. Iinohara, K. Noda, and treatments,” Acta Oncol. 42, 800–808 ͑2003͒. T. Kanai, “Design study of a raster scanning system for moving target 18A. R. Smith, “Innovations and technical developments for particle therapy irradiation in heavy-ion therapy,” Med. Phys. 34, 1085–1097 ͑2007͒. in the United States,” Proceedings, The 21st International Symposium: 43C. Bert, N. Laito, A. Schmidt, N. Chaudhri, D. Schardt, and E. Rietzel, Modern Radiation Oncology: Innovative Technologies and Translational “Target motion tracking with scanned particle beam,” Med. Phys. 34, Research, 2008. 4768–4771 ͑2007͒. 19H. Klein, C. Baumgarten, A. Geisler, J. Heese, A. Hobl, D. Krischel, M. 44H. Paganetti, H. Jiang, K. Parodi, R. Slopsema, and M. Engelsman, Schillo, S. Schmidt, and J. Timmer, “New superconducting cyclotron “Clinical implementation of full Monte Carlo dose calculation in proton driven scanning proton therapy systems,” Nucl. Instrum. Methods Phys. beam therapy,” Phys. Med. Biol. 53, 4825–4853 ͑2008͒. Res. B 241, 721–726 ͑2005͒. 45H. Paganetti, H. Jiang, and A. Trofimov, “4D Monte Carlo simulation of 20A. Mazal et al., “Robots in high precision patient positioning for confor- proton beam scanning: Modeling of variations in time and space to study mal radiotherapy,” Proceedings of World Congress on Medical Physics the interplay between scanning pattern and time-dependent patient geom- and Biomedical Engineering, Medical and Biological Engineering and etry,” Phys. Med. Biol. 50, 983–990 ͑2005͒. Computing, 1997. 46R. D. Ilie, V. Spasic-Jokic, P. Belicev, and M. Dragovic, “The Monte 21C. E. Allgower, A. N. Schreuder, J. B. Farr, and A. E. Mascia, “Experi- Carlo SRNA-VOX code for 3D proton dose distribution in voxelized ences with an application of industrial robotics for accurate patient posi- geometry using CT data,” Phys. Med. Biol. 50, 1011–1017 ͑2005͒. tioning in proton radiotherapy,” Int. J. Med. Robotics Comput. Assist. 47W. Newhauser et al., “Monte Carlo simulations of a nozzle for the treat- Surg. 3,72–81͑2007͒. ment of ocular tumors with high-energy proton beams,” Phys. Med. Biol. 22E. Pedroni et al., “The 200 MeV proton therapy project at the Paul Scher- 50, 5229–5249 ͑2005͒. rer Institute: Conceptual design and practical realization,” Med. Phys. 22, 48W. Newhauser et al., “Monte Carlo simulations for configuring and test- 37–53 ͑1995͒. ing an analytical proton dose-calculation algorithm,” Phys. Med. Biol. 52, 23A. Lomax et al., “Treatment planning and verification of proton therapy 4569–4584 ͑2007͒. using spot scanning: Initial experience,” Med. Phys. 31, 3150–3157 49D. Pflugfelder, J. J. Wilkens, and U. Oelfke, “Worst case optimization: A ͑2004͒. method to account for uncertainties in the optimization of intensity modu- 24A. L. Zeitman et al., “Comparison of conventional-dose vs. high-dose lated proton therapy,” Phys. Med. Biol. 53, 1689–1700 ͑2008͒. conformal radiation therapy in clinically localized adenocarcinoma of the 50K. Parodi et al., “Patient study of in vivo verification of beam delivery prostate: A randomized controlled trial,” JAMA, J. Am. Med. Assoc. 294, and range, using positron emission tomography and computed tomogra- 1233–1239 ͑2005͒. phy imaging after proton therapy,” Int. J. Radiat. Oncol., Biol., Phys. 68, 25M. Goitein and J. Cox, “Should randomized clinical trial be required for 920–934 ͑2007͒. proton radiotherapy?” J. Clin. Oncol. 26, 175–176 ͑2008͒. 51K. Parodi, T. Bortfeld, and T. Haberer, “Comparison between in-beam 26H. Suit et al. “Should positive phase III clinical trial data be required and offline positron emission tomography imaging of proton and carbon before proton beam therapy is more widely adopted? No,” Radiother. ion therapeutic irradiation at synchrotron- and cyclotron-based facilities,” Oncol. 86, 148–153 ͑2008͒. Int. J. Radiat. Oncol., Biol., Phys. 71, 945–956 ͑2008͒. 27M. Goitein and M. Jermann, “The relative costs of proton and x-ray 52T. Nishio and T. Ogino, “Dose-volume delivery guided proton therapy radiation therapy,” Clin. Oncol. 15, S37–S50 ͑2003͒. using beam on-line PET system,” Med. Phys. 33, 4190–4197 ͑2006͒. 28Y. Jongen, “Cyclotrons and synchrocyclotrons,” PTCOG Educational 53A. Knopf, K. Parodi, H. Paganetti, E. Cascio, A. Bonab, and T. Bortfeld, Workshop, Jacksonville, Fl, May 2008, http://ptcog.web.psi.ch/ “Quantitative assessment of the physical potential of proton beam range ptcog47_talks.html ͑accessed November 1, 2008͒. verification with PET/CT,” Phys. Med. Biol. 53, 4137–4151 ͑2008͒. 29J. Flanz, “Particle therapy: Technical approaches,” PTCOG Educational 54A. M. Cormack, “Representation of a function by its line integrals with Workshop, Jacksonville, Fl, May 2008, http://ptcog.web.psi.ch/ some radiological applications,” J. Appl. Phys. 34, 2722–2727 ͑1963͒. ptcog47_talks.html ͑accessed November 1, 2008͒. 55A. M. Cormack, “Representation of a function by its line integrals with 30R. L. Maughan and W. E. Powers, “A superconducting cyclotron for some radiological applications II,” J. Appl. Phys. 35, 2908–2913 ͑1964͒. neutron radiation therapy,” Med. Phys. 21, 779–785 ͑1994͒. 56A. M. Koehler, “Proton radiography,” Science 160, 303–304 ͑1968͒. 31M. D. Craddock, “New concepts in FFAG design for secondary beam 57A. M. Cormack and A. M. Koehler, “Quantitative proton tomography: facilities and other applications,” Proceedings of EPAC 2005, 2005, pp. Preliminary experiments,” Phys. Med. Biol. 21, 560–569 ͑1976͒. 261–263. 58K. M. Hanson, J. N. Bradbury, T. M. Cannon, R. I. Hutson, D. B. 32Y. Mori et al., “A new type of rf cavity for high intensity proton synchro- Laubacher, R. Macek, M. A. Paciotti, S. A. Sandford, and V. W. Steward, tron using high permeability magnetic alloy,” Proceedings of EPAC 1998, “Proton computed tomography of human specimens,” Phys. Med. Biol. pp. 299–301. 26, 965–983 ͑1981͒. 33M. Aiba et al., “Development of a FFAG proton synchrotron,” Proceed- 59U. Schneider and E. Pedroni, “Proton radiography as a tool for quality ings of EPAC 2000, pp. 581–583. control in proton therapy,” Med. Phys. 22, 353–363 ͑1995͒. 34C. Johnstone et al., “Fixed field circular accelerator designs,” Proceed- 60U. Schneider, J. Besserer, P. Pemler, M. Dellert, M. Moosburger, E. ings of EPAC 1999, pp. 3068–3070. Pedroni, and B. Kaser-Holz, “First proton radiography of an animal pa- 35E. Keil, A. M. Sessler, and D. Trbojevic, “Hadron cancer therapy com- tient,” Med. Phys. 31, 1046–1051 ͑2004͒. plex using nonscaling fixed field alternating gradient accelerator and gan- 61P. Zygmanski, K. P. Gall, M. S. Z. Rabin, and S. J. Rosenthal, “The try design,” Phys. Rev. ST Accel. Beams 10, 054701 ͑2007͒. measurement of proton stopping powers using proton-cone-beam com- 36C.-M. Ma et al., “Development of a laser-driven proton accelerator for puted tomography,” Phys. Med. Biol. 45, 511–528 ͑2000͒. cancer therapy,” Laser Phys., 16,1–8͑2006͒. 62R. Schulte et al., “Conceptual design of a proton computed tomography

Medical Physics, Vol. 36, No. 2, February 2009 568 Alfred R. Smith: Proton Therapy 568

system for applications in proton radiation therapy,” IEEE Trans. Nucl. 70D. Nichiporov and K. Solberg, “Multichannel detectors for profile mea- Sci. 51, 866–872 ͑2004͒. surements in clinical proton fields,” Med. Phys. 34, 2683–2690 ͑2007͒. 63U. Schneider, E. Pedroni, and A. Lomax, “The calibration of CT Houn- 71S. Boon, P. van Luijk, T. Böhringer, A. Coray, A. Lomax, E. Pedroni, B. sfield units for radiotherapy treatment planning,” Phys. Med. Biol. 41, Schaffner, and J. M. Schippers, “Performance of a fluorescent screen and 111–124, ͑1996͒. CCD camera as a two dimensional system for dynamic treatment tech- 64R. W. Schulte, V. Bashkirov, M. C. L. Klock, T. Li, A. J. Wroe, I. Evessv, niques,” Med. Phys. 27, 2198–2208 ͑2000͒. D. C. Williams, and T. Satogata, “Density resolution of proton computed 72S. Vatnitsky, “Radiochromic film dosimetry for clinical proton beams,” tomography,” Med. Phys. 32, 1035–1046 ͑2005͒. Appl. Radiat. Isot. 48, 643–651 ͑1997͒. 65J. T. de Assis et al., “Proton computed tomography as a tool for proton 73D. Nichiporov et al., “Investigation of applicability of alanine and radiotherapy planning: Preliminary computer simulations and comparisons chromic detectors to dosimetry of proton clinical beams,” Appl. Radiat. with x-ray CT basics,” X-Ray Spectrom. 34, 481–492 ͑2005͒. Isot. 46, 1355–1362 ͑1995͒. 66H. F.-W. Sadrozinski et al., “Toward proton computed tomography,” 74W. B. Warren, “Evaluation of ®Bang polymer gel dosimeters in proton IEEE Trans. Nucl. Sci. 51,3–9͑2004͒. beams,” M.S. thesis, The University of Texas Health Science Center at 67O. Jäkel, G. H. Hartmann, C. P. Karger, P. Heeg, and J. Rassow, “Quality Houston, Graduate School of Biomedical Sciences, 2007. assurance for a treatment planning system in scanned ion beam therapy,” 75G. Kraft, “The radiobiological and physical basis for radiotherapy with Med. Phys. 27, 1588–1600 ͑2000͒. protons and heavier ions,” Strahlenther. Onkol. 166, 10–13 ͑1990͒. 68E. Pedroni, S. Scheib, T. Böhringer, A. Coray, M. Grossmann, S. Lin, and 76T. Kanai et al., “Biophysical characteristics of HIMAC clinical irradiation A. Lomax, “Experimental characterization and physical modelling of the system for heavy-ion radiation therapy,” Int. J. Radiat. Oncol., Biol., dose distribution of scanned proton pencil beams,” Phys. Med. Biol. 50, Phys. 64, 201–210 ͑1999͒. 541–561 ͑2005͒. 77A. Brahme, “Recent advances in light ion radiation therapy,” Int. J. Ra- 69C. P. Karger, O. Jäkel, and G. H. Hartmann, “A system for three- diat. Oncol., Biol., Phys. 58, 603–616 ͑2004͒. dimensional dosimetric verification of treatment plans in intensity- 78R. Mohan, “Achieving what-you-see-is-what-you-get in proton therapy,” modulated radiotherapy with heavy ions,” Med. Phys. 26, 2125–2132 PTCOG Scientific Meeting, Jacksonville, Fl, May 2008, http:// ͑1999͒. ptcog.web.psi.ch/ptcog47_talks.html ͑accessed November 1, 2008͒.

Medical Physics, Vol. 36, No. 2, February 2009 Tomosynthesis imaging: At a translational crossroads ͒ James T. Dobbins IIIa Carl E. Ravin Advanced Imaging Laboratories, Department of Radiology, Department of Biomedical Engineering, and Medical Physics Graduate Program, Duke University Medical Center, Durham, North Carolina 27705 ͑Received 23 July 2008; revised 2 February 2009; accepted for publication 27 March 2009; published 5 May 2009͒ Tomosynthesis is a decades-old technique for section imaging that has seen a recent upsurge in interest due to its promise to provide three-dimensional information at lower dose and potentially lower cost than CT in certain clinical imaging situations. This renewed interest in tomosynthesis began in the late 1990s as a new generation of flat-panel detectors became available; these detectors were the one missing piece of the picture that had kept tomosynthesis from enjoying significant utilization earlier. In the past decade, tomosynthesis imaging has been investigated in a variety of clinical imaging situations, but the two most prominent have been in breast and chest imaging. Tomosynthesis has the potential to substantially change the way in which breast cancer and pulmonary nodules are detected and managed. Commercial tomosynthesis devices are now available or on the horizon. Many of the remaining research activities with tomosynthesis will be translational in nature and will involve physicist and clinician alike. This overview article provides a forward- looking assessment of the translational questions facing tomosynthesis imaging and anticipates some of the likely research and clinical activities in the next five years. © 2009 American Asso- ciation of Physicists in Medicine. ͓DOI: 10.1118/1.3120285͔

Key words: tomosynthesis, breast imaging, chest imaging, tomography

I. OVERVIEW the equinoxes and slows down near the solstices, so the rate of progress in a new imaging modality is greatest in the Digital tomosynthesis is a simple and relatively inexpensive middle of its developmental pathway. Tomosynthesis imag- method of producing section images using conventional digi- ing is clearly in March of its allegorical calendar year of tal x-ray equipment. It is a form of limited angle tomography development. Change is happening at a rapid pace, which is that produces section, or “slice,” images from a series of exciting for investigators, but it also makes the long-term projection images acquired as the x-ray tube moves over a future difficult to predict with certainty. prescribed path. The total angular range of movement is of- Although tomosynthesis has not yet passed its pivotal ten less than 40°. Because the projection images are not ac- clinical evaluation, it can, to borrow another metaphor, be quired over a full 360° rotation about the patient, the reso- said to have passed the “light box test.” A clinical colleague lution in the z direction ͑i.e., in the depth direction has often remarked that he can gauge which new imaging perpendicular to the x-y plane of the projection images͒ is modalities will be clinically successful from an intuitive ap- limited, and thus tomosynthesis does not produce the isotro- praisal of how substantially the new technique appears to pic spatial resolution achievable with computed tomography improve upon the modality it is vying to replace by viewing ͑CT͒. However, the resolution of images in the x-y plane of the reconstructed slices is often superior to CT, and the ease the images “on a light box across the room.” In the opinion of use in conjunction with conventional radiography makes of this colleague, if improvements from a new modality are tomosynthesis a potentially quite useful imaging modality. only demonstrable by comparing small changes in Az values There has been a high degree of research interest in to- following an extensive ROC study, then the improvement of mosynthesis imaging in the past decade, and at least two the new modality may be statistically significant but the level commercial products have recently been approved by the of its clinical impact may be hard to predict in advance. On Food and Drug Administration ͑FDA͒ and released on the the other hand, if the new modality produces images that are market. It is expected that other approved devices will soon so substantially superior to the predecessor technique that the follow. As such, tomosynthesis imaging is in a period of a difference is visible “on a light box viewed across the room,” high rate of change, with an increasing number of investiga- then the clinical impact is likely to be substantial. After hav- tors and manufacturers nearing completion of projects in- ing viewed several thousand tomosynthesis images in early volving both the physics and clinical aspects of the tech- clinical studies, most observers would agree that there is a nique. If one were to compare the current state of subjective but substantial improvement in the ability to ap- tomosynthesis imaging to a metaphorical calendar year, the preciate abnormal anatomy or disease in tomosynthesis im- field is firmly in the middle of spring. It has moved beyond ages relative to conventional radiography. At the current time the “winter” of initial research investigation but is not yet in there are only a limited number of completed clinical studies the “summer” as a mature and accepted clinical modality. to quantify this improvement and to determine how tomo- Just as the rate of change in daylight hours is at its greatest at synthesis affects specificity as well as sensitivity. Nonethe-

1956 Med. Phys. 36 „6…, June 2009 0094-2405/2009/36„6…/1956/12/$25.00 © 2009 Am. Assoc. Phys. Med. 1956 1957 James T. Dobbins III: Tomosynthesis imaging 2020 1957 less, based purely on the gestalt impression of the images, In the mid-1980s, several investigators explored methods most would agree that tomosynthesis passes the “light box to reduce the blur artifacts associated with tomosynthesis im- test” with what appears to be a substantial visual improve- aging. Ghosh Roy et al.,5 Chakraborty et al.,6 Ruttimann et ment over conventional radiographic imaging. al.,7 Dobbins et al.,8 and others were successful in eliminat- Notwithstanding the improved visibility of anatomy in to- ing all or part of the residual blur from overlying anatomy by mosynthesis images, the true test of the impact of a new solving for the blurring function in different reconstructed imaging modality is how it affects management of patients tomosynthesis planes. These deblurring algorithms made to- and clinical outcomes. Issues of cost, radiation dose, flexibil- mosynthesis suitable for consideration in a wider range of ity of use, and clinical workflow must be considered in ad- clinical applications dition to measures of sensitivity and specificity when deter- Another more serious challenge to the development of mining how important a new modality will be. It is precisely tomosynthesis imaging was the lack of a suitable digital de- these questions of clinical translation that will be the focus of tector for acquisition of the projection images. At the time much of the research effort in tomosynthesis in the next five that much of the work on deblurring algorithms was being years. done in the 1980s, a suitable large-area, self-scanned digital As with weather forecasting, it is difficult to predict with detector was not available. The earliest evaluation of the ma- any certainty the long-range forecast, but one can make some trix inversion tomosynthesis ͑MITS͒ algorithm in our labo- reasonable estimates of near-term effects. So it is with tomo- ratory, for example, was tested using a conventional geomet- synthesis. In this article, the short-term future of tomosyn- ric tomography table and screen-film imaging; a series of thesis research and clinical utilization in the next 5 years will screen-film projection images was acquired over a range of be assessed. A brief history of tomosynthesis will be pro- tube movement and then digitized.8 The digitized images vided so that the reader can have a context for current work were then reconstructed using the MITS algorithm, and a in the field. A summary of the current state of the art will be small phantom comprised of geometric shapes was visible in given, and then many of the current questions of clinical several reconstructed planes. Needless to say, this approach translation will be explored in more detail. was extremely time consuming and certainly not clinically feasible. Computed radiography ͑CR͒ imaging plates became commercially available in the mid-1980s, and while a substantial improvement over digitizing film, were also not suit- II. A BRIEF HISTORY OF TOMOSYNTHESIS able because of the logistical impracticality of acquiring and Tomosynthesis is one of a number of imaging modalities scanning multiple CR plates during tube movement. whose conception preceded its feasible implementation by A few investigators used image intensifiers to demonstrate several decades. The basic theoretical framework for limited the potential of tomosynthesis imaging. Image intensifiers angle tomography was provided by Ziedses des Plantes1 in allowed rapid acquisition of images, thereby resolving the the 1930s. However, with the development of digital detec- issue of how to acquire multiple images in a clinically real- tors being decades in the future, the implementation of to- istic time frame. These images demonstrated that the concept mosynthesis was clearly not feasible in those early days. of using tomosynthesis imaging could be useful in appreci- Grant2 coined the term “tomosynthesis” in a landmark paper ating disease in the chest and were a substantial in 1972 that described the method of simple tomosynthesis breakthrough.9 However, image intensifiers have notable reconstruction. A number of variants of tomosynthesis imag- drawbacks, including pincushion distortion and variable geo- ing were developed in the 1970s and 1980s, including “ec- metric uniformity when moving in the earth’s gravitational tomography” by Edholm et al.,3 and flashing tomosynthesis4 field, which make them less than ideal for tomosynthesis that provided rapid imaging for vascular applications. imaging. A number of corrections are necessary to ad- One of the difficulties encountered with these early tech- equately use image intensifiers for this purpose. niques was the residual blur from objects outside of the plane The advent of spiral CT in the late 1980s, coupled with of interest. As anyone familiar with conventional screen-film the lack of a suitable digital radiographic detector, caused based geometrical tomography knows, when the x-ray tube much of the research in digital tomosynthesis to come to a ͑and sometimes the detector͒ moves during image acquisi- halt for about a decade. This author, and others, felt that tion, objects in the fulcrum plane of motion remain in sharp spiral CT would become the way that all volumetric x-ray focus but objects outside the fulcrum plane are blurred in imaging would be done in the future and relegated tomosyn- relation to their distance from the fulcrum plane. In the case thesis to the dustheap of research ideas that looked promising of intravenous pyelograms ͑IVPs͒, for example, a zone of at first but just did not seem to pan out. The situation relatively sharp focus is centered about the opacified kid- changed substantially in the late 1990s, however, when flat- neys, ureters, and bladder, and the anatomy outside of this panel radiographic detectors were introduced. With these “zone” is relatively blurry. This type of geometrical tomog- new detectors there was finally a high-DQE, stable, low- raphy works well for imaging high contrast opacified struc- noise, self-scanned imaging device without geometric distor- tures, as with IVPs, but is not very successful at imaging tion that could image at the speeds needed for reasonable use unopacified soft-tissue anatomy because the residual blur in tomosynthesis. Several investigators, including this author, from above and below the plane of interest masks the low- retrieved tomosynthesis from the shelf of research relics, contrast soft-tissue anatomy of interest. dusted it off, and picked up again in earnest with tomosyn-

Medical Physics, Vol. 36, No. 6, June 2009 1958 James T. Dobbins III: Tomosynthesis imaging 2020 1958

FIG. 1. Images of pulmonary nodules in chest tomosynthesis images of a human subject. ͑a͒ Coned view of digital PA radiograph shows one clearly visible right lung nodule ͑arrow͒. ͑b͒ Tomosynthesis image shows the same nodule ͑vertical arrow͒ as seen on the PA radiograph in ͑a͒. A second nodule ͑horizontal arrow͒ is also visible that was not seen in the PA radiograph in ͑a͒. ͑c͒ Tomosynthesis image at a more posterior level shows an additional left lung nodule ͑arrow͒ not seen in the PA radiograph in ͑a͒. ͑d͒ CT image ͑lung window͒ confirms left lower lobe nodule seen in ͑c͒. ͑Reprinted with permission from Medical Physics, Ref. 16, Copyright © 2008, American Association of Physicists in Medicine ͑AAPM͒.͒ thesis research at that time. At last, there was a detector that III. CURRENT STATE OF THE ART made tomosynthesis feasible, and the rate of research explo- III.A. Geometry of motion ration in tomosynthesis accelerated considerably. One of the early applications of tomosynthesis with flat- The first item to consider when describing tomosynthesis panel detectors was conducted in our laboratory and was imaging is the geometry of motion of the tube and/or detec- related to chest imaging. Starting in 1998, we developed, tor. There are three basic motion geometries ͑see Fig. 2͒: optimized, and evaluated tomosynthesis with flat-panel de- parallel path ͑where the tube moves in a plane parallel to the tectors for pulmonary nodule imaging.10–16 Figure 1 illus- detector plane; the detector may also move within its plane͒, trates the advantage of using tomosynthesis for improving full isocentric motion ͑where the tube and detector are fixed the visibility of subtle pulmonary nodules. At about the same rigidly with respect to each other and move in tandem in a time, tomosynthesis with flat-panel detectors was also ap- circular path around the patient͒, and partial isocentric mo- plied to breast imaging.17–19 tion ͑the detector remains stationary, and the x-ray tube Tomosynthesis has been applied to a variety of clinical moves in an arc above the detector͒. ͑See Ref. 20 for a re- applications over the years, including dental imaging, an- view article containing more details about these motions.͒ giography, and imaging of the chest, breast, and bones ͑see All three of these motion geometries are used in contempo- the review article in Ref. 20 for a more detailed list of cita- rary tomosynthesis imaging. The parallel-path motion is typi- tions to these applications͒. The two that have garnered the cally used in chest and abdominal tomosynthesis ͑in an up- most attention since the late 1990s have been breast imaging right configuration for chest tomosynthesis and a tabletop and pulmonary nodule imaging, which will be described in configuration for IVP and other abdominal applications͒. more detail below. Partial isocentric motion is used in virtually all current breast

Medical Physics, Vol. 36, No. 6, June 2009 1959 James T. Dobbins III: Tomosynthesis imaging 2020 1959

FIG. 2. Geometries of motion for tomosynthesis image acquisition: ͑a͒ Parallel-path motion, ͑b͒ partial isocentric motion, and ͑c͒ full isocentric motion. Parallel-path motion in ͑a͒ illustrates how objects in two planes ͑circle and triangle͒ are projected onto different locations in the image plane due to parallax as the tube moves. ͑Re- printed by permission from Physics in Medicine and Biology, Ref. 20, Copy- right © 2003, Institute of Physics ͑IOP͒ Publishing Ltd.͒

tomosynthesis devices because of the ease of constructing a In the case of parallel-path geometry of motion of the tube compact rotational gantry for the x-ray tube; for simplicity, and/or detector, SAA involves shifting each of the projection the detector remains fixed beneath the breast. Complete iso- images by a given amount and then adding them together. By centric motion is used in cone-beam CT ͑which, for reasons selecting the shift amount correctly, objects in a given plane of nomenclature, is not included in the family of tomosyn- can be brought into sharp focus. thesis techniques because cone-beam CT gives a fully isotro- When performing SAA, it is important to align the shifted pic 3D reconstruction͒. Full isocentric motion is also being anatomical information correctly. With most x-ray tube gan- investigated in tomosynthesis applications using C-arm im- tries or overhead cranes, there is sufficient mechanical sta- agers and in radiation oncology applications where the x-ray bility such that SAA can be performed adequately based source and detector are mounted on the linac gantry as it solely on the known positions of the x-ray tube as it travels. rotates through a limited angle of rotation in order to verify However, patient motion must also be taken into account if positioning of the patient. Limited-angle tomosynthesis ac- the desired structures are going to align properly after the quisition can be reconstructed using a Feldkamp approach as SAA image shifting. In the case of breast tomosynthesis, described by Godfrey et al.21 or through image manipulation 22 motion is mitigated by the light compression of the breast described by Kolitsi et al. during image acquisition. In other applications, patient mo- Of the three geometries of motion, the parallel-path motion can be accounted for by placing fiducial markers on the tion enables the simplest reconstruction algorithm and also patient in order to register the final images after taking into maintains uniform magnification at each tube position. The account motion of the patient. Webber et al.24 introduced a partial isocentric motion leads to variable magnification at formalism for incorporating fiducial marker information into different tube orientations, and thus can distort small struc- the image reconstruction in a method that is a variant of tures unless care is taken in the backprojection process.23 SAA; their method, called tuned aperture computed tomog- The full isocentric motion can provide excellent reconstruc- raphy ͑TACT͒, allows images to be acquired at random tions but with a more complicated algorithm than the parallel-path motion. angles and orientations and then reconstructed in arbitrary planes using the projected locations of the fiducial markers. In our own research laboratory we have adopted a simplified III.B. Reconstruction algorithms version of the fiducial marker approach of Webber et al. in The most frequently used reconstruction algorithm for to- conjunction with parallel-path geometry to register projec- mosynthesis is commonly referred to as shift and add ͑SAA͒. tion images for chest tomosynthesis. In a research study of

Medical Physics, Vol. 36, No. 6, June 2009 1960 James T. Dobbins III: Tomosynthesis imaging 2020 1960 chest tomosynthesis, we found that most human subjects space to generate an approximate point spread function that shifted vertically or horizontally by less than 2 mm during is used to correct for the blur of out-of-plane anatomy.25 FBP acquisition of the set of projection images; however, one requires that the Fourier transform of projection images be subject shifted by as much as 8 mm. This motion did not multiplied by a ramp function to correct for the point spread result in blur within individual projection images due to the function of the SAA algorithm. This ramp function tends to very short exposure times used. Rather, the subject motion produce exaggerated noise in the high frequencies; therefore, meant that the sharp structures in individual projection im- a roll-off filter is typically used to suppress high-frequency ages did not align precisely during shift-and-add reconstruc- noise amplification. The main difference between FBP and tion. Despite this motion, most anatomical structures in the MITS is in the noise spectrum; FBP has better noise proper- subjects were reconstructed quite well with no apparent blur; ties at low frequencies than MITS, but MITS has better noise however, some low-contrast or small objects were recon- properties at high frequencies ͑no roll-off filter is required structed more poorly unless correction for patient motion with MITS͒. Effort is underway in our laboratory to combine was used. As a result, we have developed an automated al- FBP and MITS to get the optimum noise properties of each gorithm to locate the position of a fiducial marker placed on at different parts of the frequency spectrum. the patient’s back, and we recommend the use of fiducial There are also several iterative algorithms that are cur- markers for improved chest tomosynthesis. Such fiducial rently being investigated for tomosynthesis reconstruction. marker registration is not yet available in commercial tomo- Wu et al.19 published breast tomosynthesis reconstructions synthesis devices. using maximum likelihood expectation maximization ͑ML- Simple SAA reconstruction is basically the same as unfil- EM͒. An advantage of this approach is that all the compo- tered backprojection. SAA forms the basis of most tomosyn- nents of the imaging system can be modeled, but the down- thesis algorithms today because of its simplicity. It is, how- side is that the technique is iterative and quite ever, insufficient to use SAA alone for high-quality computationally intensive. In one study, ML was found to be tomosynthesis reconstructions due to the overlapping blurry superior to FBP for masses and small calcifications.26 Other anatomy from outside of the plane of interest. As mentioned investigators have also recently reported on a simultaneous earlier, deblurring algorithms are used to correct for the out- algebraic reconstruction technique ͑SART͒ that was found to of-plane blur and are almost universally adopted in contem- give results comparable to ML methods but requiring fewer porary tomosynthesis imaging. The two deblurring algo- iterations.27,28 rithms that have received the most attention in recent years Regardless of the algorithm used to do the basic tomosyn- are MITS and filtered backprojection ͑FBP͒. MITS, which thesis reconstruction, it is important when using partial iso- was developed in our laboratory, solves for the out-of-plane centric motion to account for the arc-shaped path of objects blur using the known blurring functions of all other planes projected onto the detector plane. It has been shown by Chen when a given plane is reconstructed.11–13,20 Describing the et al.23 that such arc-shaped projections can lead to distortion SAA tomosynthesis reconstructions as a sum of blurry com- of the shape of microcalcifications in breast tomosynthesis. It ponents from all planes, the unblurred structures can be ob- is important for this effect to be included in the geometry of tained by using matrix algebra to solve the set of coupled motion in the reconstruction algorithm. equations in frequency space. This method is quite fast com- Recent work by Fahrig et al.29 and Pineda et al.30 inves- putationally, and given an object composed of a finite num- tigated a novel inverse geometry in tomosynthesis imaging. ber of planes, can render an exact solution in the absence of This inverse geometry uses a scanned source with a small noise. Real patients are not merely a set of planes but are detector element, just the opposite of the geometry of con- three-dimensional structures, so there is some sharing of ventional x-ray imaging. Advantages of this device include a anatomy from plane to plane with MITS; MITS functions in reduced level of patient skin exposure, which is potentially a well-behaved way for the structures between planes, how- advantageous in high-exposure areas such as cardiac ever. imaging.31 The inverse geometry also inherently provides to- A technique that is similar to MITS is the iterative resto- mosynthesis imaging capabilities. ration approach by Ruttimann et al.7 This method solves for the blur in each of the planes using known blurring func- III.C. Acquisition parameters tions, but unlike MITS, it solves the equations iteratively in the forward direction rather than by matrix algebra as with The optimum image acquisition parameters have been in- MITS. The advantage of image restoration is that it can investigated in several laboratories and depend on both the clude all elements of the imaging system, including trunca- clinical application as well as the reconstruction algorithm tion of structures at the edge of the detector at wide angles. It used. In the case of chest imaging, research in our own labo- is, however, an iterative process, and thus is computationally ratory has determined that 71 projection images ͑an odd slower than MITS. number is preferable͒ acquired over 20° of tube movement is The deblurring algorithm that is used today by many to- best for detection of pulmonary nodules with the MITS mosynthesis investigators, and by most manufacturers, is fil- algorithm.15,16 A commercial device currently on the market tered backprojection. FBP is well known from decades of uses about 60 images acquired over 40° for chest imaging. work in CT and, like MITS, is a computationally fast algo- While the number of projection images is fairly consistent rithm. FBP takes the known sampling density in frequency between these two implementations, the angle obviously dif-

Medical Physics, Vol. 36, No. 6, June 2009 1961 James T. Dobbins III: Tomosynthesis imaging 2020 1961 fers substantially. The MITS algorithm used in our labora- response across the frequency spectrum. Other investigators tory has an impulse response that performs better at are looking at alternative reconstruction algorithms, includ- midrange angles15 and FBP used with the commercial de- ing SART.27 Various efforts are underway to compare these vices performs better at wider angles,32 thus explaining this algorithms to one another26,27,39–41 and to determine the op- difference. In application to breast imaging, anywhere from timum set of acquisition parameters.15,42–45 11 to 49 projection images have been used,33,34 with a total There is also ongoing work to determine the best visual angle of tube movement in the range of 15°–50°.33,35,36 presentation of tomosynthesis images. Subjectively, images The spacing of the reconstructed planes also varies with processed and reconstructed with deblurring algorithms can the clinical application and the reconstruction algorithm. In have a “high-pass filtered appearance” and may lose some of breast imaging, it is common to use 1 mm plane spacing,19,33 the overall grayscale range typical of conventional chest or but in chest imaging, 5 mm is more typical.16 breast imaging. Although it would be ideal to have the equivalent appearance of a sagittal or coronal CT reconstruc- III.D. Commercial implementation tion, tomosynthesis has a very broad slice profile at low frequencies that can appear somewhat “unnatural” if the image Commercial manufacturers have recently introduced to- is presented with too much of a high-pass filtered look. For mosynthesis products that can be used for chest, abdominal, this reason, with MITS imaging, for example, a fraction of and musculoskeletal applications. Two such devices are cur- the very lowest frequency bins of a conventional tomosyn- rently on the market and are FDA approved. Devices for thesis image is added back to the deblurred image. This pro- breast tomosynthesis are being developed by several manu- cess produces more of the grayscale range of a conventional facturers, and at least one manufacturer has a submission to 37 chest radiograph, which may make it easier for radiologists the FDA for breast imaging applications. It is likely that to acclimate to the new modality. Likewise, with FBP it may within 1 year there will be an FDA-approved device on the be desirable to add back in a fraction of the lowest frequency market for breast imaging in the U.S. grayscale variation to avoid the situation of the raw beam outside the patient having the same average grayscale as the IV. TOWARD CLINICAL TRANSLATION interior anatomy. Again, such change is largely cosmetic but Tomosynthesis research over the past two decades has should improve the confidence of radiologists as the tech- addressed many of the fundamental physics questions, and nique is gaining acceptance. the field has reached a level of maturity reminiscent of the Clinical evaluation studies should be performed to deter- first or second generation CT or MR scanners. With the in- mine if these modifications in visual presentation improve troduction of commercial products, many more investigators radiologists’ performance or make no difference. These and clinicians will have access to tomosynthesis imaging, projects will involve the input of both physicists and radiolo- and a host of new questions will arise regarding its appropri- gists, and will likely not be completed until tomosynthesis ate clinical utilization. Indeed, an increased interest in tomo- has been commercially available for a while and radiologists synthesis has already been seen, as reflected in the exponen- have developed some experience with it. tially expanding number of papers and presentations on this topic at recent scientific meetings. Many of the questions IV.A.2. Dose optimization ahead will largely be translational in nature, which is not to say that physicists will not be actively involved; rather, re- The question of optimum dose for tomosynthesis has not search and applications in tomosynthesis will increasingly been resolved. The doses reported for a single-view breast involve the combined efforts of both physicists and clini- tomosynthesis exam are about one to two times that of a 33,46,47 cians. In this section, some of the likely translational activi- single-view full-field digital mammogram ͑FFDM͒ ties will be explored, and a synthesis of where the field is ͓doses of 2 mGy ͑Ref. 47͒ and 4 mGy ͑Ref. 33͒ have been likely to go next will be given. reported; many publications do not state absolute dose values, rather merely citing dose relative to that of single-view ͔ IV.A. Continued physics optimization FFDM . Early clinical experience in chest tomosynthesis indicates that exposure equivalent to that of one to three lateral IV.A.1. Reconstruction algorithms chest exams is about right for reasonable imaging14,16,48 ͑in Reconstruction algorithms in tomosynthesis are relatively one study, total tomosynthesis exposures of 68–135 mR were mature at this point, but continued work on optimizing the reported,16 and in another study, an effective dose of 0.12 deblurring algorithms will occur for the next few years. For mSv was reported for chest tomosynthesis as compared with example, Chen et al.38 are investigating the combination of 0.04 mSv for a PA/lateral chest exam48͒. In both of these MITS and FBP in a technique termed Gaussian frequency clinical applications, however, the issue has not been fully blending ͑GFB͒. This method combines the mid- and high- resolved regarding whether to target the dose level to pro- frequency components of MITS with the low-frequency duce an overall “acceptable” image appearance or to address components of FBP. Doing so utilizes the excellent high- a specific clinical task. For example, in chest imaging, the frequency noise properties of MITS with the excellent low- dose level required solely to identify pulmonary nodules is frequency noise properties of FBP. The combination should likely to be perhaps one-half or less of the dose that produces enable an improved noise power spectrum and slice profile an image suitable for general diagnostic use.49 The reason for

Medical Physics, Vol. 36, No. 6, June 2009 1962 James T. Dobbins III: Tomosynthesis imaging 2020 1962 this dose disparity is that the clinical task of nodule detection large clinical trials. It will also be necessary to evaluate re- involves looking for larger objects than other general diag- call rate and biopsy rate, as well as whether the positive nostic tasks in chest imaging. In the case of breast tomosyn- predictive value for biopsy recommendation improves with thesis, the appropriate dose level depends on whether one is tomosynthesis.36 The higher sensitivity of tomosynthesis looking for both masses and calcifications or just for masses. may mean that more objects are seen that look suspicious, One component of dose optimization will be determining and thus the number of recalls may initially increase; how- the optimum x-ray spectrum to yield the highest signal-to- ever, there is some evidence that tomosynthesis may allow a noise ratio for the diagnostic tasks at hand. Currently, chest better look at potential pathologies, thereby ruling out some tomosynthesis has been performed with spectra equivalent to false positives, and thus ultimately the number of cases that conventional radiography ͑125 kVp in one report48 and 120 would be recalled may be reduced compared with conven- kVp with 0.2 mm Cu filtration in another16͒, but further tional mammography.33 The very important translational study of whether these spectra are optimum is needed. The question of how tomosynthesis affects diagnostic decision spectra reported in breast tomosynthesis have been typical of making and patient outcomes will need larger clinical studies those used in conventional digital mammography, but the to resolve.47,51 optimum spectrum may not be finally decided upon until it is A second important question is how many views to take determined whether breast tomosynthesis will be used for with breast tomosynthesis. Currently, some investigators feel both masses and calcifications or just for masses. that tomosynthesis should be performed in both mediolateral Some initial effort has gone into determining generally oblique ͑MLO͒ and craniocaudal ͑CC͒ views,52 although that acceptable dose levels in tomosynthesis using limited num- opinion is not universally held. There also remains a question bers of human subjects or computer simulation and modeling about whether or not a static view should also be obtained. studies.49,50 Further studies will be needed to first determine The answer to this question depends largely on how effective the range of diagnostic tasks for which tomosynthesis is use- tomosynthesis is at imaging microcalcifications. There are ful and then the appropriate dose level for each. These stud- several challenges with imaging microcalcifications with to- ies will likely take several years as radiologists gain experi- mosynthesis, including the reduced resolution of the method ence with tomosynthesis and develop a sense for its best compared with conventional single-image mammography clinical utilization. and also the fact that the pattern of distribution of microcalcifications is more difficult to appreciate in section imaging unless a relatively thick section is used. The reduced reso- IV.B. Breast imaging lution with tomosynthesis relative to a single-view FFDM Breast imaging has seen the greatest number of studies to image is due to the need to shift images by fractional pixel date in tomosynthesis. Because there is currently no FDA- amounts prior to adding during reconstruction. This reduced approved breast tomosynthesis device, all of the experience resolution may impact the ability to appreciate the morphol- in breast tomosynthesis has been gained in research studies ogy of small calcifications, the importance of which is open with human subjects. The total number of human subjects to debate among clinical observers. If it is decided that a imaged with breast tomosynthesis is currently over 4000 static view is needed to adequately evaluate calcifications, worldwide. Despite the large number of human subjects par- then a scenario may develop where an MLO static view ticipating in clinical studies, there is scant published data to mammogram is acquired along with MLO and CC view to- date indicating sensitivity and specificity results. One study mosynthesis exams. Nishikawa et al.53 have proposed a hy- with 98 subjects found that breast tomosynthesis had image brid scheme where a regular MLO or CC view digital mam- quality ͑lesion conspicuity and feature analysis͒ rated as mogram at normal dose is evaluated for microcalcifications, equivalent or superior to diagnostic mammography in 89% and a reduced dose and reduced resolution tomosynthesis of cases.33 Observer studies of computer simulated lesions in data set is reviewed for masses. Clinical trials will be needed a structured 3D breast model found Az scores of 0.93 for to determine which of these is the most appropriate utiliza- tomosynthesis compared with 0.76 for digital tion scheme. mammography.46 Thus, completion of the various ongoing A third translational question for breast tomosynthesis is clinical trials will be necessary before definitive sensitivity how tomosynthesis used for screening will impact diagnostic and specificity data are known in human subjects. workup procedures. Tomosynthesis used for screening will Several important translational questions in breast tomo- likely result in fewer diagnostic workups, and traditional synthesis need study. First, it will be important to determine methods such as ultrasound and magnification view mam- whether breast tomosynthesis will be most useful in screen- mography can still be used to evaluate suspicious opacities ing, diagnostic use, or both. Some investigators feel that to- noted on screening tomosynthesis. Will tomosynthesis have mosynthesis will eventually be useful in both screening and sufficient specificity that certain patients can go directly to diagnostic use, but the case for screening seems stronger at biopsy? And how will the very small number of cancers present. Because tomosynthesis may improve sensitivity of ͑e.g., circumscribed͒ that do not display well on tomosynthe- detection, it is likely to be most useful in screening where sis be handled in screening? These practical questions of most breast cancer is initially discovered. However, because utilization will likely be resolved as radiologists gain clinical more potential cancers may be visualized with tomosynthe- experience with tomosynthesis in the first few years after sis, it will be important to carefully evaluate specificity in FDA-approved devices are available.

Medical Physics, Vol. 36, No. 6, June 2009 1963 James T. Dobbins III: Tomosynthesis imaging 2020 1963

There are other new breast imaging approaches under in- tion improved from 22% with PA radiography to 70% with vestigation that may impact how tomosynthesis is used. One tomosynthesis; substantial and significant ͑pϽ0.004͒ im- example is the development of novel x-ray sources using provement was noted with tomosynthesis over a range of carbon nanotube field-emission cathodes.54 If these devices nodule sizes ͑3–5, 5–10, and Ͼ10 mm͒.16 In a recent study are successful and reasonably priced, they may enable very at the University of Gothenburg, the lesion localization frac- rapid collection of tomosynthesis projection images that tion ͑LLF͒ increased from 0.16 in PA radiography to 0.56 would eliminate the need for lengthy compression. A second with tomosynthesis; however, the nonlesion localization frac- example is the use of iodinated contrast in breast imaging. If tion ͑i.e., false positives͒ was approximately 50% higher injection of contrast is found useful in breast cancer imaging, with tomosynthesis than with PA radiography.48 In both of will it also be advantageous in tomosynthesis imaging? Ini- these studies, the sensitivity of detection of pulmonary nod- 55 tial studies indicate that it may be. If contrast-enhanced ules tripled with tomosynthesis relative to conventional PA tomosynthesis is found to be advantageous, it may be less radiography, indicating the potential for improved clinical costly and more readily available than alternatives such as detection of lung cancer. However, the increase in false posi- contrast-enhanced magnetic resonance imaging. A third and tives may reflect the need for additional clinical training with larger question is how breast tomosynthesis and cone-beam the new technique. Investigating reasons for the increase in CT of the breast will compare. CT is advantageous in that it false positives will no doubt be the subject of future work. has better depth resolution than tomosynthesis, but it also The primary translational issue for chest tomosynthesis is requires a larger room with more specialized equipment, re- determining the best clinical utilization strategy. Tomosyn- quires the patient to lie prone, and has difficulty imaging 56 thesis is partway between conventional chest radiography near the chest wall. Computer simulation studies indicated ͑CXR͒ and CT in its imaging performance. In application to that both tomosynthesis and breast CT outperformed digital detection of pulmonary nodules, it is much more appropriate mammography for detection of masses, but tomosynthesis to see tomosynthesis not as a replacement for CT but as a and CT performed roughly comparably to each other.46 The vast improvement over CXR. With that perspective, how can jury is out on this comparison, and studies comparing these tomosynthesis fit into the clinical management of patients two modalities will be necessary to decide ultimately along with CXR and CT? whether CT or tomosynthesis will prove superior. There are four likely scenarios in which tomosynthesis may have clinical utility for pulmonary nodule detection. IV.C. Chest imaging First, tomosynthesis may function as a problem-solving tool for suspicious opacities noted at CXR; if a nodulelike opac- Although chest imaging was one of the first applications ity is noted on conventional radiography, tomosynthesis may evaluated with tomosynthesis, there have not been as many enable nodule mimics to be ruled out without the expense of studies in the chest as with breast tomosynthesis. We have sending the patient to CT. Second, it may be possible to investigated detection of pulmonary nodules with tomosynthesis for many years in our laboratory, and there are other perform tomosynthesis on every patient scheduled for CXR ͑ investigators entering this area of research now that commer- who is at elevated risk for pulmonary malignancies e.g., ͒ cial chest tomosynthesis devices are available. smokers over age 50 . By acquiring a tomosynthesis exam Imaging of the chest is very complex due to the wide on all high-risk patients scheduled for CXR, it is likely that range of disease with thoracic manifestations. Partly due to some asymptomatic nodules will be detected earlier. Third, it the wide range of disease in the chest, investigators have may be possible to follow patients with known nodules using traditionally selected pulmonary nodules as one of the prin- tomosynthesis rather than CT. Such an approach would cipal areas of research in chest imaging. Pulmonary nodules likely result in monetary savings, but it would need to be are often subtle and difficult to appreciate with conventional demonstrated in clinical trials that such an approach did not radiography due to the overlying anatomy that reduces their miss new small nodules that would be actionable. Fourth, if conspicuity. Tomosynthesis is ideally suited for improving large-scale screening for lung cancer were adopted in the detection of pulmonary nodules because it eliminates the vis- future, then tomosynthesis might be a lower-dose and lower- ibility of overlying structures while still producing an image cost alternative to CT in such screening. that is reminiscent of a posteroanterior ͑PA͒ chest radiograph All four of the above scenarios require additional clinical ͑Fig. 1͒. Tomosynthesis can be performed with minor modi- studies to determine if they are feasible and effective. The fications to a conventional digital chest imaging room, mak- larger issue with pulmonary nodule detection is more diffi- ing it possible to acquire tomosynthesis images at the same cult to solve, and that is whether any of the above procedures time as a conventional chest exam. Thus, although tomosyn- results in better patient outcomes. Unlike breast imaging, thesis does not have the depth resolution of CT, it has certain which has demonstrated reduced mortality from screening practical advantages and a price and radiation dose likely mammography, there is still considerable controversy over less than those of CT. the role of chest imaging for screening for lung cancer. This Early studies have demonstrated that tomosynthesis sub- controversy is irrespective of the type of chest imaging ͑i.e., stantially increases detection sensitivity for pulmonary nod- CXR, tomosynthesis, or CT͒. The problem lies in the biology ules over conventional PA radiography. In a study of 175 of lung cancer. Studies have yet to demonstrate that detecting nodules in 21 subjects, we demonstrated that nodule detec- lung cancer earlier through imaging-based screening results

Medical Physics, Vol. 36, No. 6, June 2009 1964 James T. Dobbins III: Tomosynthesis imaging 2020 1964 in reduced mortality. One recent study found that screening IV.E. Other clinical applications 57 while with low-dose CT resulted in lengthened survival, An additional area of exciting prospect for tomosynthesis another study found that low-dose CT screening did not is in orthopedic imaging. Studies of joint and bone disease change mortality from lung cancer.58 These two prominent can be difficult with CT due to the limited resolution in sag- papers came to differing conclusions as to whether imaging- ittal or coronal planes and with conventional radiography based screening is beneficial. It is likely that this controversy because of the inability to distinguish three-dimensional will not be resolved until results from the National Lung structures. Tomosynthesis naturally addresses both of these Screening Trial ͑NLST͒͑Ref. 59͒ are available some time in 68 concerns. Flynn et al. showed approximately threefold im- the future. Tomosynthesis appears to be a promising tech- provement in spatial resolution in tomosynthesis images of nique for improving pulmonary nodule detection, but the ul- bone relative to that in CT, and yet with dose considerably timate benefit to patient outcomes will need to await the below that of CT. Flynn’s group is investigating tomosynthe- conclusion of the NLST. In the meantime, additional clinical sis in application to knee, femur, shoulder, arm, leg, ankle, studies are needed to address the best way to use tomosyn- and wrist and has found in early results that tomosynthesis is thesis as a problem-solving tool in chest imaging and to de- good at demonstrating subtle fractures and at imaging metal- termine whether it makes sense to image high-risk patients lic implants that would be difficult to image with CT. Web- scheduled for CXR with an additional tomosynthesis exam. ber’s TACT method has also been used in the evaluation of One additional translational question to address is metallic implants in joint arthroplasty.69 whether or not the lateral chest image can be eliminated Another application of tomosynthesis to orthopedic use is when using tomosynthesis. The lateral image is not as im- in evaluation of arthritis. Duryea et al.70 showed that tomo- portant as the PA radiograph for most chest imaging cases synthesis could demonstrate the joint space in the fingers but accounts for a majority of the radiation exposure in a with better clarity than on plain radiographic imaging. They conventional PA/lateral chest exam. The lateral is most com- demonstrated the ability to measure the joint space accu- monly used to confirm presence of an anomaly noted in the rately and speculated that tomosynthesis would also have the PA radiograph or to triangulate the location of a noted object. potential to evaluate erosions of the joint space; both of these Tomosynthesis is likely to be better at both those tasks, and measures can be indicative of arthritic changes, lending sup- thus, it raises the question of whether the lateral can be elimi- port to the idea that tomosynthesis could become part of the nated when using tomosynthesis; doing so would save screening for and monitoring of arthritic disease. Others are enough radiation exposure that a composite exam composed investigating tomosynthesis joint imaging with a C-arm of a PA radiograph and tomosynthesis may have comparable device.71 dose to a conventional chest exam. Eliminating the lateral Tomosynthesis has also been used in dental imaging for would make the clinical acceptance of chest tomosynthesis ͑ ͒ indications such as evaluation of implants, and there is a much easier due to dose concerns , but a clinical study will commercial dental tomosynthesis imaging unit on the mar- be required to satisfactorily answer this question. ket. However, the trend today seems to be more toward CBCT for a broader range of dental uses, and so the future of tomosynthesis imaging in dental applications is uncertain. IV.D. Radiation oncology applications Tomosynthesis is also being evaluated for use intraoperatively72 or in emergency settings where standard Tomosynthesis also has generated considerable interest CT imaging would be impractical or too time consuming. recently for application in determining patient positioning in radiation oncology.21,60–66 On-board imaging has become an important part of verification of patient positioning, espe- IV.F. Computer-aided detection and diagnosis cially with intensity-modulated radiation therapy ͑IMRT͒. Tomosynthesis offers a quicker approach to validating posi- Computer-aided detection ͑CAD͒ and computer-aided de- tioning than a full-circle cone-beam computed tomography tection diagnosis ͑CADx͒ schemes are often mentioned in ͑CBCT͒ acquisition, although it does not have the full iso- connection with tomosynthesis73 and for two primary rea- tropic volumetric information obtainable from CBCT. Tomo- sons. First, the reduction of overlying anatomy offers the synthesis has shown improved localization based upon bony potential for improved sensitivity and specificity for CAD anatomy when compared with traditional orthogonal radio- algorithms. One of the factors that limits the success of some graphs ͑e.g., for head and neck cancers͒,61 but it has been CAD algorithms is the large number of false-positive find- more difficult to use with soft-tissue localization, although it ings. Using tomosynthesis to eliminate much of the confus- has been shown subjectively to be good for visualizing tho- ing background should theoretically reduce the number of racic and abdominal soft tissues in breath-hold treatment false positives. However, in some cases ͑such as with chest techniques. Tomosynthesis has also been used for the local- tomosynthesis͒, this reduction in false positives from reduc- ization of brachytherapy seeds.67 There continues to be inter- tion of overlying soft-tissue might be limited by increased est from vendors in evaluating tomosynthesis in radiation false positives from circular cross sections of imaged vessels. oncology applications. Further physics development work Thus, exactly how much tomosynthesis will benefit CAD and clinical studies will be needed to confirm its role in these algorithms remains to be seen. There is ongoing research in applications. several laboratories, including ours, into these issues.

Medical Physics, Vol. 36, No. 6, June 2009 1965 James T. Dobbins III: Tomosynthesis imaging 2020 1965

A second reason that tomosynthesis and CAD may make sensitivity and specificity of tomosynthesis in cancer imag- a good marriage is that CAD may reduce some of the over- ing. Further studies are needed to address its full clinical head of viewing the large number of images in a set of to- performance. mosynthesis slices. One concern about tomosynthesis that is Tomosynthesis is in somewhat of a chicken and egg situ- sometimes expressed by clinical colleagues is that tomosyn- ation at the present time with regard to its clinical accep- thesis produces many more images than conventional projec- tance. Before tomosynthesis will be widely adopted in clini- tion imaging, and therefore, may slow down workflow. It is cal use, its benefit to patient outcomes must be demonstrated the opinion of this author that such reduction in workflow with further studies and wider clinical experience. However, will not scale with the number of images and will ultimately in order to complete such studies and gain such wider clini- not be too burdensome on the clinical staff. The reasoning cal experience, the technique must be used on more patients. behind that opinion is that the stack of images may be This type of impasse is often seen early in the adoption of viewed at a PACS station dynamically by paging through the any new modality, and it is certain that gaining reimburse- set quickly. The entire set of images viewed in such a dy- ment for the technique will be an important component of namic fashion will take more time than reading a single con- accelerating its clinical utilization. ventional image, to be sure, but will be much faster than Tomosynthesis is fundamentally at a translational cross- viewing each of the slice images statically ͑as was the case roads at the present time, with many of the remaining ques- long ago with CT images printed side by side on hardcopy tions not ones of physics optimization or even clinical per- film͒. Furthermore, the human eye is very sensitive to dy- formance but rather pertaining to practical matters. How will namic changes, and subjectively when anomalous objects in tomosynthesis impact workflow, and what will be the conse- tomosynthesis slices appear in a dynamically viewed stack, quences of that effect? How will tomosynthesis fit into the they are quite apparent. That being said, if CAD algorithms paradigm of clinical management as a tool halfway between could be developed to review tomosynthesis image stacks, traditional radiography and CT? Will patients that receive they might be able to speed up the process with which radi- tomosynthesis be sent on to CT ͑or other standard diagnostic ologists could review the data. Clearly, ongoing research in workup͒ afterwards in most cases anyway, thus ultimately this area is needed. not saving much money for the healthcare enterprise? Or will Despite the potential advantages of combining CAD and tomosynthesis find a niche that enables better utilization of tomosynthesis outlined above, there are considerations that dose and imaging dollars than the existing clinical paradigm? might argue that tomosynthesis would benefit less from CAD This author believes the latter will ultimately be the case, than either conventional radiography or CT. Because objects although further trials are needed to demonstrate it. Tomo- are much more easily detected in tomosynthesis images than synthesis is somewhat unique as a new imaging modality in in conventional radiography, the need for CAD may well be that it is not likely to produce a “revolution” ͑as CT did͒ but less in tomosynthesis than in conventional imaging. On the rather an “evolution” of better clinical management. We are other hand, chest CT, for example, can demonstrate such an currently in the exciting and uncertain times when the “tip- abundance of small nodules that are below the actionability ping point” will likely be seen in the next 1–3 years that will threshold of 5 mm ͑based on the recommendation of the determine the future of this interesting imaging modality. Fleischner Society74͒ that reader fatigue may make it difficult to find all nodules in a chest CT data set. Tomosynthesis of ACKNOWLEDGMENTS the chest, on the other hand, does not display as many small The author gratefully acknowledges the input and sugges- nodules, and therefore, may not be as substantially helped by tions of Joseph Y. Lo, Ph.D., Jay A. Baker, MD, Devon J. CAD as CT would be. Godfrey, Ph.D., Michael J. Flynn, Ph.D., and Donald A. Tyn- It is clear that substantial research into CAD algorithms dall, Ph.D., DDS in the preparation of this manuscript. Some for tomosynthesis using both slice-by-slice evaluation as of the research results from the author’s laboratory were sup- well as full three-dimensional evaluation will be an impor- ported by grants from NIH ͑Grant No. R01 CA80490͒ and tant area of research in the future. The impact of using CAD, GE Healthcare. GE and Duke jointly hold a patent related to either as a prereader or a secondary reader, on user workflow certain aspects of tube movement in tomosynthesis imaging. will be important things to measure before tomosynthesis Collaborative work on breast tomosynthesis at the author’s makes its full translational move from the bench to the bed- institution was supported in part by a grant from Siemens side. Medical Solutions.

͒ a Author to whom correspondence should be addressed. Electronic mail: [email protected] V. CONCLUSION AND SUMMARY 1B. G. Ziedses des Plantes, “Eine neue methode zur differenzierung in der roentgenographie ͑planigraphie͒,” Acta Radiol. 13, 182–192 ͑1932͒. It seems clear from early studies that tomosynthesis offers 2D. G. Grant, “Tomosynthesis: A three-dimensional radiographic imaging the potential for superior performance to conventional radi- technique,” IEEE Trans. Biomed. Eng. BME-19, 20–28 ͑1972͒. ography for several important clinical applications, and the 3P. Edholm, G. Granlund, H. Knutsson, and C. Petersson, “Ectomography: prospect exists that it may become a cost-effective and low- A new radiographic method for reproducing a selected slice of varying thickness,” Acta Radiol. 21, 433–442 ͑1980͒. dose imaging strategy to improve earlier detection of disease. 4H. Becher, M. Schluter, D. G. Mathey, W. Bleifeld, E. Klotz, P. Haaker, Important clinical studies are underway to quantify both the R. Linde, and H. Weiss, “Coronary angiography with ﬂashing tomosyn-

Medical Physics, Vol. 36, No. 6, June 2009 1966 James T. Dobbins III: Tomosynthesis imaging 2020 1966

thesis,” Eur. Heart J. 6, 399–408 ͑1985͒. 27Y. Zhang, H. P. Chan, B. Sahiner, J. Wei, M. M. Goodsitt, L. M. Hadji- 5D. N. Ghosh Roy, R. A. Kruger, B. Yih, and P. Del Rio, “Selective plane iski, J. Ge, and C. Zhou, “A comparative study of limited-angle cone- removal in limited angle tomographic imaging,” Med. Phys. 12, 65–70 beam reconstruction methods for breast tomosynthesis,” Med. Phys. 33, ͑1985͒. 3781–3795 ͑2006͒. 6D. P. Chakraborty, M. V. Yester, G. T. Barnes, and A. V. Lakshminaray- 28Y. Zhang, H. P. Chan, B. Sahiner, Y.-T. Wu, C. Zhou, J. Ge, J. Wei, and anan, “Self-masking subtraction tomosynthesis,” Radiology 150, 225–229 L. M. Hadjiiski, “Application of boundary detection information in breast ͑1984͒. tomosynthesis reconstruction,” Med. Phys. 34, 3603–3613 ͑2007͒. 7U. E. Ruttimann, R. A. J. Groenhuis, and R. L. Webber, “Restoration of 29R. Fahrig, A. R. Pineda, E. G. Solomon, A. N. Leung, and N. J. Pelc, digital multiplane tomosynthesis by a constrained iteration method,” “Fast tomosynthesis for lung cancer detection using the SBDX geom- IEEE Trans. Med. Imaging 3, 141–148 ͑1984͒. etry,” Proc. SPIE 5030, 371–378 ͑2003͒. 8J. T. Dobbins III, A. O. Powell, and Y. K. Weaver, “Matrix inversion 30A. R. Pineda, S. Yoon, D. S. Paik, and R. Fahrig, “Optimization of a tomosynthesis: Initial image reconstruction,” in RSNA 73rd Scientific tomosynthesis system for the detection of lung nodules,” Med. Phys. 33, Assembly, Chicago, IL, 1987 ͑unpublished͒. 1372–1379 ͑2006͒. 9S. Sone, T. Kasuga, F. Sakai, K. Oguchi, A. Itoh, F. Li, Y. Maruyama, K. 31E. G. Solomon, M. S. Van Lysel, R. E. Melen, J. W. Moorman, and B. Kubo, T. Honda, M. Haniuda, and K. Takemura, “Digital tomosynthesis Skillicorn, “Low-exposure scanning-beam x-ray fluoroscopy system,” imaging of the lung,” Radiat. Med. 14, 53–63 ͑1996͒. Proc. SPIE 2708, 140–149 ͑1996͒. 10J. T. Dobbins III, R. L. Webber, and S. M. Hames, “Tomosynthesis for 32B. Li, G. B. Avinash, J. W. Eberhard, and B. E. H. Claus, “Optimization improved pulmonary nodule detection,” in RSNA 84th Scientific Assem- of slice sensitivity profile for radiographic tomosynthesis,” Med. Phys. bly, Chicago, IL, 1998 ͑unpublished͒. 34, 2907–2916 ͑2007͒. 11R. J. Warp, D. J. Godfrey, and J. T. Dobbins III, “Applications of matrix 33S. P. Poplack, T. D. Tosteson, C. A. Kogel, and H. M. Nagy, “Digital inverse tomosynthesis,” Proc. SPIE 3977, 376–383 ͑2000͒. breast tomosynthesis: Initial experience in 98 women with abnormal digi- 12D. J. Godfrey, R. J. Warp, and J. T. Dobbins III, “Optimization of matrix tal screening mammography,” AJR Am. J. Roentgenol. 189, 616–623 inverse tomosynthesis,” Proc. SPIE 4320, 696–704 ͑2001͒. ͑2007͒. 13D. J. Godfrey, A. Rader, and J. T. Dobbins III, “Practical strategies for the 34W. Zhao, B. Zhao, P. R. Fisher, P. Warmoes, T. Mertelmeier, and J. clinical implementation of matrix inversion tomosynthesis ͑MITS͒,” Proc. Orman, “Optimization of detector operation and imaging geometry for SPIE 5030, 379–390 ͑2003͒. breast tomosynthesis,” Proc. SPIE 6510, M1–M12 ͑2007͒. 14J. T. Dobbins III, D. J. Godfrey, and H. P. McAdams, in Advances in 35T. Wu, R. H. Moore, and D. B. Kopans, “Voting strategy for artifact Digital Radiography: RSNA Categorical Course in Digital Radiography, reduction in digital breast tomosynthesis,” Med. Phys. 33, 2461–2471 edited by E. Samei and M. J. Flynn ͑Radiological Society of North ͑2006͒. America, Oak Brook, 2003͒. 36J. M. Park, E. A. J. Franken, M. Garg, L. L. Fajardo, and L. T. Niklason, 15D. J. Godfrey, H. P. McAdams, and J. T. Dobbins III, “Optimization of “Breast tomosynthesis: Present considerations and future applications,” the matrix inversion tomosynthesis ͑MITS͒ impulse response and modu- Radiographics 27, S231–S240 ͑2007͒. lation transfer function characteristics for chest imaging,” Med. Phys. 33, 37T. Wallack, “New dimension in detection,” Boston Globe, June 6, 2008. 655–667 ͑2006͒. 38Y. Chen, J. Y. Lo, J. A. Baker, and J. T. Dobbins III, “Gaussian frequency 16J. T. Dobbins III, H. P. McAdams, J.-W. Song, C. M. Li, D. J. Godfrey, D. blending algorithm with matrix inversion tomosynthesis ͑MITS͒ and fil- M. DeLong, S.-H. Paik, and S. Martinez-Jimenez, “Digital tomosynthesis tered back projection ͑FBP͒ for better digital breast tomosynthesis recon- of the chest for lung nodule detection: Interim sensitivity results from an struction,” Proc. SPIE 6142, 0E1–0E9 ͑2006͒. ongoing NIH-sponsored trial,” Med. Phys. 35, 2554–2557 ͑2008͒. 39Y. Chen, J. Y. Lo, and J. T. Dobbins III, “Impulse response analysis for 17L. T. Niklason, B. T. Christian, L. E. Niklason, D. B. Kopans, D. E. several digital tomosynthesis mammography reconstruction algorithms,” Castleberry, B. H. Opsahl-Ong, C. E. Landberg, P. J. Slanetz, A. A. Gia- Proc. SPIE 5745, 541–549 ͑2005͒. rdino, R. Moore, D. Albagli, M. C. DeJule, P. F. Fitzgerald, D. F. Fobare, 40J. T. Rakowski and M. J. Dennis, “A comparison of reconstruction algo- B. W. Giambattista, R. F. Kwasnick, J. Liu, S. J. Lubowski, G. E. Possin, rithms for C-arm mammography tomosynthesis,” Med. Phys. 33,3018– J. F. Richotte, C.-Y. Wei, and R. F. Wirth,, “Digital tomosynthesis in 3032 ͑2006͒. breast imaging,” Radiology 205, 399–406 ͑1997͒. 41J. Zhou, B. Zhao, and W. Zhao, “A computer simulation platform for the 18S. Suryanarayanan, A. Karellas, S. Vedantham, S. J. Glick, C. J. D’Orsi, optimization of a breast tomosynthesis system,” Med. Phys. 34, 1098– S. P. Baker, and R. L. Webber, “Comparison of tomosynthesis methods 1109 ͑2007͒. used with digital mammography,” Acad. Radiol. 7, 1085–1097 ͑2000͒. 42H. C. Gifford, C. S. Didier, M. Das, and S. J. Glick, “Optimizing breast- 19T. Wu, A. Stewart, M. Stanton, T. McCauley, W. Phillips, D. B. Kopans, tomosynthesis acquisition parameters with scanning model observers,” R. H. Moore, J. W. Eberhard, B. Opsahl-Ong, L. Niklason, and M. B. Proc. SPIE 6917, 0S1–0S9 ͑2008͒. Williams, “Tomographic mammography using a limited number of low- 43T. Deller, K. N. Jabri, J. M. Sabol, X. Ni, G. Avinash, R. Saunders, and R. dose cone-beam projection images,” Med. Phys. 30, 365–380 ͑2003͒. Uppaluri“Effect of acquisition parameters on image quality in digital to- 20J. T. Dobbins III and D. J. Godfrey, “Digital x-ray tomosynthesis: Current mosynthesis,” Proc. SPIE 6510, 1L1–1L11 ͑2007͒. state of the art and clinical potential,” Phys. Med. Biol. 48, R65–R106 44I. Reiser, B. A. Lau, and R. M. Nishikawa, “Effect of scan angle and ͑2003͒. reconstruction algorithm on model observer performance in tomosynthe- 21D. J. Godfrey, F.-F. Yin, M. Oldham, S. Yoo, and C. Willett, “Digital sis,” in IWDM 2008, edited by E. A. Krupinski ͑Springer-Verlag, Berlin, tomosynthesis with an on-board kilovoltage imaging device,” Int. J. Ra- 2008͒, Vol. LNCS 5116, pp. 606–611. diat. Oncol., Biol., Phys. 65, 8–15 ͑2006͒. 45H. P. Chan, J. Wei, Y. Zhang, B. Sahiner, L. M. Hadjiiski, and M. A. 22Z. Kolitsi, V. Anastassopoulos, A. Scodras, and N. Pallikarakis, “A mul- Helvie, “Detection of massses in digital breast tomosynthesis mammog- tiple projection method for digital tomosynthesis,” Med. Phys. 19, 1045– raphy: Effects of the number of projection views and dose,” in IWDM 1050 ͑1992͒. 2008, edited by E. A. Krupinski ͑Springer-Verlag, Berlin, 2008͒,Vol. 23Y. Chen, J. Y. Lo, and J. T. Dobbins III, “Importance of point-by-point LNSC 5116, pp. 279–285. back projection correction for isocentric motion in digital breast tomosyn- 46X. Gong, S. J. Glick, B. Liu, A. A. Vedula, and S. Thacker, “A computer thesis: Relevance to morphology of structures such as microcalcifica- simulation study comparing lesion detection accuracy with digital mam- tions,” Med. Phys. 34, 3885–3892 ͑2007͒. mography, breast tomosynthesis, and cone-beam CT breast imaging,” 24R. L. Webber, R. A. Horton, D. A. Tyndall, and J. B. Ludlow, “Tuned- Med. Phys. 33, 1041–1052 ͑2006͒. aperture computed tomography ͑TACT-TM͒: Theory and application for 47W. F. Good, G. S. Abrams, V. J. Catullo, D. M. Chough, M. A. Ganott, C. three-dimensional dento-alveolar imaging,” Dentomaxillofac Radiol. 26, M. Hakim, and D. Gur, “Digital breast tomosynthesis: A pilot observer 53–62 ͑1997͒. study,” AJR Am. J. Roentgenol. 190, 865–869 ͑2008͒. 25G. Lauritsch and W. H. Harer, “A theoretical framework for filtered back- 48J. Vikgren, S. Zachrisson, A. Svalkvist, Å. A. Johnsson, M. Boijsen, A. projection in tomosynthesis,” Proc. SPIE 3338, 1127–1137 ͑1998͒. Flinck, S. Kheddache, and M. Båth, “Comparison of chest tomosynthesis 26T. Wu, R. H. Moore, E. A. Rafferty, and D. B. Kopans, “A comparison of and chest radiography for detection of pulmonary nodules: Human ob- reconstruction algorithms for breast tomosynthesis,” Med. Phys. 31, server study of clinical cases,” Radiology 249, 1034–1041 ͑2008͒. 2636–2647 ͑2004͒. 49C. M. Li and J. T. Dobbins III, “Methodology for determining dose re-

Medical Physics, Vol. 36, No. 6, June 2009 1967 James T. Dobbins III: Tomosynthesis imaging 2020 1967

duction for chest tomosynthesis,” Proc. SPIE 6510, 2D1–2D10 ͑2007͒. 62H. Yan, L. Ren, D. J. Godfrey, and F.-F. Yin, “Accelerating reconstruction 50P. Timberg, M. Båth, I. Andersson, T. Svahn, M. Ruschin, B. Hemdal, S. of reference digital tomosynthesis using graphics hardware,” Med. Phys. Mattsson, and A. Tingberg, “Impact of dose on observer performance in 34, 3768–3776 ͑2007͒. breast tomosynthesis using breast specimens,” Proc. SPIE 6913, 4J1– 63L. Ren, D. J. Godfrey, H. Yan, Q. J. Wu, and F.-F. Yin, “Automatic 4J10 ͑2008͒. registration between reference and on-board digital tomosynthesis images 51D. Gur, “Tomosynthesis: Potential clinical role in breast imaging,” AJR for positioning verification,” Med. Phys. 35, 664–672 ͑2008͒. Am. J. Roentgenol. 189, 614–615 ͑2007͒. 64H. Yan, D. J. Godfrey, and F.-F. Yin, “Fast reconstruction of digital to- 52E. A. Rafferty, L. T. Niklason, and L. A. Jameson-Meehan, “Breast tomosynthesis using on-board images,” Med. Phys. 35, 2162–2169 ͑2008͒. mosynthesis: One view or two?,” in RSNA 92nd Scientific Assembly, 65G. Pang, A. Bani-Hashemi, P. Au, P. F. O’Brien, J. A. Rowlands, G. Chicago, IL, 2006 ͑unpublished͒. Morton, T. Lim, P. Cheung, and A. Loblaw, “Megavoltage cone beam 53R. M. Nishikawa, I. Reiser, and P. Seifi, “A new approach to digital breast digital tomosynthesis ͑MV-CBDT͒ for image-guided radiotherapy: A tomosynthesis for breast cancer screening,” Proc. SPIE 6510, 3C1–3C8 clinical investigational system,” Phys. Med. Biol. 53, 999–1013 ͑2008͒. ͑2007͒. 66M. Descovich, O. Morin, J. F. Aubry, M. Aubin, J. Chen, A. Bani- 54G. Yang, R. Rajaram, G. Cao, S. Sultana, Z. Liu, D. Lalush, J. Lu, and O. Hashemi, and J. Pouliot, “Characteristics of megavoltage cone-beam digi- Zhou, “Stationary digital breast tomosynthesis system with a multi-beam tal tomosynthesis,” Med. Phys. 35, 1310–1316 ͑2008͒. field emission x-ray source array,” Proc. SPIE 6913, 1A1–1A10 ͑2008͒. 67I. B. Tutar, R. Managuli, V. Shamdasani, P. S. Cho, S. D. Pathak, and Y. 55S. C. Chen, A.-K. Carton, M. Albert, E. F. Conant, M. D. Schnall, and A. Kim, “Tomosynthesis-based localization of radioactive seeds in prostate D. A. Maidment, “Initial clinical experience with contrast-enhanced digi- brachytherapy,” Med. Phys. 30, 3135–3142 ͑2003͒. tal breast tomosynthesis,” Acad. Radiol. 14, 229–238 ͑2007͒. 68M. J. Flynn, R. McGee, and J. Blechinger, “Spatial resolution of x-ray 56A. Karellas, J. Y. Lo, and C. G. Orton, “Cone beam x-ray CT will be tomosynthesis in relation to computed tomography for coronal/sagittal superior to digital x-ray tomosynthesis in imaging the breast and delin- images of the knee,” Proc. SPIE 6510, 0D1–0D9 ͑2007͒. eating cancer,” Med. Phys. 35, 409–411 ͑2008͒. 69F. H. Fahey, R. L. Webber, F. S.-K. Chew, and B. A. Dickerson, “Appli- 57The International Early Lung Cancer Action Program Investigators, “Sur- cation of TACT® to the evaluation of total joint arthroplasty,” Med. Phys. vival of patients with stage I lung cancer detected on CT screening,” N. 30, 454–460 ͑2003͒. Engl. J. Med. 355, 1763–1771 ͑2006͒. 70J. Duryea, J. T. Dobbins III, and J. A. Lynch, “Digital tomosynthesis of 58P. B. Bach, J. R. Jett, U. Pastorino, M. S. Tockman, S. J. Swensen, and C. hand joints for arthritis assessment,” Med. Phys. 30, 325–333 ͑2003͒. B. Begg, “Computed tomography screening and lung cancer outcomes,” 71S. Li and H. Jiang, “A practical method for three-dimensional reconstruc- JAMA, J. Am. Med. Assoc. 297, 953–961 ͑2007͒. tion of joints using a C-arm system and shift-and-add algorithm,” Med. 59D. R. Aberle, C. Chiles, C. Gatsonis, B. J. Hillman, C. D. Johnson, B. L. Phys. 32, 1491–1499 ͑2005͒. McClennan, D. G. Mitchell, E. D. Pisano, M. D. Schnall, and A. G. 72G. Bachar, J. H. Siewerdsen, M. J. Daly, D. A. Jaffray, and J. C. Irish, Sorensen, “Imaging and cancer: Research strategy of the American Col- “Image quality and localization accuracy in C-arm tomosynthesis-guided lege of Radiology Imaging Network,” Radiology 235, 741–751 ͑2005͒. head and neck surgery,” Med. Phys. 34, 4664–4677 ͑2007͒. 60D. J. Godfrey, L. Ren, H. Yan, Q. J. Wu, S. Yoo, M. Oldham, and F.-F. 73H. P. Chan, J. Wei, B. Sahiner, E. A. Rafferty, T. Wu, M. A. Roubidoux, Yin, “Evaluation of three types of reference image data for external beam R. H. Moore, D. B. Kopans, L. M. Hadjiiski, and M. A. Helvie, radiotherapy target localization using digital tomosynthesis ͑DTS͒,” Med. “Computer-aided detection system for breast masses on digital tomosyn- Phys. 34, 3374–3384 ͑2007͒. thesis mammograms: Preliminary experience,” Radiology 237, 1075– 61Q. J. Wu, D. J. Godfrey, Z. Wang, J. Zhang, S. Zhou, S. Yoo, D. M. 1080 ͑2005͒. Brizel, and F.-F. Yin, “On-board patient positioning for head-and-neck 74H. MacMahon, J. H. M. Austin, G. Gamsu, C. J. Herold, J. R. Jett, D. P. IMRT: Comparing digital tomosynthesis to kilovoltage radiography and Naidich, E. F. Patz, Jr., and S. J. Swensen, “Guidelines for management of cone-beam computed tomography,” Int. J. Radiat. Oncol., Biol., Phys. 69, small pulmonary nodules detected on CT scans: A statement from the 598–606 ͑2007͒. Fleischner Society,” Radiology 237, 395–400 ͑2005͒.

Medical Physics, Vol. 36, No. 6, June 2009 The evolution of brachytherapy treatment planning ͒ Mark J. Rivarda Department of Radiation Oncology, Tufts University School of Medicine, Boston, Massachusetts 02111 Jack L. M. Venselaar Department of Medical Physics, Instituut Verbeeten, P.O. Box 90120, 5000 LA Tilburg, The Netherlands Luc Beaulieu Département de Radio-Oncologie et Centre de Recherche en Cancérologie de l’Université Laval, Centre Hospitalier Universitaire de Québec, 11 Côte du Palais, Québec, Québec G1R 2J6, Canada and Département de Physique, de Génie Physique et d’Optique, Université Laval, Québec, Québec G1K 7P4, Canada ͑Received 2 February 2009; revised 5 April 2009; accepted for publication 6 April 2009; published 8 May 2009͒ Brachytherapy is a mature treatment modality that has beneﬁted from technological advances. Treatment planning has advanced from simple lookup tables to complex, computer-based dose- calculation algorithms. The current approach is based on the AAPM TG-43 formalism with recent advances in acquiring single-source dose distributions. However, this formalism has clinically relevant limitations for calculating patient dose. Dose-calculation algorithms are being developed based on Monte Carlo methods, collapsed cone, and solving the linear Boltzmann transport equation. In addition to improved dose-calculation tools, planning systems and brachytherapy treatment planning will account for material heterogeneities, scatter conditions, radiobiology, and image guidance. The AAPM, ESTRO, and other professional societies are working to coordinate clinical integration of these advancements. This Vision 20/20 article provides insight into these endeavors. © 2009 American Association of Physicists in Medicine. ͓DOI: 10.1118/1.3125136͔

Key words: brachytherapy, treatment planning

I. HISTORY OF BRACHYTHERAPY DOSIMETRY lished after World War I in medical institutes such as the Radium Hemmet in Stockholm, the Memorial Hospital in Many of our technological discoveries are distinctly marked New York, and the Radium Institute in Paris. Arrangement of in history. Independent of each other, two of these discover- the radioactive sources in certain geometric patterns, with ies launched the start of the radiation oncology era. Wilhelm definitions of the strength, distance, and treatment time, de- Röentgen discovered x rays in November 1895, and shortly veloped into a set of rules for patient treatments. For intrac- afterward, Henri Becquerel accidentally exposed a photo- avitary treatments, the Stockholm and Paris methods were graphic plate to uranium in 1896, identifying the phenomenon of emitted radiation.1 The work of Pierre and Marie described in 1914 and 1919, respectively. Paterson and Curie in 1898 was needed to extract radium from pitchblende Parker set the basis of the 1930 rules for the Manchester system,7 which was extensively described in a book by ore to determine the origin of this penetrating radiation. Very 8 soon after these first steps, new pathways were explored to Meredith. apply these radiations in the first treatments of patients. Bec- Two other steps are important to date the development of querel himself experienced the effects of radiation exposure brachytherapy. First, the discovery of artificial radioactivity by carrying a tube containing decigrams of radium chloride in 1934, allowing the use of manufactured radioactive mate- in his vest pocket. He recorded the progression of his skin rials in radiotherapy. Second, in the 50’s and 60’s of the 20th reaction.2 The first medical experiences belong to Danlos and Century, the development of remote afterloading devices al- Bloch3 in 1901 of Paris and Abbé4 in 1904 of New York. The lowed improved personnel radiation protection and gave Radium Biological Laboratory was created in Paris in 1906, more flexibility to the applications. New radionuclides like 60 137 182 198 and Finze in London started treatments with radium in 1909. Co, Cs, Ta, and Au were applied with designs ini- 226 9 A book on radium therapy, which is now known as brachy- tially similar to Ra sources. Henschke was the first to 192 therapy, was published in 1909 by Wickham and Degrais.5 explore the use of Ir. This radionuclide is currently the These early 20th century achievements established the medi- most widely applied radioactive source in the field of brachy- cal application of radiation within one decade of its discov- therapy. The rules for interstitial therapy using low-dose rate ery. The first investigators were by necessity led by clinical ͑LDR͒ 192Ir wire sources, which could be applied in various observations and developed from their experiences the rules lengths and strengths, were developed in a very precise and to avoid errors in clinical applications. In medical science, consistent manner in Paris.10,11 Hollow tubes, in the form of such processes soon lead to systems or schools. For brachy- either needles or plastic catheters, were surgically implanted, therapy, 226Ra was the only radionuclide for these systems.6 equidistant and parallel, to allow placement of radioactive The basic principles of its use in brachytherapy were estab- wires or seed ribbons with an afterloading procedure. Using

2136 Med. Phys. 36 „6…, June 2009 0094-2405/2009/36„6…/2136/18/$25.00 © 2009 Am. Assoc. Phys. Med. 2136 2137 Rivard, Venselaar, and Beaulieu: The evolution of brachytherapy treatment planning 2137 conventional x-ray and dummy sources, imaging for implant nal x rays, and ͑ii͒ summation of dose patterns of the indi- localization was possible to completely eliminate operating vidually reconstructed sources. The conventional systems room staff exposure. were applicator based, not anatomy based. They did not uti- The first afterloaders were developed simply to minimize lize the anatomical information, so the relation between dose exposure from the radioactive sources. Using a cable attach- deposition and the tumor volume as well as the volume of ment, they just pushed the sources mechanically into the pre- healthy tissue and organs at risk ͑OARs͒ was underdevel- inserted applicators.12,13 Only later its function changed to- oped. Implementation of modern resources with accurate cal- ward multiple-programmable source trains and, eventually, culation techniques and imaging procedures allows us to in- to miniature stepping source technology. High-activity crease the efficacy of brachytherapy in terms of clinical sources, for high-dose rate ͑HDR͒ and pulsed dose rate outcome by demonstrating whether or not a chosen isodose ͑PDR͒ applications with the latter type mostly used in Eu- covers the clinical target volume ͑CTV͒ and spares OARs. rope, have largely replaced the use of LDR afterloading—the Patient-specific treatment planning is presently considered exception is permanent implant technology for LDR prostate useful in our treatments and is essential for achieving the brachytherapy. Miniaturized 192Ir sources with a typical outer treatment planning standards of modern radiation oncology diameter of 1 mm replaced the 137Cs tube and pellet appli- in more complicated cases. cations. Optimization, modulating the dose distribution by varying the dwell times, has become a standard feature in I.B. Prescription dose brachytherapy systems, providing the user of the afterloader with greater flexibility. Further development and history of Historically, brachytherapy prescriptions were stated in brachytherapy technology and medical physics practice dur- terms of exposure and exposure rate. In intracavitary gyne- ing the past 50 years, covering the period in which the re- cologic brachytherapy, the use of mg h radium or radium- motely controlled afterloaders were introduced and refined, equivalent dosimetry was the standard for decades. Intersti- has been described in a review article by Williamson in tial brachytherapy was often performed using the rules of the Physics in Medicine and Biology.14 Ibbott et al.15 described Quimby or Manchester implant systems.17,18 These systems 50 years of AAPM involvement in radiation dosimetry, in- specified the geometric arrangement of radium needles and cluding dosimetric issues in brachytherapy, in Medical Phys- their radioactive contents relative to the target volume. The ics. Issues and trends in brachytherapy physics were further basis for a treatment time calculation was the implanted area discussed in the Medical Physics Anniversary Paper by Tho- or volume to obtain exposure or mg h estimates from dose- madsen et al.16 In this invited Vision 20/20 article, we focus specification criteria for the idealized needle arrangements on the current trends and challenges in brachytherapy, spe- described by the system. Reconstructions of the real implant cifically on the medical physics practice of brachytherapy were made from planar x-ray images. This method could treatment planning and the research activities for advance- reconstruct the needles, but fundamentally had limitations ment. recognizing the clinical target. Using manual tools, such as the tables and nomograms published for these systems, the I.A. Brachytherapy dosimetry systems reference dose rate was estimated and the treatment time calculated. Real implants frequently deviated significantly The term dosimetry can have a very narrow interpretation from the idealized source arrangements used as examples for but may just as well have a much broader meaning. It may the system rules.18 Nevertheless, the dose calculation itself ͑ refer only to the measurements in a radiation field of radio- was generally accurate as demonstrated in comparisons with ͒ active sources or of radiation beams , it may refer to the published data tables. For example, see the work of Shalek methodology for calculation of a dose or dose rate value at a and Stovall who reviewed the calculation models for 226Ra specific point in a given medium, or it may also reflect the tubes and needles.19 full chain from imaging and reconstruction to dose delivery For 192Ir wire interstitial implants with continuously and then also includes the prescription of dose. In this article, loaded and parallel placed sources, the Paris system was de- dosimetry is used mainly in the context of the calculation scribed in conjunction with an escargot ͑snail͒ diagram ͑Fig. process. A dosimetry system essentially consists of three 1͒ to ease the calculation process.11,20 Such a diagram con- parts: tains information on a variety of dose rates for a standardized ͑i͒ a set of rules to distribute the sources inside a defined linear source strength of 1 mCi/cm for a series of source volume to achieve a clinically acceptable dose distri- lengths. Using such a diagram, one can derive the contribu- bution, tion of dose to a point in terms of dose rates from each ͑ii͒ a method to calculate patient dose, and individual source. Basal dose points are used in the Paris ͑iii͒ a system for dose prescription. system and are found as the points at the center of gravity between the neighboring sources at the central plane of the These steps were already acknowledged and defined in an implant. By adding the contributions and successively re- era when computers were not available and imaging tools peating the procedure for each basal dose point, the basal were not integrated into brachytherapy procedures. A stan- dose or the average dose in all basal dose points can be dard system relies essentially on two steps: ͑i͒ implant source found. The reference prescription isodose line/surface is then reconstruction, originally and for decades based on orthogo- taken as 85% of the basal dose in this system, assuming to

Medical Physics, Vol. 36, No. 6, June 2009 2138 Rivard, Venselaar, and Beaulieu: The evolution of brachytherapy treatment planning 2138

FIG. 2. Coordinate system for the AAPM TG-43 brachytherapy source dosimetry formalism from Rivard et al. ͑Ref. 24͒.

tion such as bone and lung. Then, these values must be taken from textbooks or other resources where it is easy to find great ͑ϳ25%͒ disparities in the tabulated values.21 This is apparent when trying, for example, to list ⌫ values from the literature for a radionuclide with a complex photon spectrum such as 192Ir. These flaws may lead to errors, for example, when the effective activity is measured from dose rate in air by the vendor while the user of a given calculation system has included a different ⌫ value. The fact that this concern FIG. 1. The escargot diagram in the Paris system is a tool for manual calculation of the dose rate at points at distances in the plane transversal to is not imaginary but very real is demonstrated in the IAEA the source. The curves represent the dose rate in cGy h−1 for sources of 1 survey on misadministrations in medical radiation ap- up to 7 cm length and a linear strength of 1 mR h−1 m2 cm−1 plications, often occurring in coordination with a lack of ͑8.7 ␮Gy h−1 m2 cm−1͒. From Dutreix et al. ͑Ref. 20͒. training and supervision of the personnel involved in the procedures.22 ⌫ ͑ ͒ cover the planned target volume ͑PTV͒. As with the older As the quantities for A, , and Fm in Eq. 1 are not in Quimby and Manchester rules, the methods were manual and accordance with the SI system, and therefore considered ob- ͑ ͒ based on tabulated or nomogram-derived datasets. solete, Eq. 1 needs to be rephrased for the dose rate to ˙ ͑ ͒ water DW r . A very detailed step-by-step description is I.C. Classical form of calculation algorithm given in the recent book by Baltas et al.23 resulting in Eqs. for point sources ͑2͒ and ͑3͒, Classically, the dose rate for a source is derived from its ␮ W r 2 ˙ ͑ ͒ ˙ ͑ ͒ͩ enͪ ͩ 0 ͪ ͑ ͒ ͑ ͒ DW r = KR 1−g␣ fas,W r , 2 contents, i.e., the amount of radioactivity contained within ␳ ␣ r the source. The activity was first expressed as the weight of 226 the contents, for Ra in mg. With the unit Ci defined as the ␮ W 1 2 226 ˙ ͑ ͒ ͑ ͒ͩ enͪ ͩ ͪ ͑ ͒ ͑ ͒ activity of 1 g of Ra, an important step was made. The DW r = SK 1−g␣ fas,W r . 3 ␳ ␣ r dose rate in Gy/h at distance r from a point source was de- ˙ scribed as The reference air-kerma rate KR and air-kerma strength SK ⌫ ͑ ͒ are mutually related through the inverse-square law to the A · · fas,W r · Fm D˙ ͑r͒ = , ͑1͒ ˙ ͑ / ͒2 W r2 reference distance r0 as KR =SK 1 r0 . g␣ is the fraction of electron energy liberated by photons in air that is lost due to in which A is the effective activity in Ci, deduced from dose radiative processes such as bremsstrahlung and fluorescence. ⌫ ͑␮ /␳͒W rate measurements in air, is the exposure rate per Ci of the The term en ␣ is the ratio of the mass-energy absorption ͑ ͒ radionuclide in R/h at 1 m, fas,W r is the correction for ab- coefficient of water to that of air. sorption and scatter effects of the photons at distance r in water when compared to the same point in vacuo, and F is m I.D. Calculations with encapsulated and elongated the medium conversion factor from R to Gy. sources Inspection of this equation reveals a number of flaws and possibilities for errors. First, there is the confusion between A real source such as the one depicted in Fig. 2 has finite the real and the effective, assumed, or apparent activity. Sec- dimensions compared to an idealized point source. The most ond, we have, at least quantitatively, a poorly defined me- common shape of a brachytherapy source is the cylinder. The dium that is related to the value of the Fm factor. It differs for design of the source, its shape, and the choice of the active water, tissue, and materials with strongly deviating composi- material influence the resulting dose distribution. Brems-

Medical Physics, Vol. 36, No. 6, June 2009 2139 Rivard, Venselaar, and Beaulieu: The evolution of brachytherapy treatment planning 2139

strahlung photons generated in the capsule by beta particles Either the 1D or 2D equation used to calculate dose rate may contribute to the dose, and the capsule may filter the are used in modern TPS, as shown in Eqs. ͑4͒ and ͑5͒, re- radiation emitted by the bare source material. The photon spectively, with dosimetry parameters defined below, energy spectrum of a realistic source can therefore deviate r 2 ˙ ͑ ͒ ⌳ ͩ 0 ͪ ͑ ͒ ␾ ͑ ͒ ͑ ͒ substantially from that of a bare source, with especially sig- D r = SK · · · gP r · an r , 4 nificant deviations along the source long axis. The calcula- r tion process according to the Sievert-integration procedure G ͑r,␪͒ considers the dose at a point near the source as the summa- D˙ ͑r,␪͒ = S · ⌳ · L · g ͑r͒ · F͑r,␪͒. ͑5͒ K ͑ ␪ ͒ L tion of point-source contributions. An elongated source is GL r0, 0 then divided into a series of infinitesimal source elements. ͑ ͒ ͑ ͒ Identical to Eqs. 2 and 3 , SK is the air-kerma strength of The path-length attenuation through the source and the cap- the brachytherapy source and is determined for specific sule wall using the effective-attenuation coefficients for the sources either by the clinical medical physicist or provided small source elements takes into account most of the 34 2 −1 25 137 by the manufacturer. SK has units U=cGy cm h and its effects. This method is accurate to within 2%–8% for Cs measured value should be traceable to a primary standards sources but is less accurate at low- and intermediate-photon dosimetry laboratory ͑PSDL͒ like the National Institute of ͑ ͒ 26 energies e.g., less than 0.4 MeV . The evolution of dose- Standards and Technology ͑NIST͒.35 The dose rate constant calculation methods has been discussed and reviewed else- −1 −1 27,28 ⌳ has units of cGy h U such that ⌳=D˙ ͑r ,␪ ͒/S since where for 137Cs and low-energy photon-emitting sources. 0 0 K the other dosimetry parameters from Eq. ͑5͒ take values of Computer algorithms have previously been based on the unity at P͑r ,␪ ͒. Dose rate variations in the source trans- use of tabulated data in Cartesian or polar coordinates, or 0 0 verse plane are accounted for by the geometry function made use of directly calculated data from the Sievert- and radial dose function. The geometry function takes the integration procedure. Both the manual and the classical ap- simple form of point-source or inverse-square approximation proaches in dose-calculation algorithms used in computer- ͑r /r͒2 for the 1D formalism as is most commonly used in ized systems are rather simplistic. Generally, the influence of 0 brachytherapy TPS for LDR low-energy photon-emitting tissue heterogeneity, organ or body outline, or applicator het- 125 erogeneity is ignored, excluding an occasional one- brachytherapy using sources such as I. However, the dimensional ͑1D͒ correction to the total dose to account for a 2D formalism approximates the distribution of radiation 29 L predefined ovoid shield. Interseed attenuation ͑ISA͒ or in- emissions as a line-segment with length and is most com- terapplicator shielding is not addressed. Other effects are dif- monly used for HDR high-energy photon-emitting brachy- 192 ͑ ␪͒ ␤/ ͑␪͒ therapy sources such as Ir. Here, GL r, = L·r sin . ficult to quantify since they depend on many patient-specific ͑ ͒ circumstances. These effects will be discussed in Sec. III. The point-source radial dose function gP r ˙ ͑ ͒/ ˙ ͑ ͒ ͑ / ͒2 =D r D r0 · r r0 , whereas the line-source radial dose ͑ ͒ ˙ ͑ ␪ ͒/ ˙ ͑ ␪ ͒ ͑ ␪ ͒/ ͑ ␪ ͒ function gL r =D r, 0 D r0 , 0 ·GL r0 , 0 GL r, 0 . For II. CURRENT STATUS OF BRACHYTHERAPY calculating dose rate off the transverse-plane where dose an- TREATMENT PLANNING isotropy from brachytherapy sources comes into play, the 1D ␾ ͑ ͒ ͑ ␪͒ As of 2009, the current approach for brachytherapy dose anisotropy function an r or 2D anisotropy function F r, calculation is based on the AAPM TG-43 dosimetry is used. All these dosimetry parameters are explained in great formalism,24,30 which relies on superposition of single-source detail in the 2004 AAPM TG-43U1 report,24 along with re- dose distributions obtained in a liquid water phantom with a porting criteria and good practice recommendations for do- fixed volume for radiation scattering. This approach was de- simetry investigators obtaining these parameters using mea- veloped through computerized treatment planning systems surements and/or Monte Carlo ͑MC͒ methods. ͑TPSs͒ to replace the antiquated approaches such as the Manchester and Paris systems.31–33 II.B. Dosimetry parameter datasets Often there are several dosimetry publications on a given II.A. Dosimetry formalism brachytherapy source model, and thus there is potential for Based on the assumption of cylindrically symmetric variable administration of dose with clinically relevant rami- brachytherapy source dose distributions, the TG-43 brachy- fications. To subjugate this problem, the AAPM prepares therapy dosimetry formalism utilizes a polar coordinate sys- consensus dosimetry datasets for use in brachytherapy TPS. tem along the source long axis ͑z axis͒ with the coordinate As of 2009, 16 consensus datasets for LDR 125I and 103Pd system origin located at the center of radioactivity, as shown sources have been issued by the AAPM TG-43U1 and TG- in Fig. 2. Dose distributions at point P͑r,␪͒ are obtained in 43U1S1 reports.24,36 These datasets are incorporated by TPS the vicinity of the source with radial distance r and polar software vendors as machine data, analogous to external angle ␪ expressed relative to the origin and source long axis, beam treatment planning data, and are also used in practice ͑ ␪ ͒ respectively. A special reference point P r0 , 0 is positioned for treatment planning of patients on cooperative group clini- ␪ at r0 =1 cm and 0 =90° on the transverse plane of the cal trials. Incorrect application of data could cause variability ␤ ␪ ␪ source. For Fig. 2, = 2 − 1, and t is the capsule thickness in clinical practice and unnecessary variations in adminis- in the transverse-plane direction. tered dose or even serious dose-calculation errors. A brief

Medical Physics, Vol. 36, No. 6, June 2009 2140 Rivard, Venselaar, and Beaulieu: The evolution of brachytherapy treatment planning 2140 description is provided of the main publicly accessible archives or databases of dosimetry datasets to provide guidance on dosimetry parameter choice. Toward providing guidance on dataset choice, recommendations to medical physicists by Rivard et al.37 are presented below: ͑a͒ AAPM-recommended consensus data from the TG- 43U1 and TG-43U1S1 reports;24,36 ͑b͒ data from the joint AAPM/Radiological Physics Center ͑RPC͒ Source Registry using data in the original publications to check for agreement; and ͑c͒ if a given source model is not posted on the joint AAPM/RPC Source Registry, this suggests that it may not have met even the most basic dosimetric practice standards. The burden then falls upon the user to perform an analysis to ensure that seed calibrations are FIG. 3. Effect of phantom medium on absorbed dose and attenuation at r=1 cm as a function of photon energy. NIST traceable with an acceptable level of accuracy and that available published and unpublished dosimetry data exhibit an acceptable level of rigor and redun- III.A.1. Differences between absorbed dose in dancy to safely treat patients. Early adopters of a new water and tissue seed product should consider closely working with the vendor, the vendor’s dosimetry consultant, and the Under charged-particle equilibrium, the mass-energy ab- treatment planning software vendor to ensure that the sorption coefﬁcient as a function of photon energy E and ͑␮ /␳͒ conditions outlined in the relevant AAPM recommen- atomic number Z, notated as en E,Z, may be used to ac- dations are met.24,38,39 Coordinated action by the medi- count for differences in absorbed dose between water and ͑␮ /␳͒ ͑␮ /␳͒ tissue as Dtissue en E,tissue=Dwater en E,water. Using the cal community using a particular source model, rather 40 than isolated and possibly inconsistent individual soft tissue characterization from ICRU 44, with water and tissue mass densities of 1.00 and 1.06 g/cm3, Fig. 3 presents analyses, are preferred to maximize uniformity of do- water simetric practice. For a product with a track record of the ratio of absorbed dose in water to tissue Dtissue as a func- use for which the vendor has not successfully submit- tion of photon energy. Over the range of photon energies ted an AAPM/RPC Registry application ͑e.g., a source examined, 0.01–10 MeV, the absorbed dose in tissue is widely used in Europe but new to North America͒, nearly equal to that in liquid water as shown by the solid clinical users should consider following GEC-ESTRO curve. This ratio dips to 0.96 near 0.05 MeV due to slightly higher photoelectric effect cross sections of tissue compared recommendations. If available, datasets on the ESTRO 41,42 or Carleton University websites may be useful. to water.

In all instances the medical physicist should document the III.A.2. Differences between radiation attenuation source of the brachytherapy dosimetry parameter data and in water and tissue provide rationale for why a given dataset and/or website Similarly, the mass-attenuation coefﬁcient as a function of tabulation was chosen. ͑␮/␳͒ photon energy and atomic number E,Z may approximate differences in radiation attenuation between water and tissue −␳Z·͑␮ / ␳͒E,Z·t −␮E,Z·t 43 III. DOSIMETRY FORMALISM LIMITATIONS I=I0e or I=I0e . Again using the water and tissue mass densities, but with a simple path length approach While dataset standardization is a key element for acqui- using t=1 cm, the ratio of radiation attenuation between the sition of high-quality clinical results, especially from clinical ␮ ␮ two media ͑I/I ͒ /͑I/I ͒ =e− E,water·1 cm/e− E,tissue·1 cm trials, dosimetry parameter datasets used in the AAPM 0 water 0 tissue is presented in Fig. 3 as the dashed curve. Unlike the ab- TG-43 dosimetry formalism are obtained in a liquid water sorbed dose ratios, the larger mass density of tissue contrib- phantom with a ﬁxed volume for radiation scattering. Con- utes to the increased attenuation. Further, increased attenua- sequently, the formalism does not readily account for several tion by tissue below 0.05 MeV is caused by the larger important aspects that undermine clinical application of the photoelectric effect cross section of tissue compared to wa- TG-43 formalism with these datasets. ter.

III.A. Dosimetric circumstances highlighting III.A.3. Source shielding or applicator radiation formalism limitations interactions Due to the simplicity of brachytherapy dosimetry in com- For multisource clinical applications, ISA may be signiﬁ- parison to external beam dosimetry, a basic understanding of cant. Applicator:radiation interactions and applicator shield- radiological physics interactions can generally explain ﬁve ing may detract from the accuracy of conventional TG-43 limitations of the AAPM TG-43 dosimetry formalism. based dose calculations.44 For radiation shielding between

Medical Physics, Vol. 36, No. 6, June 2009 2141 Rivard, Venselaar, and Beaulieu: The evolution of brachytherapy treatment planning 2141

192 FIG. 5. Comparison of Ir g͑r͒ values calculated for a given spherical FIG. 4. Photon transmission ratios through water or high-Z attenuators as a function of photon energy. The Ag K edge ͑0.02 551 MeV͒ is indicated in water phantom radius R compared to R=50 cm, which is assumed to pro- the dashed curve. vide full scatter conditions. Data include curves for R=5, 10, 15, 20, 25, 30, 35, 40, and 45 cm. Reproduced from Fig. 1͑c͒ of Ref. 43 with permission from C. S. Melhus and M. J. Rivard, Med. Phys. 33, 1729 ͑2006͒. Copyright 2006, American Association of Physicists in Medicine. sources or by an applicator, the attenuation of water is replaced with a high-Z material. For LDR low-energy photon- emitting sources, this high-Z material may for example be a disequilibrium in homogeneous media due to brachytherapy silver ͑Z=47͒ radio-opaque marker used for identification inverse-square increases in photon fluence upon moving to- during postimplant CT localization. For HDR high-energy ward a brachytherapy source. Concern for dose:kerma photon-emitting sources, the material may be a stainless steel equivalence is not commonly observed in brachytherapy ͑ ͒ ␳ / 3 ␳ / applicator Z=26 . Using Ag=10.5 g cm and Fe=7.8 g measurements or MC calculations of conventional high- cm3 with a minimal thicknesses of 0.1 mm and negligible energy sources since the required distance is ϳ5 mm for water attenuation, the high-Z photon attenuations are given greater than a 5% effect.54 For LDR 137Cs sources, this dis- in Fig. 4. As in the prior two examples, the photoelectric tance is adjacent to the source capsule. For HDR 192Ir or effect is largely responsible for the differences in comparison 60Co sources, dose/kerma of Ն1.05 occurs at distances be- to water. low 2 and 7 mm from the source center, respectively. Break- down of CPE can also occur at material boundaries such as III.A.4. Differences between radiation scattering for tissue:high-Z interfaces. Another aspect of electrons in dataset acquisition and patient treatment brachytherapy dosimetry ignored with current TPS is the dose contribution from betas emitted upon radionuclide The effect of phantom dimensions and volume in MC disintegration.55 dosimetry has been reported in literature as early as 1991.43,45–49 For high-energy photon-emitting brachytherapy sources such as 192Ir, dose differences greater than 5% are possible within 10 cm of the source, as shown in Fig. 5. However, studying varying phantom dimensions quantifies only the effect of excess material or missing backscatter close to the phantom boundary as source position is fixed and phantom radius decreases. Therefore, as argued and shown in Pantelis et al.50 and later by Lymperopoulou et al.,51 “corresponding findings cannot be readily translated to the effect expected in actual clinical practice where a source dwell position is programmed close to the patient contour as scattering conditions are altered in total, including lateral scatter.” Further, the proportion of dose due to primary and scattered radiation significantly changes as a function of distance from the source, as shown in Fig. 6, which is also for 192Ir.52

III.A.5. Dose, kerma, and electrons 192 Subtleties associated with dose calculation include the as- FIG. 6. Components of Ir dose as a function of radial distance. Repro- duced with permission from R. E. Taylor and D. W. Rogers, Med. Phys. 35, sumption of equivalence of absorbed dose and kerma. 4933 ͑2008͒. Copyright 2008, American Association of Physicists in 53 Roesch ﬁrst considered the possibility for charged-particle Medicine.

Medical Physics, Vol. 36, No. 6, June 2009 2142 Rivard, Venselaar, and Beaulieu: The evolution of brachytherapy treatment planning 2142

TABLE I. Sensitivity of commonly treated anatomic sites to dosimetric limitations of the current brachytherapy dose calculation formalism. Items ﬂagged as “Y” indicate the authors opinion that signiﬁcant differences between administered and delivered dose are possible due to the highlighted dosimetric limitation.

Anatomic site Source energy Absorbed dose Attenuation Shielding Scattering Beta/kerma dose

Prostate High N N N N N Low Y Y Y N N Breast High N N N Y N Low Y Y Y N N GYN High N N Y N N Low Y Y N N N Skin High N N Y Y N Low Y N Y Y N Lung High N N N Y Y Low Y Y N Y N Penis High N N N Y N Low Y N N Y N Eye High N N Y Y Y Low Y Y Y Y N

III.A.6. Summary of dosimetric concerns translated throughout the implanted plastic catheters and thus Absorbed dose in water is about Ϫ4% and +2% compared none of the other effects are prominent. For low-energy to tissue for low- and high-energy photons, respectively. Per photon-emitting sources in the prostate, the D90 is generally centimeter, the attenuation of high-energy photons is about within 1 cm of the gland and water:tissue attenuation differ- the same between water and tissue. However, there are sig- ences are minimal. However, absorbed dose can differ by nificant differences in attenuation for low-energy photons, several percent, and ISA can exceed 10% along the needle increasing as photon energy decreases. The presence of direction. LDR prostate implants typically utilize the largest high-Z materials can substantially alter dose distributions for number of implanted sources among all anatomic sites, and low-energy photons. Dose differences of Ͼ5% are possible may be subject to dosimetric effects of calcifications.61 for high-energy sources within 5 cm of the skin. Equivalence Breast implants using HDR 192Ir share similar circumstances of dose and kerma within 5% does not hold true within a few as HDR 192Ir prostate implants. However, the radiation scat- millimeters of high-energy photon-emitting sources. Dosim- tering conditions differ and generally overestimate dose etric contributions from beta emissions at these distances are deposition in clinical implants—especially near the skin sur- also ignored in the current TG-43 formalism. face. For breast implants using low-energy photon emitting sources such as LDR 103Pd or the Xoft Axxent 50 kVp III.B. Clinical circumstances highlighting formalism source, scattering differences are negligible between the limitations treatment plan using superposition of source locations in liq- In addition to dosimetric limitations, there are limitations uid water and the clinical environment. However, absorbed to applying the AAPM TG-43 dosimetry formalism to certain dose in breast at these energies is generally underestimated clinical circumstances. For instance, the formalism does not by several percent, source-to-source shielding can be signifi- 103 readily permit calculation of dose distributions for curved cant for Pd sources, and differences between prescribed brachytherapy sources such as LDR 192Ir wire. This is also and administered doses can also be significant due to differ- ˙ ͑ Ͻ / ␪ ͒ ences in radiation attenuation between water and tissue— true for long sources where D r L 2, 0 is needed, but is challenging to implement on TPS with the 2D formalism especially at large distances. Gynecological implants often since high F͑r,␪͒ gradients near the source long axis require use high-Z colpostats for shielding the bladder and rectum— high-resolution dosimetry parameters. Beyond these TPS particularly for treating the uterus. For treating the vagina/ limitations, the scope of anatomic sites commonly consid- cuff, treatment through a plastic applicator is de rigueur and ered for application of brachytherapy are practically subject contributes to differences in radiation attenuation. Absorbed to the limitations of the AAPM TG-43 dosimetry formalism dose is underestimated by several percent for low-energy as described in the previous dosimetric section. A breakdown sources. However, radiation scattering is not of concern due is presented in Table I of the relative sensitivity of these to the deep-seated position within the body. Brachytherapy anatomic sites to the five dosimetric limitations. of the skin is most sensitive to scattering conditions. Use of In our opinion, Table I highlights the sensitivity of each bolus material will provide better agreement between anatomic site to the aforementioned dosimetric limitations. planned dose and delivered dose, but skin dose outside the Prostate implants using high-energy sources such as HDR treatment field can be minimized without bolus. Further, 192Ir are deep seated and not as sensitive to radiation scatter- most high- and low-energy brachytherapy treatments of the ing conditions as are other sites. Further, a single source is skin use some form of shielding to protect the unintended

Medical Physics, Vol. 36, No. 6, June 2009 2143 Rivard, Venselaar, and Beaulieu: The evolution of brachytherapy treatment planning 2143 tissues, and conventional TPS cannot account for this shield- the collapsed cone ͑CC͒,79,80 and attempts to directly solve ing. Again, absorbed dose is underestimated by several per- the transport equation via discrete ordinates ͑DO͒ using cent for low-energy brachytherapy sources. Lung implants Attila/Acuros™ are underway.81,82 We also refer the readers typically include tissues with mass densities three to four to reviews on this subject.83,84 times less than conventional tissues. Consequently, scattering conditions for both high- and low-energy brachytherapy IV.B. Analytical models primary/scatter sources are not congruent between the clinical implant and „ … the planned approach. Absorbed dose and attenuation are Separation of primary and scattered photon contributions also significantly different for low-energy sources, and dose to the total dose has been successful in the Compton- calculations close to high-energy sources such as HDR 192Ir dominated conditions of external beam conditions,85,86 ulti- can be in error by several percent within a few millimeters of mately leading to various dose-calculation algorithms such the source. Brachytherapy of the penis is performed using as the pencil beam,87 CC,79 and superposition convolu- either HDR high-energy sources or LDR low-energy sources. tion.88,89 Advantages of CC and superposition-convolution Both applications overestimate administered dose due to ra- implementations are their availability as TPS dose- diation scattering conditions. Further, low-energy sources un- calculation algorithms. Furthermore, they can accurately ac- derestimate dose due to differences in tissue composition be- count for material inhomogeneities in external beam radia- tween water and tissue. Eye plaque brachytherapy has been tion therapy through clinically validated algorithms. conducted for several decades but is sensitive to all of the For convolution methods, the energy deposition is gener- aforementioned dosimetric limitations. ally composed of two terms. The first one describes the in- In summary, it is clear that most applications of brachy- teraction of the primary photons with the medium, specifi- therapy are subject to limitations of the current dose- cally the total energy release per unit mass or terma. The calculation formalism. Thus, it is imperative that advances be second component addresses the details of how the energy made to resolve these discrepancies and provide clinical us- release is deposited at various distances from the interaction ers a realistic depiction of individualized brachytherapy dose site. This is accomplished by energy deposition kernels. Usu- administration. ally, the kernels are separated in two or three components: primary dose, the first-scatter dose, and the multiple-scatter IV. BRACHYTHERAPY TREATMENT PLANNING dose ͑the last two components may be combined into a RESEARCH single kernel͒. When inhomogeneities are present, the kernels can be scaled according to the average mass or electron IV.A. Introduction density, depending on the implementation. It is the superpo- In recent years, advanced dose-calculation methods have sition ͑or convolution͒ of the various kernels, weighted by been considered to perform explorative and retrospective the terma, that generates the dose distribution. clinical studies. These studies identified limitations of the In the CC approach, the kernels are polyenergetic and current protocol for clinical practice. Others have looked at represented by an analytical function of the nonisotropic en- dose comparison in clinical geometries such as a shielded ergy deposition around the primary interaction site in a vaginal cylinder51,57 or shielded rectal applicator.56 In these spherical coordinate system.79 The interaction site is as- cases, the dose differences were dramatic. For seed implants, sumed to be located at the origin of a set of lines, each being ISA was thought to be a negligible effect due to the physical the central axis of a cone. The energy deposited in this cone size of the seed.58 Meigooni et al.59 first showed that the is further described, or collapsed, on the central line. Imple- minimum peripheral dose was decreased by ϳ6% due to mentation for dose calculation along Cartesian coordinate ISA; Mobit and Badragan60 calculated a 10% decrease de- volumes requires the number of cone axes or transport lines pending on the seed configuration. Clinical seed configura- to adequately cover the voxels in the geometry of interest. tions were studied by Chibani et al.61 and Carrier et al.62 A Photon energies are lower in brachytherapy than for ex- decrease of 2%–5% can be expected on the clinical param- ternal beam. As such, the radiation path length is shorter and 63 eter, D90. The decrease was dependent on the radionuclide the contribution of scattered radiation to the dose, at relevant choice,61 seed density,62 and seed design.64 Furthermore, tis- distances, can be of the same order of magnitude as the pri- sue heterogeneity was also shown to be of importance for mary dose.90 Furthermore as photon energy decreases, the 62,65 low-energy seeds, contributing to further decrease in D90. amount of energy released per interaction decreases and mul- This effect was more pronounced for 103Pd than 125I.66 tiscatter quickly becomes the dominant contribution of the However, for 192Ir, tissue heterogeneity was negligible for total scatter component.91 This is illustrated in Fig. 6, which rϽ10 cm,43 covering most of the clinical situations. Finally, shows that for 192Ir, the multiple-scatter component has a eye plaque dosimetric effects were also studied in detail.67,68 higher contribution to the dose than the single scatter at 6 cm While most of these studies were conducted using from the source and constitute the highest contributor to the 69,70 71,72 52 general-purpose MC codes ͑MCNP and GEANT4 ͒ or total dose after 10 cm. For most modern brachytherapy thoroughly tested radiation therapy-specific MC codes ͑e.g., radionuclides with photon energies of 192Ir or less, the sec- 73 74 75,76 EGS4, EGSnrc, PTRAN ͒, new MC codes are being de- ondary electron range is small and kerma well approximates veloped specifically for brachytherapy such as MCPI ͑Ref. 77͒ dose. In this context, the calculation of primary dose can be 78 and BRACHYDOSE. Other avenues are also explored such as performed quickly and with high accuracy. However, accu-

Medical Physics, Vol. 36, No. 6, June 2009 2144 Rivard, Venselaar, and Beaulieu: The evolution of brachytherapy treatment planning 2144 rate calculations of the multiple-scatter components necessi- IV.C. Deterministic solution to the transport equation tate the full 3D geometry, especially in the presence of material inhomogeneities for which the interaction cross Monte Carlo uses stochastic approaches ͑random num- sections can vary greatly. bers͒ to sample the probability density functions describing An early implementation of a convolution method for the phenomena underlying the transport of particles through brachytherapy has been demonstrated by Williamson et al.92 matter for simulations. With sufficient statistics or particle In this approach, the multiple-scatter component is provided histories, MC obtains precise solutions to a variety of prob- by precomputed MC dose spread array. For 125I and 137Cs lems in radiation therapy. Another calculation approach con- point-source dose calculations, the results were shown to be sists of directly solving the linear Boltzmann transport equa- within 3% of the MC calculations with a gain in speed of tion ͑LBTE͒ through deterministic means. Two general factors of 20–50 at that time. In this approach, heterogeneity approaches with application to brachytherapy can be seen in corrections were accounted for by rescaling the dose spread the literature: solving the differential LBTE81,101 or the inte- of the once-scattered photons. Another approach proposed by gral formulation.102 The LBTE is commonly solved by dis- 93 Williamson et al. used a scatter-subtraction method based cretization of the parameters phase space. The most com- on 1D scatter integration. While being about 1000 times monly seen method in scholarly articles is the angular faster than MC, it was limited to water-equivalent heteroge- domain or the use of DO. Discretization is also performed in neities for cylindrical geometries. This method was further ͑ ͒ 94 space finite difference or finite element and in energy with extended to a 2D scatter integration, allowing arbitrary ge- appropriate multigroup cross sections. The system can be ometry. However, its heterogeneity correction was limited by coupled to handle neutral, charged, and coupled photon- analytical correction factors for a wide range of atomic num- 95 electron-positron transport for iterative solutions. The dis- bers and material densities. The latter incarnation was cretization of the space dimension is well suited to problems shown to be 50 000–100 000 times faster than MC while in radiation therapy where voxel-based geometries of pa- maintaining an accuracy of 10% except for low-energy pho- 101 tients are constructed from tomographic images. tons and high-atomic number heterogeneity materials. How- It is generally understood that the accuracy of determin- ever, in this approach multiple scattering is neglected and the istic approaches is directly related to discretization,101,103 heterogeneity geometry was limited to a thin slab. with fine steps leading to accurate solutions at the price of a The application of a CC algorithm in brachytherapy has larger system of equations to be solved. Thus, the technique been pursued for many years by the Helax/Nucletron group is numerically intensive. As noted by Daskalov et al.,101 the in Uppsala, Sweden. With this algorithm, a successive- deterministic concept of accuracy is not the same as for MC scattering superposition method has been developed in which dose calculation and is related to a systematic difference be- the first-scatter dose distribution is used to derive the higher tween the solution and the “truth.” With deterministic tools, order multiple-scatter distributions. In this formalism, the multiple-scatter kernel can be isotropic for low-energy uncertainty does not have a stochastic component, while MC photons96 or when oriented along the primary photon.80 A uncertainties have stochastic and systematic components. An scaling method was also developed for the successive- important issue for brachytherapy is the “ray effect,” which scattering superposition in the presence of high-Z and high- results from the nonphysical fluence buildup due to the lim- density materials.97 A source description formalism was also ited number of angles for near pointlike sources in low- proposed in the context of primary and scatter dose separa- density media. To diminish this artifact, stochastic or semi- tion ͑PSS formalism͒ that is backward compatible with the analytic methods are generally used to determine the once- scattered dose distribution within the discretized phase current TG-43 dose-calculation formalism and is used as in- 81,101 put into the CC algorithm.98 CC performance was recently space. studied for relevant brachytherapy geometries and for 28, 60, The first application of a deterministic approach to HDR and 350 keV sources. A total of 31 800 voxels/s ͑0.2 mm3 brachytherapy used a finite-difference multigroup-DO solver voxel, 52 directions͒ were calculated for permanent prostate from Los Alamos National Laboratory ͑LANL͒ called 104 seed geometry.90 The authors further tested implementation DANTSYS. Though limited to 2D, the results were within 101 on parallel hardware, specifically GPU cards, and showed it 2␴ of EGS4 MC calculations. This approach was further to be 100 times faster for the same geometry.90 extended, namely, by reducing the energy group cross sec- 125 Finally, Wang and Sloboda99,100 also proposed a formal- tions, to calculation of the absorbed dose rate around a I ism of primary, once-scatter and multiple-scatter separation. brachytherapy seed for a 2D cylindrical geometry. The deter- The novelty is that the once-scatter is evaluated using a “mi- ministic method was shown to be 100-fold more efficient 105 crobeam” ray-tracing algorithm, which includes basic inter- than the EGS4 MC code. 102 action physics such as Compton, Rayleigh, and photoelectric Zhou and Inanc introduced another approach to solve effect. The advantage of this approach is that the once-scatter the integral representation of the LBTE and studied ISA in contribution does not have to be scaled to account for mate- 125I seed implants. The algorithms were extended to account rial heterogeneities.99 The multiple-scatter dose is obtained for fluorescence x rays, and parallelization was introduced. from a nonlinear curve fitting of MC multiple-scatter dose in Single seeds and more complex configurations such as the various heterogeneous media.100 Accuracy was within 10% Quality Assurance Review Center ͑www.qarc.org͒ geometry for all cases studied. for clinical protocol accreditation were studied.106 The calcu-

Medical Physics, Vol. 36, No. 6, June 2009 2145 Rivard, Venselaar, and Beaulieu: The evolution of brachytherapy treatment planning 2145 lation took ϳ2.5 h on a 64 processor computer cluster. speed by looking into variance reduction techniques such as However, the multiseed configuration results were not com- correlated sampling.110 Chibani and Williamson77 developed pared to reference MC calculations. MCPI, an MC code dedicated to low-energy permanent seed More recently, the LANL developments were transferred implants. MCPI uses source phase-space files to avoid track- to a commercial spin-off, Transpire Inc. ͑Gig Harbor, WA͒. ing particles within the seeds but allows full calculation of Their Attila™ product is a multidimensional finite-element ISA, arbitrary seed orientation and material heterogeneities. multigroup-DO solver. A mathematical description of the A similar “dedicated” route was taken with EGSnrc that led 78 various components can be found in the 2006 paper of Gif- to BRACHYDOSE. 81 ford et al. Born from nuclear science, it handles electron Others have pursued MC integration by implementing and photon beams and brachytherapy sources. A specific DICOM-RT support to generate voxel-based geometry from package enables 3D geometry construction from various clinical implants exported directly from the TPS and im- 71 CAD formats. Interestingly, the results of solving the trans- ported into general-purpose codes such as GEANT4 or 81 111 port equation are energy-dependent fluence maps, not dose. PTRAN. This has enabled retrospective dose comparison The final dose distribution is obtained by multiplying the studies, essential when considering new dose-calculation ͑␮/␳͒ fluence by the appropriate E,Z value. Gifford et al. con- methods. One such study has argued strongly in favor of MC ducted a comparative study between Attila™, MCNPX, and dose calculation as a clinical standard for postimplant dose EGS4 ͑Ref. 81͒ and a detailed application to 3D dose calcu- 192 evaluation, since time constraints are less important for lation around a HDR Ir source. In the latter case, calcula- follow-up procedures and will lead to better dose-outcome tion times were about 15 min and the deterministic method 65 81 studies. Similarly, in HDR brachytherapy, retrospective was over 100 times more efficient than MCNPX. dose comparisons for a shielded rectal applicator have shown large differences in delivered doses for a cohort of 40 patients.56 The success of subminute MC codes for seed im- IV.D. Monte Carlo plants has yet to be repeated for the higher energy 192Ir; the longer mean free path makes the calculation time for similar Direct MC simulation is based on a random sampling of statistical uncertainty much longer. To include some of the particle histories to estimate the quantity of interest, ab- benefits of MC in the presence of high-Z materials but keep sorbed dose in the patient. A comprehensive overview of the calculation time clinically acceptable, a hybrid approach has possibilities of MC methodology is given in the doctoral been proposed in which MC is used to calculate modified thesis of Carlsson Tedgren, “since interaction details can be TG-43 parameters that includes the source and the applica- implemented with no other limits than time, this is poten- tors ͑skin applicators, breast brachytherapy applicators, and tially the most accurate method available for dose 112 107 COMS-based eye plaque͒. In the above examples, the im- calculations.” MC already plays an important role in sev- portance of material heterogeneities has been demonstrated eral aspects of brachytherapy dose calculation. For example, MC methods revealed theoretically that dose rates from 125I for a wide range of brachytherapy procedures. While ad- were lower by 10%–14% due to air-kerma contributions vanced MC software may soon be available for dose recal- culation, the question of advanced methods for dose optimi- from titanium characteristic x rays in the NIST SK,N85 calibration standard.26,108 MC is an obligatory part of the confir- zation has also been put forward. A method has recently been matory process and is equal to measurements for AAPM shown using a MC dose-calculation technique for plan opti- brachytherapy dosimetry parameter datasets.24 It is also used mization in afterloading brachytherapy. This method in- to characterize radiation sources in terms of their spatial dis- volves a full MC precalculation in the treatment geometry ͑including heterogeneities͒ for all possible dwell positions, tribution of primary and scattered radiation to allow simple 113 input data for modeling clinical sources. Further, it can be which are then used in an inverse planning software. used to derive transmission data through materials and thus Even though MC has been an integral part of many dif- contributes to radiation protection data as shown recently.109 ferent aspect of brachytherapy, commercial implementation As discussed in detail in Sec. IV A, MC methods are a key into a brachytherapy TPS is currently unavailable. A number tool to characterize shielding effects, ISA, and other relevant of open questions remain to be addressed for efficient clini- factors to clinical brachytherapy dose calculation. A thor- cal integration. The first task would be to address source ough discussion of dose-calculation algorithms was prepared geometry definition. It would be a great loss of resources for by Carlsson Tedgren and others.80,84,98 each institution to characterize its commonly available However, the MC calculation time for direct brachy- sources. A standard reference dataset must be made avail- therapy applications is affected by the inverse-square law fall able, leaving the medical physicist to validate test cases off in the primary photon fluence with distance, as it leads to against published data. These will probably need to also in- a low density of primary photons at a distance. Another prob- clude a standard format for applicator definitions. Similarly, lem is the nearly elastic scattering at relatively low energies, the issue of organ or tissue segmentation in terms of material as it requires many interactions until the initial energy is lost. composition can be critical for low-energy seeds and elec- Such reasons have obstructed the use of MC algorithms in tronic brachytherapy sources. While CT is the imaging stan- direct calculation of dose distributions around implants. dard, it only provides electron density, not average elemental Methods have been developed to increase MC calculation composition or mass density. Dual-energy CT could be a

Medical Physics, Vol. 36, No. 6, June 2009 2146 Rivard, Venselaar, and Beaulieu: The evolution of brachytherapy treatment planning 2146

114–116 potential solution. Still, some guidelines must be pro- TABLE II. Overview of active AAPM Brachytherapy Subcommittee working vided to the end user, otherwise large variations would result groups and task groups. when using MC methods. AAPM BTSC Active Working Groups

͑ ͒ V. PREDICTIONS AND RATIONALE FOR Brachytherapy Source Registry Geoffrey Ibbott ͑ ͒ BRACHYTHERAPY TPS TRENDS Special Brachytherapy Modalities Bruce Thomadsen High-Energy Brachytherapy Dosimetry ͑José Pérez-Calatayud͒ The previous sections describe the past, present, and fu- Low-Energy Brachytherapy Dosimetry ͑Michael Mitch͒ ture of brachytherapy dosimetry in a narrow interpretation of Robotic Brachytherapy ͑Bruce Thomadsen and Yan Yu͒ the term dosimetry as a dose-calculation procedure. We followed the history from the systems of the precomputer era, AAPM BTSC Active Task Groups from the table or nomogram based manual systems, via the TG-129 Eye Plaque Dosimetry ͑Sou-Tung Chiu-Tsao͒ ͑ ͒ classical Sievert-based dose calculation Sec. I D ,tothe TG-137 Prostate Dose Prescription and Reporting Methods present-day TG-43 based system ͑Sec. II͒, toward the com- ͑Ravinder Nath͒ plex algorithms for primary-scatter separation superposition/ TG-138 Brachytherapy Dosimetric Uncertainties ͑Larry DeWerd͒ convolution models and the MC approach ͑Sec. IV D͒.We TG-143 Dosimetric Evaluation of Elongated Brachytherapy Sources ͑ ͒ now summarize a number of activities by committees within Ali Meigooni TG-144 Dosimetry for 90Y microsphere Brachytherapy for Liver Cancer the AAPM and jointly with other professional societies to ͑Andy Dezarn͒ help shape the future of brachytherapy dosimetry; here used TG-167 Novel and Developmental Brachytherapy Sources in the wider interpretation of the term. A detailed uncertainty ͑Ravinder Nath͒ analysis will help identify areas where the largest benefits TG-186 Advanced Brachytherapy Dosimetry ͑Luc Beaulieu͒ can be achieved from research activities. Easily accessible traceable source strength calibration methods, preferably in the quantity dose to water are helpful and reassuring for in- and recommendations. It is not our intention to provide an house check procedures of source deliveries. We must strive extensive overview of these committees and reports, but ex- for a situation where dose is interpreted unequivocally amples are easily found in the report series of the German among institutions, for the same starting points whichever DIN, French SFMP, Dutch/Belgian NCS, IPEM in the U.K., system is used. Easily accessible consensus datasets for and those of ESTRO ͑GEC-ESTRO, Braphyqs͒ and IAEA. source characterization, both in TG-43 format and in the Many of these reports can be found on and downloaded from more complex algorithms, are then required for commission- the Internet. ing TPS and for quality control. Maybe the most important It is worth mentioning the current status of groups within evolution in brachytherapy dosimetry is the consequence of this framework. The high-energy brachytherapy dosimetry modern imaging technologies. Section V presents our views ͑HEBD͒ working group aims to prepare and issue AAPM on a number of these issues. recommendations on brachytherapy dosimetry parameters and dosimetry algorithms for high-energy photon-emitting V.A. Working groups and joint „inter…national sources. At the same time, this group works on solutions for coordination a number of practical problems associated with differences The aim of physicists’ work in radiation oncology, and compared to low-energy photon-emitting brachytherapy thus in brachytherapy dosimetry, is to provide a safe and sources. The low-energy brachytherapy dosimetry ͑LEBD͒ reliable technical environment for patient treatments. As dis- working group is developing consensus datasets for new cussed in previous sections and elsewhere in several recent low-energy photon-emitting brachytherapy sources such as publications,14–16 there are distinct areas where significant 131Cs and will include expansion of acceptable and bench- improvements can be made, either to improve the accuracy marked measurement and simulation techniques considering of given steps in the dosimetry chain or to speed up or im- advances in dosimetry research. LEBD works closely with prove the procedures for certain techniques to benefit pa- the Calibration Laboratory Accreditation Subcommittee un- tients or improve cost effectiveness. This is essentially the der TPC, NIST, and the RPC to oversee dosimetric and cali- work of individual researchers or the aim of joint profes- bration aspects. Under LEBD are TG-137, TG-138, and TG- sional groups. The results of such efforts are usually pub- 167. The report of the TG-137 on “Prostate dose prescription lished in national or international reports. Tables II and III and reporting methods” is in the final AAPM review stage, show the activities of the current working groups and task with plans to publish in Medical Physics. The charge of TG- groups and their chairs under the Brachytherapy Subcommit- 138 is “Photon brachytherapy source dosimetric uncertainty tee ͑BTSC͒ of the AAPM Therapy Physics Committee analysis,” and the report is nearing completion. This report ͑TPC͒, as well as a list of the reports that were published on focuses on measurement system uncertainty components, brachytherapy by the AAPM. As is clear from this table, a MC simulation uncertainty components, uncertainty in the tremendous effort was demonstrated especially from 1995 TG-43 dosimetry formalism parameters, and the uncertain- onward, leading to production of about one report per year. ties associated with the transfer to the clinics. If this topic Furthermore, other professional societies have presented was further extended to include the uncertainties of the more work in the same area usually in the form of national reports clinically related steps in the dosimetry chain, including im-

Medical Physics, Vol. 36, No. 6, June 2009 2147 Rivard, Venselaar, and Beaulieu: The evolution of brachytherapy treatment planning 2147

TABLE III. Overview of AAPM reports on brachytherapy with report number based dose-calculation techniques in brachytherapy: Status and year of publication. and clinical requirements for implementation beyond AAPM 21 1987 Radiation Therapy Committee Task Group No. 32. Specification TG-43.” The aim is to review the potential next generation of brachytherapy source strength brachytherapy dose-calculation algorithms, and to provide 41 1993 Remote Afterloading Technology Task Group No. 41. Remote guidance for early adopters in using model-based dose- afterloading technology calculation algorithms in brachytherapy, especially for com- 51 1995 Radiation Therapy Committee Task Group No. 43. Dosimetry missioning, handling of patient data, and prescription defini- of interstitial brachytherapy sources tion. 59 1997 Radiation Therapy Committee Task Group No. 56. Code of practice for brachytherapy physics 61 1998 Radiation Therapy Committee Task Group No. 59. High-dose V.B. Dose-calculation engines for clinical routine rate brachytherapy treatment delivery 66 1999 Radiation Therapy Committee Task Group No. 60. Intravascular To be useful in the clinic, MC TPS may come with pre- brachytherapy physics. defined CAD based applicator geometries and physical prop- 68 1999 Radiation Therapy Committee Task Group No. 64. Permanent erties. We expect that source modeling and its associated prostate seed implant brachytherapy phase-space file will be mandatory as per a new AAPM pre- 69 2000 Recommendations of the American Association of Physicists in Medicine on 103Pd interstitial source calibration and dosimetry: requisite. These might be specific to the type of MC code Implications for dose specification and prescription implemented by the commercial vendor, but would still have 84 2004 Brachytherapy Subcommittee Workgroup on low-energy to meet stringent validation, akin to the AAPM brachy- brachytherapy source dosimetry. Update of AAPM Task Group No. 43 therapy dosimetry prerequisites. As we expect most of the Report: A revised AAPM protocol for brachytherapy dose calculations applicators, catheters, and needles to become MRI/CT com- 84S 2007 Brachytherapy Subcommittee Workgroup on low-energy patible, artifacts will become less of an issue. However, im- brachytherapy source dosimetry. Supplement to the 2004 update of the AAPM Task Group No. 43 Report age processing will be implemented to minimize streaking of 89 2005 Therapy Physics Committee Subcommittee on photon-emitting permanent seed implants. brachytherapy dosimetry. Recommendations of the AAPM regarding It is expected that the next generation algorithms will be the impact of implementing the 2004 Task Group 43 report on dose able to deal with a number of the problems related to the 103 125 specification for Pd and I interstitial brachytherapy accuracy of dose calculation discussed in Sec. III. The influ- 98 2008 Brachytherapy Subcommittee Workgroup on low energy ence of tissue density and tissue composition effects on the brachytherapy source calibration. Report of the AAPM Low-Energy Brachytherapy Source Calibration Working Group: Third-party resulting dose distribution was discussed in detail in the re- brachytherapy source calibrations and physicist responsibilities cent AAPM Anniversary Paper on Brachytherapy Physics by Thomadsen et al.16 While the reader is referred to that document, we summarize that a direct MC calculation approach can address the substantial dose effects of several percent aging and reconstruction procedures and registration of possible with tissue composition changes such as soft tissue images,117,118 the contouring of target organs, and tissues at calcifications,61 adipose, and fatlike tissues123 depending on risk and the analysis of dosimetric parameters, this would the photon energy. The challenge remains in the design of lead to a rather complete overview of all uncertainties in imaging technology to allow advanced brachytherapy TPS to brachytherapy dosimetry. In this context, work is ongoing by account for the relevant spatial and density information. Ap- the GEC-ESTRO ͑Group Européen de Curiethérapie͒ Bra- plicator and catheter shielding effects have similar influence phyqs physics network on quality of imaging proce- on the dose deposition.124,125 Further, those involved with dures,119–121 on the accuracy of present day dose volume TPS algorithm development would benefit if vendors provide histogram calculation algorithms,122 and the initiation of a a full description of their applicators. This is one step beyond new project on “uncertainties in seed definition and contour- the tools currently available for full applicator geometry de- ing due to interobserver variability in prostate postplanning” scription for reconstruction, viewing, and manipulation in by De Brabandere. These topics are complementary to the 3D. An open database to share the information on material TG-138 work. Thus, the time is ready for a joint effort to composition in addition to a series of systematic MC re- delineate high-priority topics for further basic or clinical research studies on the influence of a wide spectrum of photon search. The joint AAPM/RPC Brachytherapy Source Regis- radiation on dose is welcomed. Brachytherapy TPS develop- try is overseen by the Brachytherapy Source Registry work- ment should be less vendor specific and instead provide coming group, and endeavors to expand the current Registry to patibility with afterloading equipment from other vendors. include high-energy photon-emitting sources. The Robotic Standardization efforts for brachytherapy ͑DICOM-BT͒ by Brachytherapy working group was established in late 2008 the cross-societal Integrating the Healthcare Environment for and is underway to gather data and recommend robotic Radiation Oncology ͑IHE-RO͒ taskforce are underway. brachytherapy standards. The Special Brachytherapy Modali- There are more problems that can be addressed in the ties working group oversees TG-129, TG-143, and TG-144. coming years. One is a systematic and comprehensive study Its TG-149 on intravascular brachytherapy was published by on the influence of secondary photon radiation on dose from Medical Physics in 2007. In 2009, another task group ͑TG- beta components ͑e.g., bremsstrahlung͒ of radionuclides used 186͒ was established directly under BTSC to build on the or proposed for brachytherapy. Often the beta particles them- expertise of international scientists for a report on “Model- selves or low-energy photons are absorbed in the source ma-

Medical Physics, Vol. 36, No. 6, June 2009 2148 Rivard, Venselaar, and Beaulieu: The evolution of brachytherapy treatment planning 2148 terial or source capsule or have a penetration of 1–2 mm. All modern TPSs are built in a modular fashion. Software However, if high-energy electrons are emitted and sources components are developed at specialized centers, often uni- have high-Z capsule materials, penetration of the secondary versity groups, and are combined into the main system. The radiation may be significant. MC studies are ideal for such TPS vendor is then responsible for component integration work. Discrepancies between the outcome of the codes used and the user interface. This process will continue as a form for MC calculations can sometimes be attributed to the use of outsourcing research and development. Consequently, the of different cross-section libraries.126 Differences in the use splitting of external beam and brachytherapy TPS compo- of certain databases for energy spectra of the radionuclide nents over the past two decades may be undone by some of under investigation might be a cause for deviation.42 As men- the vendors, making possible dual-modality dose summation tioned in Sec. II B, source characterization databases are use- within a 3D patient matrix. ful for further development of direct MC or MC-based algorithms. Similar to the consensus datasets, clear V.C. Dose-to-water calibration recommendations on which data to be used for such work would be useful. The professional organizations might take A dose-to-water calibration standard for source strength this task to implement a web-based resource for sharing in- determination appears to be the next goal of the PSDLs and ͑ ͒ formation. secondary standard dosimetry laboratories SSDLs in their Unmentioned in the previous sections, brachytherapy support to the brachytherapy community. Just as with external beam therapy, the brachytherapy dose calculation system dose optimization is a critical tool. This is due to the flex- 128,129 ibility of single HDR source stepping technology. It is often is specific to a single point. For example, if the refer- ˙ ͑ ␪ ͒NIST not recognized by the user that for a set of restrictions or ence dose rate to liquid water D r0 , 0 water as determined at ͑ ͒ requirements, multiple solutions are possible. Inverse plan- NIST was to replace SK in Eq. 5 for source strength as ning has been shown to be superior to any form of manual determined at an accredited dosimetry calibration laboratory ͑ ͒ ˙ ͑ ␪ ͒NIST/ planning in term of simultaneous fulfillment of CTV cover- ADCL or SSDL ND,W =D r0 , 0 water M ·Cel·Cel·Aion, then age, organs at risk, and dose sparing while providing better the reference dose rate to liquid water as determined in a ˙ ͑ ␪ ͒clinic dose conformity and homogeneity. More importantly, it clinic D r0 , 0 water for use in a new 2D formalism could handles increased complexity without effort and the repro- follow, ducibility from patient to patient becomes user independent. ˙ ͑ ␪ ͒clinic ͑ ͒ Just like for IMRT, dose optimization will become the stan- D r0, 0 water = ND,W · M · Cel · CTP · Pion 6 dard for brachytherapy treatment planning for many ana- with the dose rate at any point determined as tomic sites. Still, there is an adagium that tells us that opti- G ͑r,␪͒ mization cannot make a good dose distribution out of a bad D˙ ͑r,␪͒ = D˙ ͑r ,␪ ͒clinic · L · g ͑r͒ · F͑r,␪͒, ͑7͒ 0 0 water ͑ ␪ ͒ L implant. The larger contiguous high-dose volumes ͑e.g., GL r0, 0 ͒ V200 that should be avoided are evident after optimization of where N is the ionization chamber calibration as used bad implants,127 but these are often not used for optimization D,W currently, M is the chamber reading, Cel and CTP are the restriction. Furthermore, there is a wide variety of parameters electrometer and temperature/pressure correction factors, re- proposed to help evaluate implants—generally based on the spectively, and Aion and Pion are the chamber collection effi- outcome of DVH analysis. Still, their value for predicting ciency and recombination factors. clinical outcomes has not been validated, and clinical studies At the European laboratories, there is noticeably a re- to demonstrate efficacy of certain approaches need to be ad- newed interest in these questions for brachytherapy and it is dressed in the next decade. accepted as an explicit part of a new research activity in the Use of radiobiology in external beam TPS is only recently EURAMET network of national measurement institutes being considered, and brachytherapy would also benefit from ͑NMIs͒. The iMERA joint research project on brachytherapy planning beyond physical dose. However, many basic ques- aims at developing a primary standard of absorbed dose to tions and reference data still need to be addressed. Unlike for water for 192Ir to be available at three NMIs, and similarly external beam today, radiobiology is faced with an interest- for 125I available at four NMIs in about 3 years. While the ing challenge in brachytherapy. For the prostate example, the National Physical Laboratory ͑NPL͒ in the United Kingdom duration of the dose delivery varies markedly from very low- offers 125I calibrations for only a specific source model 125 dose rates as with I seed implants to hypofractionated ͑6711͒ and in an ad hoc manner, the Physikalisch-Technische HDR monotherapy schedules. A better understanding of nor- Bundesanstalt ͑PTB͒ in Germany provides a similar calibra- mal tissue and target tissue response to these dose rates is tion service which is not limited to only one source type and required. Essentially this process, tissue recognition and accepted by EURAMET. Implicitly this means that the pre- characterization in terms of ␣/␤ ratios, is completely analo- vious lack of European PSDLs offering calibration of low- gous to external beam planning and there is no reason to and intermediate-energy photon-emitting sources appears to assume that it will not be implemented for brachytherapy. be solved. PTB has performed ad hoc intercomparisons of However, patient-specific radiobiological information is 125I and 103Pd seeds with the University of Wisconsin lacking in a general sense, and further investigation is ADCL.130 Regardless of how this advance is further imple- needed. mented, there is still much work to be done before direct

Medical Physics, Vol. 36, No. 6, June 2009 2149 Rivard, Venselaar, and Beaulieu: The evolution of brachytherapy treatment planning 2149 chamber calibrations for liquid water dose rate are available proposed indices for which the evidence of the predictive to clinical users. We believe it is the responsibility of the value is often poor or lacking. TRUS-guided permanent136,137 international PSDL community to coordinate efforts to uni- and HDR temporary138,139 implantation have become stan- formly transition to develop dose-to-water standards world- dard practice for prostate brachytherapy in North America wide and to disseminate these standards to the clinical source and Europe. For other body sites, especially gynecology, 3D users. Coordination for this transition from reference air imaging is now or will be soon included in the newest rec- kerma to dose to water across the entire field of brachy- ommendations as a standard guidance for volume definition therapy is key. A distinct requirement from the clinical user and dose prescription,140,141 and will lead to new clinical is that such a new approach should at least give the same, but studies for a systematic evaluation of the responses.142 As a preferably, lower source calibration uncertainties. Further co- spin-off of these developments, the interaction between ra- operation with NIST and other PSDLs is essential for mutual diation oncologists, medical physicists, and the equipment validation and to harmonize methodologies. Within the next vendors may lead to a new generation of applicators in few years, PSDL intercomparisons will be organized by the which a combination of intracavitary and interstitial tech- BIPM and will include 192Ir source calibrations. There is no niques is pursued to increase the flexibility for source posi- plan yet for a similar intercomparison for 125I seeds. The tion optimization in the implant geometry. As a consequence, success of such collaboration between laboratories is clearly ICRU reports such as Report 38 from 1985 on gynecology demonstrated in the review paper of Williamson14 in which and Report 58 from 1997 on interstitial implants will need to development of modern quantitative approaches to brachy- be updated.143,144 therapy dosimetry at NIST is linked with clinical utilization Although MRI is slowly entering the field, it is widely of low-energy seeds. recognized that this technique readily adds to the quality of It is expected that the AAPM will continue to play a ma- the treatments for its ability to discriminate between different jor role in the further development of both the calibration tissue types. Contouring will increasingly be based on this standards and the recommendations of the dose-calculation imaging technology. Functional MRI depends on its ability algorithm datasets. Research groups working with or in con- to demonstrate active parts of the tissue under consideration, tact with the vendors and the standards laboratories should allowing suborgan identification. If tissue contouring can be be included in the working groups and task groups in order performed in this way, this would allow a spatially modu- to avoid any disparities to occur either from new consensus lated dose deposition ͑dose painting) procedure, in which the algorithm types or the dose-to-water concept for calibration full organ ͑e.g., a prostate͒ is treated to the required dose but that might otherwise distract and confuse individual users. subparts are administered a much higher dose.145,146 There is The importance of a clinical implementation plan cannot be a similar expectation for the use of PET and PET-CT imag- underestimated. It will require an international organizational ing for identifying active tumor areas.147,148 leadership to bring together the treatment planning vendors, One of the challenges in brachytherapy imaging is the PSDLs, source manufacturers, and medical physics societies, further development of registration for different modalities possibly on an annual basis. and image sets made at different points in time. A key to this challenge is the need to address deformable image registration. In brachytherapy, not only organ movements or the in- V.D. Developments in brachytherapy imaging crease or decrease of tumor volume, but also the required Use of x-ray CT and other 3D imaging modalities ͑MR, transportation of a patient from one location to the other US, and more recently PET͒ marks a distinct improvement in ͑e.g., operating area to radiology department͒ may influence brachytherapy planning, to be considered as a departure from the relative position of the applicators and the organs. Not the surgical practice of brachytherapy. As with many other only the tools themselves but also QA of these imaging pro- developments, the ideas are not new as demonstrated by cedures adapted to the needs of radiation oncology. New QA early publications of, for example by Herskovic et al.,131 protocols are required specific to the clinical applications in Pierquin and Fayos,132 Ling et al.,133 and Schoeppel et al.134 brachytherapy. The step forward is made primarily due to direct availability of the radiological equipment for interventional procedures. Low-cost ultrasound forms the basis of prostate implant VI. CONCLUSION technology, but the far more expensive other modalities are It is a great challenge to introduce these new techniques nowadays available in every modest-sized hospital, whereas into medical practice and in cooperation with physicians to in many radiotherapy departments 3D imaging has replaced help design prospective clinical trials to demonstrate their the conventional RT simulator for patient setup. CTV local- values and efficacy. It is expected that as the new-generation ization and dose-limiting normal tissues allows the absorbed algorithms find their way to early adopters, retrospective do- dose from the implanted sources to be specified according to simetric studies will be conducted to revisit prescription anatomy-based parameters, such as the coverage index. In level, target dose, OAR doses, and their relationship to out- the classical systems, dosimetry quantities for analysis of comes, either survival or toxicities. Improved accuracy of implant quality were difficult to correlate with clinical out- brachytherapy dose calculations, and flexible coregistration come as they lacked 3D volumetric information of the rel- of external beam and brachytherapy dose distributions, will evant structures. As discussed by Feuvret et al.,135 this led to enable true dose summation of external beam with LDR

Medical Physics, Vol. 36, No. 6, June 2009 2150 Rivard, Venselaar, and Beaulieu: The evolution of brachytherapy treatment planning 2150 and/or HDR brachytherapy ͑e.g., a salvage prostate HDR radium therapy,” Am. J. Roentgenol., Radium Ther. Nucl. Med. 70, 739– ͑ ͒ brachytherapy after a seed implant͒. These advances will 740 1953 . 18W. J. Meredith, “Radiotherapeutic physics: V. Dosage control in intersti- also allow researchers to explore implants containing mul- tial gamma-ray therapy,” Br. J. Radiol. 24, 380–384 ͑1951͒. tiple radionuclides based on a solid foundation that will take 19R. J. Shalek and M. A. Stovall, in Radiation Dosimetry, edited by F. H. into account varying RBE. Joint databases for MC-based al- Attix and E. Tochlin ͑Academic, New York, 1969͒, Vol. 3, pp. 776–798. 20 gorithms will form the backbone of the new generation of A. Dutreix, G. Marinello, and A. Wambersie, Dosimétrie en Curi- ethérapie ͑Masson, Paris, 1982͒. commercial treatment planning systems, in combination with 21S. Jayaraman, L. H. Lanzl, and S. K. Agarwal, “An overview of errors in a new validation prerequisite for those new algorithms. A line source dosimetry for gamma-ray brachytherapy,” Med. Phys. 10, dose-to-water standard for brachytherapy source calibration 871–875 ͑1983͒. 22 ͑ ͒ will become available with a better or at least similar uncer- IAEA Report No. 17 IAEA, Vienna, 2000 . 23D. Baltas, L. Sakelliou, and N. Zamboglou, The Physics of Modern tainty level. It is expected that above all, if anything will Brachytherapy for Oncology ͑Taylor & Francis, New York, 2007͒. make a change in clinical outcome to the beneﬁt of our pa- 24M. J. Rivard, B. M. Coursey, L. A. DeWerd, W. F. Hanson, M. S. Huq, G. tients, it is the wide introduction of modern imaging tools S. Ibbott, M. G. Mitch, R. Nath, and J. F. Williamson, “Update of AAPM into the clinical practice. Task Group No. 43 Report: A revised AAPM protocol for brachytherapy dose calculations,” Med. Phys. 31, 633–674 ͑2004͒. 25J. F. Williamson, “Recent developments in brachytherapy physics,” Pro- ACKNOWLEDGMENTS ceedings of the ABS 1994 Summer School ͑Medical Physics, Madison, WI, 1995͒. The authors gratefully acknowledge the careful and de- 26J. F. Williamson, “Monte Carlo and analytic calculation of absorbed dose 137 tailed comments from the referees. The comments and sug- near Cs intracavitary sources,” Int. J. Radiat. Oncol. Biol. Phys. 15, 227–237 ͑1988͒. gestions of Tony Aalbers, Todd Wareing, Marco Zaider, 27J. F. Williamson, “The Sievert integral revisited: evaluation and extension Michael Mitch, Larry DeWerd, Hans-Joachim Selbach, to 125I, 169Yb, and 192Ir brachytherapy sources,” Int. J. Radiat. Oncol., Christopher Melhus, Ali Meigooni, and Panos Papagiannis Biol., Phys. 36, 1239–1250 ͑1996͒. 28 are also greatly appreciated. The authors have not received J. F. Williamson, “Monte Carlo-based dose-rate tables for the Amersham CDCS.J and 3M model 6500 137Cs tubes,” Int. J. Radiat. Oncol. Biol. any ﬁnancial support in relation to the preparation of this Phys. 41, 959–970 ͑1998͒. article. 29R. van der Laarse, presented at Proceedings of the Seventh Intern Con- ference on the Use of Computers in Radiation Therapy, Japan, 1980 ͑un- ͒ a Electronic mail: [email protected] published͒. 1J. Dutreix, M. Tubiana, and B. Pierquin, “The hazy dawn of brachy- 30R. Nath, L. L. Anderson, G. Luxton, K. A. Weaver, J. F. Williamson, and therapy,” Radiother. Oncol. 49, 223–232 ͑1998͒. A. S. Meigooni, “Dosimetry of interstitial brachytherapy sources: Recom- 2H. Becquerel and P. Curie, “Action physiologique des rayons du radium,” mendations of the AAPM Radiation Therapy Committee Task Group No. Acad. Sci., Paris, C.R. 132, 1289–1291 ͑1901͒. 43. American Association of Physicists in Medicine,” Med. Phys. 22, 3H. Danlos and P. Bloch, “Note sur le traitement du lupus érythèmateux 209–234 ͑1995͒. par des applications de radium,” Ann. Dermatol. Syphil. ͑Paris͒ 2, 986– 31R. Paterson, “A dosage system for gamma ray therapy. Part I. Clinical 988 ͑1901͒. aspects,” Br. J. Radiol. 7, 592–612 ͑1943͒. 4R. Abbé, “Notes on the physiologic and therapeutic action of radium,” 32H. Parker, “A dosage system for gamma ray therapy. Part II. Physical Wash. Med. Ann. 2, 363–377 ͑1904͒. aspects,” Br. J. Radiol. 7, 612–632 ͑1943͒. 5L. Wickham and P. Degrais, Radiumthérapie ͑Bailliére, Paris, 1909͒. 33B. Pierquin and G. Marinello, A Practical Manual of Brachytherapy 6R. F. Mould, A Century of X-Rays and Radioactivity in Medicine ͑Insti- ͑Medical Physics, Madison, WI, 1997͒. tute of Physics, Bristol, 1993͒. 34W. M. Butler, W. S. Bice, Jr., L. A. DeWerd, J. M. Hevezi, M. S. Huq, G. 7R. Paterson and H. M. Parker, “A dosage system for interstitial radium S. Ibbott, J. R. Palta, M. J. Rivard, J. P. Seuntjens, and B. R. Thomadsen, therapy,” Br. J. Radiol. 1, 252–340 ͑1938͒. “Third-party brachytherapy source calibrations and physicist responsibili- 8W. J. Meredith, Radium Dosage: The Manchester System ͑Livingston, ties: Report of the AAPM Low Energy Brachytherapy Source Calibration Edinburgh, 1967͒. Working Group,” Med. Phys. 35, 3860–3865 ͑2008͒. 9U. Henschke, B. S. Hilaris, and G. D. Mahan, “Afterloading in interstitial 35S. M. Seltzer, P. J. Lamperti, R. Loevinger, M. G. Mitch, J. T. Weaver, and intracavitary radiation therapy,” Am. J. Roentgenol., Radium Ther. and B. M. Coursey, “New national air-kerma-strength standards for 125I Nucl. Med. 90, 386–395 ͑1963͒. and 103Pd brachytherapy seeds,” J. Res. Natl. Inst. Stand. Technol. 108, 10D. Chassagne, M. Raynal, and B. Pierquin, “Technique of endocuri- 337–358 ͑2003͒. etherapy by iridium 192 with plastic tubes in the breast tumors,” J. Ra- 36M. J. Rivard, W. M. Butler, L. A. DeWerd, M. S. Huq, G. S. Ibbott, A. S. diol., Electrol., Med. Nucl. 44, 269–271 ͑1963͒. Meigooni, C. S. Melhus, M. G. Mitch, R. Nath, and J. F. Williamson, 11B. Pierquin, D. J. Chassagne, C. M. Chahbazian, and J. F. Wilson, “Supplement to the 2004 update of the AAPM Task Group No. 43 Re- Brachytherapy ͑W.H. Green, St Louis, MO, 1978͒. port,” Med. Phys. 34, 2187–2205 ͑2007͒. 12R. Walstam, “Remotely-controlled afterloading radiotherapy apparatus,” 37M. J. Rivard, C. S. Melhus, and J. F. Williamson, “Brachytherapy dose Phys. Med. Biol. 7, 225–228 ͑1962͒. calculation formalism, dataset evaluation, and treatment planning system 13U. K. Henschke, B. S. Hilaris, and G. D. Mahan, “Intracavitary radiation implementation,” in Clinical Dosimetry for Radiotherapy: AAPM Sum- therapy of cancer of the uterine cervix by remote afterloading with cy- mer School, edited by D. W. O. Rogers and J. E. Cygler ͑Medical Physics, cling sources,” Am. J. Roentgenol., Radium Ther. Nucl. Med. 96, 45–51 Madison, WI, 2009͒. ͑1966͒. 38L. A. DeWerd, M. S. Huq, I. J. Das, G. S. Ibbott, W. F. Hanson, T. W. 14J. F. Williamson, “Brachytherapy technology and physics practice since Slowey, J. F. Williamson, and B. M. Coursey, “Procedures for establish- 1950: A half-century of progress,” Phys. Med. Biol. 51, R303–R325 ing and maintaining consistent air-kerma strength standards for low- ͑2006͒. energy, photon-emitting brachytherapy sources: Recommendations of the 15G. S. Ibbott, C. M. Ma, D. W. O. Rogers, S. M. Seltzer, and J. F. Will- Calibration Laboratory Accreditation Subcommittee of the American As- iamson, “Anniversary paper: Fifty years of AAPM involvement in radia- sociation of Physicists in Medicine,” Med. Phys. 31, 675–681 ͑2004͒. tion dosimetry,” Med. Phys. 35, 1418–1427 ͑2008͒. 39Z. Li, R. K. Das, L. A. DeWerd, G. S. Ibbott, R. W. Kline, A. S. Mei- 16B. R. Thomadsen, J. F. Williamson, M. J. Rivard, and A. S. Meigooni, gooni, J. Perez-Calatayud, M. J. Rivard, R. S. Sloboda, and J. F. William- “Anniversary paper: Past and current issues, and trends in brachytherapy son, “Dosimetric prerequisites for routine clinical use of photon emitting physics,” Med. Phys. 35, 4708–4723 ͑2008͒. brachytherapy sources with average energy higher than 50 keV,” Med. 17E. H. Quimby and V. Castro, “The calculation of dosage in interstitial Phys. 34, 37–40 ͑2007͒.

Medical Physics, Vol. 36, No. 6, June 2009 2151 Rivard, Venselaar, and Beaulieu: The evolution of brachytherapy treatment planning 2151

40ICRU Report No. 44, 1989. 63R. G. Stock, N. N. Stone, A. Tabert, C. Iannuzzi, and J. K. DeWyngaert, 41D. E. Cullen, J. H. Hubbell, and L. Kissel, Lawrence Livermore National “A dose-response study for I-125 prostate implants,” Int. J. Radiat. On- Laboratory Report No. UCRL-50400, Vol. 6, Rev. 5, 1997. col., Biol., Phys. 41, 101–108 ͑1998͒. 42National Nuclear Data Center, “NUDAT 2.5,” Brookhaven National 64H. Afsharpour, M. D’Amours, B. Cote, J. F. Carrier, F. Verhaegen, and L. Laboratory, 2009; http://www.nndc.bnl.gov/nudat2/reCenter.jsp?zϭ77&n Beaulieu, “A Monte Carlo study on the effect of seed design on the ϭ115 ͑last accessed 3 May 2009͒. interseed attenuation in permanent prostate implants,” Med. Phys. 35, 43C. S. Melhus and M. J. Rivard, “Approaches to calculating AAPM TG-43 3671–3681 ͑2008͒. brachytherapy dosimetry parameters for 137Cs , 125I, 192Ir, 103Pd, and 65J. F. Carrier, M. D’Amours, F. Verhaegen, B. Reniers, A. G. Martin, E. 169Yb sources,” Med. Phys. 33, 1729–1737 ͑2006͒. Vigneault, and L. Beaulieu, “Postimplant dosimetry using a Monte Carlo 44J. Markman, J. F. Williamson, J. F. Dempsey, and D. A. Low, “On the dose calculation engine: a new clinical standard,” Int. J. Radiat. Oncol., validity of the superposition principle in dose calculations for intracavi- Biol., Phys. 68, 1190–1198 ͑2007͒. tary implants with shielded vaginal colpostats,” Med. Phys. 28, 147–155 66B. Reniers, F. Verhaegen, and S. Vynckier, “The radial dose function of ͑2001͒. low-energy brachytherapy seeds in different solid phantoms: Comparison 45J. Perez-Calatayud, D. Granero, and F. Ballester, “Phantom size in between calculations with the EGSnrc and MCNP4C Monte Carlo codes brachytherapy source dosimetric studies,” Med. Phys. 31, 2075–2081 and measurements,” Phys. Med. Biol. 49, 1569–1582 ͑2004͒. ͑2004͒. 67C. S. Melhus and M. J. Rivard, “COMS eye plaque brachytherapy dosim- 46D. Granero, J. Perez-Calatayud, M. C. Pujades-Claumarchirant, F. Ball- etry simulations for 103Pd, 125I, and 131Cs,” Med. Phys. 35, 3364–3371 ester, C. S. Melhus, and M. J. Rivard, “Equivalent phantom sizes and ͑2008͒. shapes for brachytherapy dosimetric studies of 192Ir and 137Cs,” Med. 68R. M. Thomson, R. E. P. Taylor, and D. W. O. Rogers, “Monte Carlo Phys. 35, 4872–4877 ͑2008͒. dosimetry for 125I and 103Pd eye plaque brachytherapy,” Med. Phys. 35, 47T. Mauceri, P. Biggs, J. Beatty, and D. Flynn, “Scatter and attenuation 5530–5543 ͑2008͒. measurements at distances greater than 10 cm from an 192Ir source,” Med. 69X-5 Monte Carlo Team, MCNP–A General Monte Carlo N-Particle Phys. 26, 97–99 ͑1999͒. Transport Code, Version 5 ͑Los Alamos National Laboratory, Los Ala- 48J. F. Williamson, “Comparison of measured and calculated dose rates in mos, 2003͒. water near I-125 and Ir-192 seeds,” Med. Phys. 18, 776–786 ͑1991͒. 70L. S. Waters, G. W. McKinney, J. W. Durkee, M. L. Fensin, J. S. Hen- 49L. Sakelliou, K. Sakellariou, K. Sarigiannis, A. Angelopoulos, A. Perris, dricks, M. R. James, R. C. Johns, and D. B. Pelowitz, “The MCNPX and G. Zarris, “Dose rate distributions around 60Co , 137Cs, 198Au, 192Ir, Monte Carlo radiation transport code,” AIP Conf. Proc., 896, 81–90 241Am, 125I ͑models 6702 and 6711͒ brachytherapy sources and the nu- ͑2007͒. clide 99mTc,” Phys. Med. Biol. 37, 1859–1872 ͑1992͒. 71S. Agostinelli, J. Allison, K. Amako, J. Apostolakis, H. Araujo, P. Arce, 50E. Pantelis, P. Papagiannis, P. Karaiskos, A. Angelopoulos, G. Anagnosto- M. Asai, D. Axen, S. Banerjee, G. Barrand, F. Behner, L. Bellagamba, J. poulos, D. Baltas, N. Zamboglou, and L. Sakelliou, “The effect of finite Boudreau, L. Broglia, A. Brunengo, H. Burkhardt, S. Chauvie, J. Chuma, patient dimensions and tissue inhomogeneities on dosimetry planning of R. Chytracek, G. Cooperman, G. Cosmo, P. Degtyarenko, A. Dell’Acqua, 192Ir HDR breast brachytherapy: A Monte Carlo dose verification study,” G. Depaola, D. Dietrich, R. Enami, A. Feliciello, C. Ferguson, H. Fes- Int. J. Radiat. Oncol., Biol., Phys. 61, 1596–1602 ͑2005͒. efeldt, G. Folger, F. Foppiano, A. Forti, S. Garelli, S. Giani, R. Gianni- 51G. Lymperopoulou, E. Pantelis, P. Papagiannis, H. Rozaki-Mavrouli, L. trapani, D. Gibin, J. J. Gomez Cadenas, I. Gonzalez, G. Gracia Abril, G. Sakelliou, D. Baltas, and P. Karaiskos, “A Monte Carlo dosimetry study Greeniaus, W. Greiner, V. Grichine, A. Grossheim, S. Guatelli, P. Gum- of vaginal 192Ir brachytherapy applications with a shielded cylindrical plinger, R. Hamatsu, K. Hashimoto, H. Hasui, A. Heikkinen, A. Howard, applicator set,” Med. Phys. 31, 3080–3086 ͑2004͒. V. Ivanchenko, A. Johnson, F. W. Jones, J. Kallenbach, N. Kanaya, M. 52R. E. Taylor and D. W. Rogers, “EGSnrc Monte Carlo calculated dosim- Kawabata, Y. Kawabata, M. Kawaguti, S. Kelner, P. Kent, A. Kimura, T. etry parameters for 192Ir and 169Yb brachytherapy sources,” Med. Phys. Kodama, R. Kokoulin, M. Kossov, H. Kurashige, E. Lamanna, T. Lam- 35, 4933–4944 ͑2008͒. pon, V. Lara, V. Lefebure, F. Lei, M. Liendl, W. Lockman, F. Longo, S. 53W. C. Roesch, “Evaluation of high-energy brachytherapy source elec- Magni, M. Maire, E. Medernach, K. Minamimoto, P. Mora de Freitas, Y. tronic disequilibrium and dose from emitted electrons,” Radiat. Res. 9, Morita, K. Murakami, M. Nagamatu, R. Nartallo, P. Nieminen, T. Nish- 399–410 ͑1958͒. imura, K. Ohtsubo, M. Okamura, S. O’Neale, Y. Oohata, K. Paech, J. 54D. Baltas, P. Karaiskos, P. Papagiannis, L. Sakelliou, E. Loeffler, and N. Perl, A. Pfeiffer, M. G. Pia, F. Ranjard, A. Rybin, S. Sadilov, E. Di Salvo, Zamboglou, “Beta versus gamma dosimetry close to Ir-192 brachytherapy G. Santin, T. Sasaki, N. Savvas, Y. Sawada, S. Scherer, S. Sei, V. Siro- sources,” Med. Phys. 28, 1875–1882 ͑2001͒. tenko, D. Smith, N. Starkov, H. Stoecker, J. Sulkimo, M. Takahata, S. 55F. Ballester, D. Granero, J. Perez-Calatayud, C. S. Melhus, and M. J. Tanaka, E. Tcherniaev, E. Safai Tehrani, M. Tropeano, P. Truscott, H. Rivard, “Evaluation of electronic equilibrium and electron contribution to Uno, L. Urban, P. Urban, M. Verderi, A. Walkden, W. Wander, H. Weber, dose near brachytherapy sources,” Med. Phys. ͑submitted͒. J. P. Wellisch, T. Wenaus, D. C. Williams, D. Wright, T. Yamada, H. 56E. Poon, J. F. Williamson, T. Vuong, and F. Verhaegen, “Patient-specific Yoshida, and D. Zschiesche, “G4—a simulation toolkit,” Nucl. Instrum. Monte Carlo dose calculations for high-dose-rate endorectal brachy- Methods Phys. Res. A 506, 250–303 ͑2003͒. therapy with shielded intracavitary applicator,” Int. J. Radiat. Oncol., 72J. Allison, K. Amako, J. Apostolakis, H. Araujo, P. A. Dubois, M. Asai, Biol., Phys. 72, 1259–1266 ͑2008͒. G. Barrand, R. Capra, S. Chauvie, R. Chytracek, G. A. P. Cirrone, G. 57C. S. Sureka, P. Aruna, S. Ganesan, C. S. Sunny, and K. V. Subbaiah, Cooperman, G. Cosmo, G. Cuttone, G. G. Daquino, M. Donszelmann, M. “Computation of relative dose distribution and effective transmission Dressel, G. Folger, F. Foppiano, J. Generowicz, V. Grichine, S. Guatelli, around a shielded vaginal cylinder with 192Ir HDR source using P. Gumplinger, A. Heikkinen, I. Hrivnacova, A. Howard, S. Incerti, V. MCNP4B,” Med. Phys. 33, 1552–1561 ͑2006͒. Ivanchenko, T. Johnson, F. Jones, T. Koi, R. Kokoulin, M. Kossov, H. 58Y. Yu, L. L. Anderson, Z. Li, D. E. Mellenberg, R. Nath, M. C. Schell, F. Kurashige, V. Lara, S. Larsson, F. Lei, O. Link, F. Longo, M. Maire, A. M. Waterman, A. Wu, and J. C. Blasko, “Permanent prostate seed implant Mantero, B. Mascialino, I. McLaren, P. M. Lorenzo, K. Minamimoto, K. brachytherapy: Report of the American Association of Physicists in Medi- Murakami, P. Nieminen, L. Pandola, S. Parlati, L. Peralta, J. Perl, A. cine Task Group No. 64,” Med. Phys. 26, 2054–2076 ͑1999͒. Pfeiffer, M. G. Pia, A. Ribon, P. Rodrigues, G. Russo, S. Sadilov, G. 59A. S. Meigooni, J. A. Meli, and R. Nath, “Interseed effects on dose for Santin, T. Sasaki, D. Smith, N. Starkov, S. Tanaka, E. Tcherniaev, B. 125I brachytherapy implants,” Med. Phys. 19, 385–390 ͑1992͒. Tome, A. Trindade, P. Truscott, L. Urban, M. Verderi, A. Walkden, J. P. 60P. Mobit and I. Badragan, “Dose perturbation effects in prostate seed Wellisch, D. C. Williams, D. Wright, and H. Yoshida, “Geant4 develop- implant brachytherapy with I-125,” Phys. Med. Biol. 49, 3171–3178 ments and applications,” IEEE Trans. Nucl. Sci. 53, 270–278 ͑2006͒. ͑2004͒. 73W. R. Nelson, H. Hirayama, and D. W. O. Rogers, Stanford Linear Ac- 61O. Chibani, J. F. Williamson, and D. Todor, “Dosimetric effects of seed celerator Report No. SLAC-265, 1985. anisotropy and interseed attenuation for 103Pd and 125I prostate implants,” 74I. Kawrakow and D. W. O. Rogers, NRCC Report No. PIRS-701, 2006. Med. Phys. 32, 2557–2566 ͑2005͒. 75J. F. Williamson, “Monte Carlo evaluation of kerma at a point for photon 62J. F. Carrier, L. Beaulieu, F. Therriault-Proulx, and R. Roy, “Impact of transport problems,” Med. Phys. 14, 567–576 ͑1987͒. interseed attenuation and tissue composition for permanent prostate im- 76Z. Li and J. F. Williamson, “Volume-based geometric modeling for radia- plants,” Med. Phys. 33, 595–604 ͑2006͒. tion transport calculations,” Med. Phys. 19, 667–677 ͑1992͒.

Medical Physics, Vol. 36, No. 6, June 2009 2152 Rivard, Venselaar, and Beaulieu: The evolution of brachytherapy treatment planning 2152

77O. Chibani and J. F. Williamson, “MCPI: A sub-minute Monte Carlo dose therapy dose calculations,” Phys. Med. Biol. 48, 73–93 ͑2003͒. calculation engine for prostate implants,” Med. Phys. 32, 3688–3698 103C. Borgers, “Complexity of Monte Carlo and deterministic dose- ͑2005͒. calculation methods,” Phys. Med. Biol. 43, 517–528 ͑1998͒. 78R. E. Taylor, G. Yegin, and D. W. Rogers, “Benchmarking brachydose: 104R. E. Alcouffe, R. S. Baker, F. W. Brinkley, D. R. Marr, R. D. O’Dell, Voxel based EGSnrc Monte Carlo calculations of TG-43 dosimetry pa- and W. F. Walters, Los Alamos National Laboratory Report No. LA- rameters,” Med. Phys. 34, 445–457 ͑2007͒. 12969-M, 1995. 79A. Ahnesjo, “Collapsed cone convolution of radiant energy for photon 105G. M. Daskalov, R. S. Baker, D. W. Rogers, and J. F. Williamson, “Mul- dose calculation in heterogeneous media,” Med. Phys. 16, 577–592 tigroup discrete ordinates modeling of 125I 6702 seed dose distributions ͑1989͒. using a broad energy-group cross section representation,” Med. Phys. 29, 80A. K. Carlsson and A. Ahnesjo, “The collapsed cone superposition algo- 113–124 ͑2002͒. rithm applied to scatter dose calculations in brachytherapy,” Med. Phys. 106C. Zhou, F. Inanc, and J. M. Modrick, “Distortions induced by radioactive 27, 2320–2332 ͑2000͒. seeds into interstitial brachytherapy dose distributions,” Med. Phys. 31, 81K. A. Gifford, J. L. Horton, Jr., T. A. Wareing, G. Failla, and F. Mourtada, 3393–3405 ͑2004͒. “Comparison of a finite-element multigroup discrete-ordinates code with 107A. Carlsson Tedgren, Ph.D. thesis, Stockholm University, 2003. Monte Carlo for radiotherapy calculations,” Phys. Med. Biol. 51, 2253– 108H. Kubo, “Comparison of two independent exposure measurement tech- 2265 ͑2006͒. niques for clinical I-125 seeds,” Med. Phys. 12, 221–224 ͑1985͒. 82O. N. Vassiliev, T. A. Wareing, I. M. Davis, J. McGhee, D. Barnett, J. L. 109P. Papagiannis, D. Baltas, D. Granero, J. Perez-Calatayud, J. Gimeno, F. Horton, K. Gifford, G. Failla, U. Titt, and F. Mourtada, “Feasibility of a Ballester, and J. L. Venselaar, “Radiation transmission data for radionu- multigroup deterministic solution method for three-dimensional radio- clides and materials relevant to brachytherapy facility shielding,” Med. therapy dose calculations,” Int. J. Radiat. Oncol., Biol., Phys. 72, 220– Phys. 35, 4898–4906 ͑2008͒. 227 ͑2008͒. 110H. Hedtjarn, G. A. Carlsson, and J. F. Williamson, “Accelerated Monte 83A. Ahnesjo and M. M. Aspradakis, “Dose calculations for external photon Carlo based dose calculations for brachytherapy planning using correlated beams in radiotherapy,” Phys. Med. Biol. 44, R99–R155 ͑1999͒. sampling,” Phys. Med. Biol. 47, 351–376 ͑2002͒. 84D. W. O. Rogers, “Fifty years of Monte Carlo simulations for medical 111E. Poon, Y. Le, J. F. Williamson, and F. Verhaegen, “BrachyGUI: An physics,” Phys. Med. Biol. 51, R287–R301 ͑2006͒. adjunct to an accelerated Monte Carlo photon transport code for patient- 85H. E. Johns and J. R. Cunningham, The Physics of Radiology, 4th ed. specific brachytherapy dose calculations and analysis,” J. Phys.: Conf. ͑Charles C Thomas, Springfield, IL, 1983͒. Ser. 102, 012018 ͑2008͒. 86F. M. Khan, The Physics of Radiation Therapy, 3rd ed. ͑Lippincott Wil- 112M. J. Rivard, C. S. Melhus, D. Granero, J. Perez-Calatayud, and F. Ball- liams & Wilkins, 2003͒. ester, “An approach to using conventional brachytherapy software for 87R. Mohan, C. Chui, and L. Lidofsky, “Differential pencil beam dose clinical treatment planning of complex, Monte Carlo-based brachytherapy computation model for photons,” Med. Phys. 13, 64–73 ͑1986͒. dose distributions,” Med. Phys. 36, 1968–1975 ͑2009͒. 88T. R. Mackie, J. W. Scrimger, and J. J. Battista, “A convolution method of 113M. D’Amours, J. Carrier, E. Lessard, J. Pouliot, F. Verhaegen, and L. calculating dose for 15-MV x rays,” Med. Phys. 12, 188–196 ͑1985͒. Beaulieu, “A new approach for afterloading brachytherapy inverse 89A. Boyer and E. Mok, “A photon dose distribution model employing planned dose optimization based on the accurate Monte Carlo method,” convolution calculations,” Med. Phys. 12, 169–177 ͑1985͒. Med. Phys. 35, 2969 ͑2008͒. 90A. Carlsson Tedgren and A. Ahnesjo, “Optimization of the computational 114J. F. Williamson, S. Li, S. Devic, B. R. Whiting, and F. A. Lerma, “On efficiency of a 3D, collapsed cone dose calculation algorithm for brachy- two-parameter models of photon cross sections: Application to dual- therapy,” Med. Phys. 35, 1611–1618 ͑2008͒. energy CT imaging,” Med. Phys. 33, 4115–4129 ͑2006͒. 91K. R. Russell and A. Ahnesjo, “Dose calculation in brachytherapy for a 115M. Bazalova, J. F. Carrier, L. Beaulieu, and F. Verhaegen, “Tissue seg- 192Ir source using a primary and scatter dose separation technique,” Phys. mentation in Monte Carlo treatment planning: A simulation study using Med. Biol. 41, 1007–1024 ͑1996͒. dual-energy CT images,” Radiother. Oncol. 86, 93–98 ͑2008͒. 92J. F. Williamson, R. S. Baker, and Z. F. Li, “A convolution algorithm for 116M. Bazalova, J. F. Carrier, L. Beaulieu, and F. Verhaegen, “Dual-energy brachytherapy dose computations in heterogeneous geometries,” Med. CT-based material extraction for tissue segmentation in Monte Carlo dose Phys. 18, 1256–1265 ͑1991͒. calculations,” Phys. Med. Biol. 53, 2439–2456 ͑2008͒. 93J. F. Williamson, Z. Li, and J. W. Wong, “One-dimensional scatter- 117P. Petric, J. Dimopoulos, C. Kirisits, D. Berger, R. Hudej, and R. Potter, subtraction method for brachytherapy dose calculation near bounded het- “Inter- and intraobserver variation in HR-CTV contouring: Intercompari- erogeneities,” Med. Phys. 20, 233–244 ͑1993͒. son of transverse and paratransverse image orientation in 3D-MRI as- 94A. S. Kirov and J. F. Williamson, “Two-dimensional scatter integration sisted cervix cancer brachytherapy,” Radiother. Oncol. 89, 164–171 method for brachytherapy dose calculations in 3D geometry,” Phys. Med. ͑2008͒. Biol. 42, 2119–2135 ͑1997͒. 118K. Tanderup, T. P. Hellebust, S. Lang, J. Granfeldt, R. Potter, J. C. Linde- 95G. M. Daskalov, A. S. Kirov, and J. F. Williamson, “Analytical approach gaard, and C. Kirisits, “Consequences of random and systematic recon- to heterogeneity correction factor calculation for brachytherapy,” Med. struction uncertainties in 3D image based brachytherapy in cervical can- Phys. 25, 722–735 ͑1998͒. cer,” Radiother. Oncol. 89, 156–163 ͑2008͒. 96A. K. Carlsson and A. Ahnesjo, “Point kernels and superposition methods 119B. Al-Qaisieh, D. W. Smith, E. Brearley, S. St Clair, and P. Bownes, for scatter dose calculations in brachytherapy,” Phys. Med. Biol. 45, 357– “Comprehensive I-125 multi-seed comparison for prostate brachytherapy: 382 ͑2000͒. Dosimetry and visibility analysis,” Radiother. Oncol. 84, 140–147 ͑2007͒. 97A. K. Carlsson Tedgren and A. Ahnesjo, “Accounting for high Z shields 120F. A. Siebert, M. De Brabandere, C. Kirisits, G. Kovacs, and J. Venselaar, in brachytherapy using collapsed cone superposition for scatter dose cal- “Phantom investigations on CT seed imaging for interstitial brachy- culation,” Med. Phys. 30, 2206–2217 ͑2003͒. therapy,” Radiother. Oncol. 85, 316–323 ͑2007͒. 98K. R. Russell, A. K. Carlsson Tedgren, and A. Ahnesjo, “Brachytherapy 121F. A. Siebert, A. Srivastav, L. Kliemann, H. Fohlin, and G. Kovacs, source characterization for improved dose calculations using primary and “Three-dimensional reconstruction of seed implants by randomized scatter dose separation,” Med. Phys. 32, 2739–2752 ͑2005͒. rounding and visual evaluation,” Med. Phys. 34, 967–975 ͑2007͒. 99R. Wang and R. S. Sloboda, “Brachytherapy scatter dose calculation in 122C. Kirisits, F. A. Siebert, D. Baltas, M. De Brabandere, T. P. Hellebust, D. heterogeneous media. I. A microbeam ray-tracing method for the single- Berger, and J. Venselaar, “Accuracy of volume and DVH parameters scatter contribution,” Phys. Med. Biol. 52, 5619–5636 ͑2007͒. determined with different brachytherapy treatment planning systems,” 100R. Wang and R. S. Sloboda, “Brachytherapy scatter dose calculation in Radiother. Oncol. 84, 290–297 ͑2007͒. heterogeneous media. II. Empirical formulation for the multiple-scatter 123A. S. Meigooni and R. Nath, “Tissue inhomogeneity correction for contribution,” Phys. Med. Biol. 52, 5637–5654 ͑2007͒. brachytherapy sources in a heterogeneous phantom with cylindrical sym- 101G. M. Daskalov, R. S. Baker, D. W. Rogers, and J. F. Williamson, “Do- metry,” Med. Phys. 19, 401–407 ͑1992͒. simetric modeling of the microselectron high-dose rate 192Ir source by the 124J. F. Williamson, “Dose calculations about shielded gynecological col- multigroup discrete ordinates method,” Med. Phys. 27, 2307–2319 postats,” Int. J. Radiat. Oncol., Biol., Phys. 19, 167–178 ͑1990͒. ͑2000͒. 125G. Lymperopoulou, P. Papagiannis, A. Angelopoulos, P. Karaiskos, E. 102C. Zhou and F. Inanc, “Integral-transport-based deterministic brachy- Georgiou, and D. Baltas, “A dosimetric comparison of 169Yb and 192Ir for

Medical Physics, Vol. 36, No. 6, June 2009 2153 Rivard, Venselaar, and Beaulieu: The evolution of brachytherapy treatment planning 2153

HDR brachytherapy of the breast, accounting for the effect of finite pa- stage prostate cancer: A feasibility report,” Int. J. Radiat. Oncol., Biol., tient dimensions and tissue inhomogeneities,” Med. Phys. 33, 4583–4589 Phys. 49, 61–69 ͑2001͒. ͑2006͒. 139G. Kovacs, R. Potter, T. Loch, J. Hammer, I. K. Kolkman-Deurloo, J. J. 126J. J. DeMarco, R. E. Wallace, and K. Boedeker, “An analysis of MCNP de la Rosette, and H. Bertermann, “GEC/ESTRO-EAU recommendations cross-sections and tally methods for low-energy photon emitters,” Phys. on temporary brachytherapy using stepping sources for localised prostate Med. Biol. 47, 1321–1332 ͑2002͒. cancer,” Radiother. Oncol. 74, 137–148 ͑2005͒. 127A. Gerbaulet, R. Pötter, J.-J. Mazeron, H. Meertens, and E. Van Limber- 140C. Haie-Meder, R. Potter, E. Van Limbergen, E. Briot, M. De Brabandere, gen, The GEC ESTRO Handbook of Brachytherapy ͑ESTRO, Brussels, J. Dimopoulos, I. Dumas, T. P. Hellebust, C. Kirisits, S. Lang, S. Mus- 2002͒. chitz, J. Nevinson, A. Nulens, P. Petrow, and N. Wachter-Gerstner, “Rec- 128R. Nath, L. Anderson, D. Jones, C. Ling, R. Loevinger, J. Williamson, ommendations from Gynaecological ͑GYN͒ GEC-ESTRO Working and W. Hanson, AAPM Report No. 21, 1987. Group ͑I͒: Concepts and terms in 3D image based 3D treatment planning 129NCS Report No. 4, 1991. in cervix cancer brachytherapy with emphasis on MRI assessment of 130H.-J. Selbach, H.-M. Kramer, and W. S. Culberson, “Realization of ref- GTV and CTV,” Radiother. Oncol. 74, 235–245 ͑2005͒. erence air-kerma rate for low-energy photon sources,” Metrologia 45, 141R. Potter, C. Haie-Meder, E. Van Limbergen, I. Barillot, M. De Braban- 422–428 ͑2008͒. dere, J. Dimopoulos, I. Dumas, B. Erickson, S. Lang, A. Nulens, P. 131A. Herskovic, S. Lee, and T. Padikal, “Utilization of the computed to- Petrow, J. Rownd, and C. Kirisits, “Recommendations from gynaecologi- mography scanner in interstitial dosimetry,” Radiology 135, 781–782 cal ͑GYN͒ GEC ESTRO working group ͑II͒: Concepts and terms in 3D ͑1980͒. image-based treatment planning in cervix cancer brachytherapy-3D dose 132B. Pierquin and J. V. Fayos, “Dosimetry by tomography in interstitial volume parameters and aspects of 3D image-based anatomy, radiation curietherapy: Point technique,” Am. J. Roentgenol., Radium Ther. Nucl. physics, radiobiology,” Radiother. Oncol. 78, 67–77 ͑2006͒. Med. 87, 585–592 ͑1962͒. 142R. Potter, J. Dimopoulos, P. Georg, S. Lang, C. Waldhausl, N. Wachter- 133C. C. Ling, M. C. Schell, K. R. Working, K. Jentzsch, L. Harisiadis, S. Gerstner, H. Weitmann, A. Reinthaller, T. H. Knocke, S. Wachter, and C. Carabell, and C. C. Rogers, “CT-assisted assessment of bladder and rec- Kirisits, “Clinical impact of MRI assisted dose volume adaptation and tum dose in gynecological implants,” Int. J. Radiat. Oncol., Biol., Phys. dose escalation in brachytherapy of locally advanced cervix cancer,” Ra- 13, 1577–1582 ͑1987͒. diother. Oncol. 83, 148–155 ͑2007͒. 134S. L. Schoeppel, M. L. LaVigne, M. K. Martel, D. L. McShan, B. A. 143ICRU Report No. 38, 1985. Fraass, and J. A. Roberts, “Three-dimensional treatment planning of int- 144ICRU Report No. 58, 1997. racavitary gynecologic implants: Analysis of ten cases and implications 145J. Pouliot, Y. Kim, E. Lessard, I. C. Hsu, D. B. Vigneron, and J. for dose specification,” Int. J. Radiat. Oncol., Biol., Phys. 28, 277–283 Kurhanewicz, “Inverse planning for HDR prostate brachytherapy used to ͑1994͒. boost dominant intraprostatic lesions defined by magnetic resonance spec- 135L. Feuvret, G. Noel, J. J. Mazeron, and P. Bey, “Conformity index: A troscopy imaging,” Int. J. Radiat. Oncol., Biol., Phys. 59, 1196–1207 review,” Int. J. Radiat. Oncol., Biol., Phys. 64, 333–342 ͑2006͒. ͑2004͒. 136H. H. Holm, N. Juul, J. F. Pedersen, H. Hansen, and I. Stroyer, “Trans- 146K. Tanderup, D. R. Olsen, and C. Grau, “Dose painting: Art or science?,” perineal 125iodine seed implantation in prostatic cancer guided by tran- Radiother. Oncol. 79, 245–248 ͑2006͒. srectal ultrasonography,” J. Urol. ͑Paris͒ 130, 283–286 ͑1983͒. 147R. S. Malyapa, S. Mutic, D. A. Low, I. Zoberi, W. R. Bosch, R. Laforest, 137J. C. Blasko, P. D. Grimm, and H. Ragde, “Brachytherapy and organ T. R. Miller, and P. W. Grigsby, “Physiologic FDG-PET three- preservation in the management of carcinoma of the prostate,” Semin. dimensional brachytherapy treatment planning for cervical cancer,” Int. J. Radiat. Oncol. 3, 240–249 ͑1993͒. Radiat. Oncol., Biol., Phys. 54, 1140–1146 ͑2002͒. 138A. A. Martinez, I. Pataki, G. Edmundson, E. Sebastian, D. Brabbins, and 148U. Nestle, W. Weber, M. Hentschel, and A. L. Grosu, “Biological imaging G. Gustafson, “Phase II prospective study of the use of conformal high- in radiation therapy: Role of positron emission tomography,” Phys. Med. dose-rate brachytherapy as monotherapy for the treatment of favorable Biol. 54, R1–R25 ͑2009͒.

Medical Physics, Vol. 36, No. 6, June 2009