Journal of the Korean Physical Society, Vol. 50, No. 5, May 2007, pp. 1385∼1389 Review Articles

Accelerators and Medicine

William T. Chu∗ EO Lawrence Berkeley National Laboratory, Berkeley, California, U.S.A.

(Received 22 November 2006)

In 1930 Ernest Orlando Lawrence at the University of California, Berkeley invented the cy- clotron, which accelerated protons to 80 keV using less than 1 kV on a semi-circular “dee.” The 60-Inch (150-cm) Cyclotron (1939) that accelerated deuterons to 19 MeV, enabled the first ther- apeutic applications anywhere of artificially produced radioisotopes on human patients, thereby a new medical modality called nuclear medicine was born. Around the world, there are about 100 isotope-producing cyclotrons (accelerating protons, and much less frequently deuterons, to energies in the range of 15-20 MeV). After WWII, Lawrence completed the 184-Inch (4.7-m) Synchrocy- clotron that produced 340-MeV protons. The synchrocyclotrons in Berkeley and Uppsala, together with the Harvard cyclotron, would perform pioneering work in treatment of human cancer using accelerated hadrons. At the 184-Inch, in 1954 Cornelius Tobias and John Lawrence performed the first therapeutic exposure of human patients to hadron (deuteron and helium ion) beams. Clinical trials to treat human cancer using helium ions took place at the 184-Inch and the Bevalac, where trials using heavier ions including carbon, neon, silicon and argon ions were carried out to exploit their biological advantages over proton beams. Aside from the Berkeley trials, other clinical trials have been conducted at more than a dozen physics accelerators around the world. There are now proton and carbon-ion accelerator facilities dedicated for medical use around the world.

PACS numbers: 29.20.Hm, 29.20.Lq, 87.52.Df, 87.52.Ln, 87.53.-j Keywords: Accelerator, Cyclotron, Synchrotron, Cancer treatment, Nuclear medicine

I. INVENTION OF CYCLOTRON ated deuterons to 19 MeV. It was housed in the Crocker Laboratory, where scientists first made transmutations of some elements, discovered several transuranic ele- The invention of the cyclotron by Ernest Orlando ments, and created hundreds of radioisotopes of known Lawrence at the University of California, Berkeley elements. At the Crocker Laboratory the new medical seventy-five years ago profoundly changed the way we treat human diseases. Lawrence conceived the idea of the cyclotron early in 1929 after reading an article by Rolf Wider¨oeon high-energy accelerators [1]. In the spring of 1930 one of his students, Nels Edlefsen, constructed two crude models of a cyclotron [2]. Later in the fall of the same year, another student, M. Stanley Livingston, constructed a 13-cm diameter model (Fig. 1) that had all the features of early cyclotrons, accelerating protons to 80 keV using less than 1 kV on a semi-circular accel- erating electrode, now called the “dee” [3]. Following the discovery by J. D. Cockcroft and E. T. S. Walton of how to produce larger currents at higher voltages [4], Lawrence constructed the first two- dee 27-Inch (69-cm) Cyclotron, which produced protons and deuterons of 4.8 MeV. The 27-Inch Cyclotron was used extensively in early investigations of nuclear re- actions involving neutrons and artificial radioactivity. In 1939, working with William Brobeck, Lawrence con- structed the 60-Inch (150-cm) Cyclotron, which acceler- Fig. 1. The first cyclotron made by Lawrence and Liv- ingston (1930). ∗E-mail: [email protected] -1385- -1386- Journal of the Korean Physical Society, Vol. 50, No. 5, May 2007 modality called nuclear medicine was born, which used 60-Inch Cyclotron. Their research discovered the nature radioisotopes for diagnosis and treatment of human dis- of decompression sickness, known as the “the bends,” eases. In 1939 Lawrence was awarded the Nobel Prize that many military aviators suffered when flying at high in Physics, and later Element 103 was named “Lawren- altitudes without pressurized suits [5]. It is interesting to cium” in his honor. note that after more than a half century later, 81mKr gas Just before WWII, Lawrence and Brobeck designed is still used at hospitals to yield functional images of pul- the 184-inch cyclotron, but the war prevented the monary ventilation. Now it became routine for nuclear building of this machine. Immediately after the war medicine procedures that use radioisotopes to provide ended, the Veksler-McMillan principle of phase stability diagnostic information about the functioning of a per- was put forward, which enabled the transformation of son’s specific organs, or to treat diseases. The thyroid, conventional cyclotrons to successful synchrocyclotrons. bones, heart, liver and many other organs can be readily When completed, the 184-Inch Synchrocyclotron pro- imaged, and disorders in their function revealed. It is duced 340-MeV protons. Soon after, more modern syn- estimated that 15 to 20 million nuclear medicine imag- chrocyclotrons were built around the globe, notably at ing and therapeutic procedures are performed every year Columbia University, Carnegie Institute of Technology, around the world, and demand for radioisotopes is in- and University of Chicago in the United States, and an- creasing rapidly. In developed countries (about a quarter other in Uppsala, Sweden. The synchrocyclotrons in of world population) the frequency of diagnostic nuclear Berkeley and Uppsala, together with the Harvard cy- medicine procedures performed is approximately two per clotron, would perform pioneering work in treatment of 100 persons per year, and the frequency of therapy with human cancer using accelerated hadrons. radioisotopes is about one tenth of this. In the 1950s larger synchrotrons were built in the GeV A radioisotope used in Single Photon Emission Com- region at Brookhaven (3-GeV Cosmotron) and at Berke- puted Tomography (SPECT) must emit gamma rays of ley (6-GeV Bevatron), which produced antiprotons and sufficient energy to escape from the body yet it must antineutrons, many of the transuranic nuclei, and many have a halflife short enough for most of it to decay away excited states of hadrons. Today most of the world’s soon after imaging is completed. A positron emitter largest accelerators are synchrotrons, such as the 1-TeV with a similarly short halflife is needed in Positron Emis- Tevatron at Fermilab near Chicago and the 450-GeV Su- sion Tomography (PET). PET’s most important clinical per Proton Synchrotron (SPS) at CERN in Switzerland, role is in oncology, where fluorodeoxy glucose (FDG) is and all are direct descendents of Lawrence’s cyclotron used (incorporating 18F as the tracer), due to its accu- invented 75 years ago. racy in detecting and evaluating most cancers in a non- invasive way. It is also used in cardiac and brain imag- ing. Positioning of the radiation source within the body is the fundamental difference between nuclear medicine II. BEGINNING OF NUCLEAR MEDICINE imaging and other imaging techniques such as X-rays. Gamma imaging by either SPECT or PET provides a Lawrence’s interest in building accelerators centered, view of the position and concentration of the radioiso- of course, on nuclear physics; but from the onset he was tope within the body. Organ malfunction can be indi- keenly aware of their important applications in medicine. cated if the isotope is either partially taken up in the To study radiation in medicine, Lawrence brought to organ (a cold spot), or taken up in excess (a hot spot). Berkeley his physician brother, John Hundale Lawrence, If a series of images is taken over a period of time, an M.D., from Yale School of Medicine, who soon demon- unusual pattern or rate of isotope movement could indi- strated the isotope-making cyclotron’s worth in disease cate malfunction in the organ. Nuclear fission reactors research. John Lawrence became Director of the Divi- produce the bulk of medical radioisotopes [6], but iso- sion of Medical Physics at the University of California, topes of very short halflives, especially those for PET, Berkeley. Starting in 1936, John Lawrence operated a are produced by cyclotrons located near PET machines clinic to treat leukemia and polycythemia patients with in hospitals. Around the world, there are about 100 radioactive phosphorus produced at Crocker Laboratory, isotope-producing cyclotrons (accelerating protons, and then the site of the 60-Inch Cyclotron. These were much less frequently deuterons, to energies in the range the first therapeutic applications anywhere of artificially of 15 – 20 MeV). The typical beam power of such a cy- produced radioisotopes on human patients. Thus John clotron is of the order of 15 kW. In the foreseeable future, Lawrence became the “Father of Nuclear Medicine.” >100-MeV cyclotrons, and linacs, with beam power ten Ernest Lawrence himself became a consultant to the In- times greater, will be required to produce isotopes for stitute of Cancer Research at Columbia University. newer nuclear medicine procedures. One of the earliest biomedical uses of radioactive el- Radioisotopes produced at cyclotron facilities for var- ements was research conducted during WWII by John ied nuclear medicine applications include: Positron emit- Lawrence and Cornelius Tobias, another student of ters 11C, 13N, 15O, and 18F, which are used in PET to Ernest Lawrence. They used radioactive nitrogen, argon, study brain physiology and pathology, in particular to krypton, and xenon gases, which were produced at the localize epileptic focus, and in dementia, psychiatry and Accelerators and Medicine – William T. Chu -1387- neuropharmacology studies. They also have a significant for future implementation of hadron therapy facilities. role in cardiology. 18F in FDG has become very impor- When both the 184-Inch and Bevatron accelerators tant in detection of cancers and monitoring of treatment were closed in Berkeley, 2,054 cancer patients had been progress. Other radioisotopes are: 57Co (a marker to treated with helium ions and 433 patients with neon ions. estimate organ size), 67Ga (for cancer diagnosis), 111In Aside from these, many other clinical trials have been (for diagnostic brain studies), 123I (for diagnosis of thy- conducted at accelerators originally built for physics re- roid function; it is a gamma emitter without the beta ra- search, such as at the Gustaf Werner Institute (now diation of 131I), 81mKr (produced from 81Rb; 81mKr gas Theodore Svedberg Laboratory in Uppsala) [12], the is used for functional images of pulmonary ventilation), Harvard Cyclotron Laboratory (Cambridge) [13], Insti- 82Rb (produced from 92Sr; 82Rb is used in myocardial tute of Theoretical and Experimental Physics (ITEP in perfusion imaging with PET), 195mHg (for studies of the Moscow), Joint Institute of Nuclear Research (JINR in blood flow rate), 201Tl (for myocardial scintigraphy). Dubna), B. P. Konstantinov Institute of Nuclear Physics (in Gatchina near St. Petersburg) [14], National In- stitute of Radiological Sciences (NIRS in Chiba), Pro- ton Medical Research Center (PMRC in Tsukuba), Paul III. ACCELERATORS IN CURING CANCER Scherrer Institute (PSI in Villigen), Clatterbridge Hos- pital (UK), University of Louvain (Belgium), iThemba When the 184-Inch Synchrocyclotron was built, Ernest Laboratory for Accelerator-Based Sciences (originally Lawrence asked Robert Wilson, one of his graduate stu- NAC in Faure, S. Africa), Centre Protontherapie d’Orsay dents, to look into the shielding requirements for of the (CPO in Orsay), Crocker Nuclear Laboratory at Univer- new accelerator. Wilson soon realized that the 184-Inch sity of California in Davis, and the Midwest Proton Ra- would produce copious protons that had enough energy diotherapy Institute at the Indiana University Cyclotron to penetrate human body, which could be used for treat- Facility (IUCF in Bloomington). The experience at these ment of deep-seated diseases. Realizing the advantages centers has confirmed the efficacy of protons and light of delivering a larger dose in the Bragg peak [7] when ions in increasing the tumor dose relative to normal tis- placed inside deep-seated tumors (today we call it “con- sue dose, with significant improvements in local control formal” treatment), he published a seminal paper on his and patient survival for several tumor sites. M.R. Raju rationale to use accelerated hadrons for treatment of hu- reviewed the early clinical studies [15]. man cancer [8–10]. Soon after the 184-Inch Synchrocy- In 1991, the Loma Linda University Medical Center clotron was operating, Lawrence very generously parti- in California heralded in the age of dedicated medical tioned the limited space on the experimental floor for accelerators when it commissioned its proton therapy treating patients. In 1954 Cornelius Tobias and John facility with a 250-MeV synchrotron, which now treats Lawrence performed the pioneering first therapeutic ex- more than 1,200 patients per year. Soon after, many pro- posure of human patients to hadron (deuteron and he- ton therapy facilities were constructed worldwide. Syn- lium ion) beams [11]. Very active clinical trials to treat chrotrons, typically accelerating 200 – 250 MeV protons, human cancer using helium ions took place at the 184- are used in Japan at the Proton Medical Research Cen- Inch until 1986, when it was demolished to make room ter (PMRC) of the University of Tsukuba, Wakasa-Wan for the Advanced Light Source. The helium ion trials Energy Research Center, and Shizuoka Cancer Center. continued at the Bevalac, where trials using heavier ions A new 250-MeV synchrotron facility has been commis- including carbon, neon, silicon and argon ions were car- sioned in 2006 at the MD Anderson Cancer Center in ried out to exploit their biological advantages over proton Houston, where they plan to treat more than 3,000 can- beams. It is worth noting that in the early 1970s when cer patients per year. Cyclotrons, accelerating 235 MeV the aging Bevatron was converted to accelerate heavier protons, are used at the National Cancer Center Hospi- ions, the main push came from biomedical users who tal East in Kashiwa, Tokyo, the Northeast Proton Ther- wanted to use high-LET radiation for treating human apy Center in Boston, in Jacksonville (Florida), in Zibo cancer. (China), and Ilsan (Korea, under construction). Super- The hallmark of charged particle therapy with pro- conducting cyclotrons accelerating 250 MeV protons are tons and heavier ions is precise dose localization with being installed at the Paul Scherrer Institute (PSI in Vil- tight margins to spare normal tissues. The clinical im- ligen, Switzerland), and the Rinecker Proton Therapy plementation of proper techniques at Berkeley Lab led Center (Munich, Germany). to outstanding success in treating skull base and jux- With advances in accelerator design in the early 1970s, taspinal tumors with an unparalleled control and higher synchrotrons at Berkeley [16] and Princeton [17] accel- rates survival. These trials clearly demonstrated that the erated ions with atomic numbers between 6 and 18, at use of protons and helium ions is of value in the treat- energies that permitted the initiation of several biological ment of unresectable or partially resectable neoplasms studies [18]. In 1967, Tobias and Todd gave the scientific in critical locations such as the orbit, eye, skull base, justification for utilizing light-ion beams combining the head and neck, juxtaspinal area, retroperitoneum, biliary characteristics of light-ion beams in linear energy trans- tract and pelvis. The Berkeley results formed a model fer (LET), relative biological effectiveness (RBE) and -1388- Journal of the Korean Physical Society, Vol. 50, No. 5, May 2007 oxygen enhancement ratio (OER) [19]. In 1980 LBNL to provide both proton and carbon-ion beam therapy, published a report compiling the results of research in which provides protons of maximum energy of 230 MeV physics, biology and medicine about light-ion therapy and carbon ions of maximum energy per nucleon of 320 [20]. The conjecture was that the most advantageous MeV. Six therapy rooms are available with seven treat- species of ions for cancer treatment are located at higher ment ports. Three rooms are dedicated to carbon ion values of “oxygen gain factor,” which is a parameter pro- beams: one with a vertical beam line, one with a hori- portional to the inverse of OER, and at the same time zontal and one with a 45 degree oblique beam line. Two at higher values of RBE. For the smaller and shallower proton treatment rooms are equipped with commercially targets, it appeared that carbon and neon-ion beams are designed rotating gantries. By the end of 2005, HIBMC superior to other ions. For larger and deeper targets, has treated 825 patients using protons and 53 patients the relative placement of each of the therapy modalities with carbon-ion beams. is altered, and proton, helium and carbon-ion beams are The Heidelberg Ion Beam Therapy Center (HIT) is quite similar. constructing the Ion Therapy Unit in Heidelberg, Ger- The radiobiological rationale for using these high-Z many. It is a joint project of the University Clinic Hei- ions for therapy [21,22], as understood then, can be sum- delberg, the German Cancer Research Center (DKFZ), marized as follows: (a) The high resistance of hypoxic the Gesellschaft fur Schwerionenforschung (GSI) and the cells relative to oxic cells is reduced when irradiated with Research Center Rossendorf (FZR). Two ion sources feed high-LET radiation. (b) Slowly proliferating cells (in G0 the synchrotron via a linear accelerator. It houses three or long G1 phase in cell cycle) show a similar increase treatment rooms: two with a horizontal beam and one in sensitivity, if irradiated with high-LET radiation. (c) with a rotating gantry, which makes it possible to aim Overall treatment time with high-LET radiation can be the beam at the patient from all directions. This sys- shortened since fewer fractions of larger doses may be tem, which will be capable of treating tumors with both used instead of multiple fractions of small doses when carbon ions and protons, is expected to begin treating the surrounding normal tissue damage in a fewer frac- patients in 2007. tion can be kept comparable to that of a standard low- European Network for LIGHt ion Therapy (EN- LET fraction. The last point squarely contrasts against LIGHT) plans for four national centers: Heidelberg Ion the rationale that there is an advantage in using mul- Therapy (HIT); the Centro Nazionale di Adroterapia tiple, small fractions of low-LET radiation for sparing Oncologica (CNAO) in Pavia; MedAustron in Wiener late damage [23]. Cutting down the number of ion-beam Neustadt; and ETOILE in Lyon. There is an increas- treatments would benefit individual patients as well as ing interest in further initiatives and more countries are the management of the clinic. expressing interest in creating national projects, in par- In 1994 the National Institute of Radiological Sciences ticular Sweden, the Netherlands, Belgium, Spain and the (NIRS) in Chiba, Japan, commissioned its Heavy Ion UK. In Japan, a carbon-ion therapy facility project has Medical Accelerator in Chiba (HIMAC), which has two started in Gunma, and additional facilities are planned synchrotrons and produces ion beams from 4He to 40Ar in Tokyo, Kanagawa, and Nagoya. There are other ini- up to a maximum energy per nucleon of 800 MeV. The tiatives for light-ion facilities in several locations in the HIMAC houses two treatment rooms, one with both a US, in Lanzhou, China, in Busan, Korea, and elsewhere. horizontal and a vertical beam, and the other with a vertical beam only. There are also a secondary (radioac- tive) beam room, a biology experimental room, and a physics experimental room, all equipped with horizontal IV. CONCLUDING REMARKS beam lines. All beam lines are of the fixed beam type, in contrast to rotating gantries. Currently, their clinical We recall the words of the late Luis Alvarez, a No- trials use carbon ions, and they have successfully treated bel Laureate and one of the Ernest Lawrence’s closest a total of 2,867 patients by 2006. Currently, Phase I and colleagues: “Lawrence will always be remembered as II clinical trials are under way. They have demonstrated the inventor of the cyclotron, but more importantly, he safety and efficacy of carbon ions to a great extent. In should be remembered as the inventor of the modern the near future they plan to establish an optimum irra- way of doing science.” J. L. Heilbron and R. W. Sei- diation method, identify the sites and histological types del, in the introduction of their book, “Lawrence and in which carbon ions are particularly effective, and clar- His Laboratory” [24] stated, “The motives and mecha- ify differences in indication from low-LET radiation. In nisms that shaped the growth of the Laboratory helped 2004 HIMAC has obtained for the carbon-ion treatment to force deep changes in the scientific estate and in the the Japanese government approval as “highly advanced wider society. In the entrepreneurship of its founder, medical technology,” which is comparable to the US FDA Ernest Orlando Lawrence, these motives, mechanisms, Clearance. and changes came together in a tight focus. He mobilized In 2001 at Harima Science Garden City, Japan, the great and small philanthropists, state and local govern- Hyogo Ion Beam Medical Center (HIBMC) was commis- ments, corporations, and plutocrats, volunteers and vir- sioned as the first hospital-based facility in the world tuosos. The work they supported, from astrophysics and Accelerators and Medicine – William T. Chu -1389- atomic bombs, from radiochemistry to nuclear medicine, utilize 99mTc, whose precursor 99Mo is produced shaped the way we observe, control, and manipulate our in nuclear fission reactors. Also, 125I and 192Ir for environment.” Indeed, all over the civilized world, the cancer therapy are produced through neutron capture ways we do science changed forever after Lawrence built in reactors. Many of these aging nuclear reactors must his famed Radiation Laboratory. be replaced either with spallation neutron sources or There are currently several particle accelerator 150-MeV cyclotrons (or linacs) with high-power proton beams. projects in Korea, and their successes and future expan- [7] W. H. Bragg and R. Kleeman, Philosophical Magazine sions will critically depend on how to obtain sustained 8, 726 (1904). public (and private) funding, which requires strong pub- [8] R. R. Wilson, Radiol. 47, 487 (1946); R. R. Wilson, lic support. Just as Lawrence successfully secured the in Advances in Hadrontherapy edited by U. Amaldi, B. public and private funding for doing medicine with his Larsson and Y. Lemoigne, Excerpta Medica, Elsevier, accelerators, we could strengthen the public support by International Congress Series 1144, ix-xiii (1997). doing medicine with our accelerators. With the limited [9] Y. K. Lim, B. S. Park, S. K. Lee, K. R. Kim and T. K. funding, our accelerators will contribute little in the cut- Yang, J. Korean Phys. Soc. 48, 777 (2006). ting edge scientific research, yet they will be decisively [10] B. S. Park, K. R. Kim, S. K. Lee, M. Y. Lee and J. S. useful in novel applications of moderately sized accelera- Chai, J. Korean Phys. Soc. 48, 772 (2006). tors, such as in producing radioisotopes for newer nuclear [11] C. A. Tobias and J. H. Lawrence et al., Cancer Research 18, 121 (1958). medicine procedures or in cancer treatment. When we [12] B. Larsson, Brit. J. Radiol. 34, 143 (1961). take the leadership in several fronts in medical research, [13] H. D. Suit, M. Goitein, J. Tepper, A. M. Koehler, R. A. the public support of our accelerator projects will grow, Schmidt and R. Schneider, Cancer 35, 1646 (1975). and we could hope for brighter future for particle accel- [14] L. L. Goldin and V. P. Dzhelepov et al., Sov. Phys. Usp. erator development in Korea. 16, 402 (1973). [15] M. R. 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