Nuclear Physics for Medicine

Nuclear Physics European Collaboration Committee (NuPECC) Nuclear Physics for Medicine European Science Foundation (ESF) Nuclear Physics European Collaboration The European Science Foundation (ESF) was Committee (NuPECC) established in 1974 to provide a common platform NuPECC is an Expert Committee of the European for its Member Organisations to advance European Science Foundation. The aim of NuPECC is to research collaboration and explore new directions for strengthen collaboration in nuclear science by research. It is an independent organisation, owned by promoting nuclear physics, and its trans-disciplinary 66 Member Organisations, which are research funding use and application, in collaborative ventures between organisations, research performing organisations European research groups, and particularly those from and academies from 29 countries. ESF promotes countries linked to the European Science Foundation collaboration in research itself, in funding of research (ESF). NuPECC encourages the optimal use of a and in science policy activities at the European level. network of complementary facilities across Europe, Currently ESF is reducing its research programmes provides a forum for discussing the provision of future while developing new activities to serve the science facilities and instrumentation, and advises and makes community, including peer review and evaluation recommendations to the ESF and other bodies on the services. development, organisation, and support of European nuclear research, particularly on new projects. The www.esf.org Committee is supported by its subscribing institutions which are, in general, member organisations of the ESF involved in nuclear science and research or The European Science Foundation hosts six Expert research facilities. Boards and Committees: • The European Space Sciences Committee (ESSC) www.nupecc.org • The Nuclear Physics European Collaboration Committee (NuPECC) • The European Marine Board (EMB) Nuclear Physics for Medicine edited by: • The European Polar Board (EPB) Faiçal Azaiez, Angela Bracco, Jan Dobeš, Ari Jokinen, • The Committee on Radio Astronomy Frequencies Gabriele-Elisabeth Körner, Adam Maj, Alexander (CRAF) Murphy and Piet Van Duppen • The Materials Science and Engineering Expert Committee (MatSEEC) In the statutory review of the Expert Boards For further information contact: and Committees conducted in 2011, the Review Panel concluded unanimously that all Boards and • Professor Angela Bracco Committees provide multidisciplinary scientific NuPECC Chair services in the European and in some cases global Università degli Studi di Milano framework that are indispensable for Europe’s Dipartimento di Fisica and INFN sez. Milano scientific landscape, and therefore confirmed the need Via Celoria 16 – 20133 Milano – Italy for their continuation. Tel: +39 02 50317252 The largely autonomous Expert Boards and Email: [email protected] Committees are vitally important to provide • Dr Gabriele-Elisabeth Körner in-depth and focused scientific expertise, targeted NuPECC Scientific Secretary scientific and policy advice, and to initiate strategic c/o Physik-Department E12 developments in areas of research, infrastructure, Technische Universität München environment and society in Europe. 85748 Garching – Germany Tel: +49 172 89 15 011 / +49 89 2891 2293 Email: [email protected]

http://www.nupecc.org/index.php?display=staff/contacts

Cover pictures: Top: Nuclei consist of protons (red) and neutrons (blue), which are each made up of three elementary quarks held together by gluons. Below: (left) Advanced approaches to high intensity laser-driven ion acceleration, see page 123. (Right) Image of an FDG-injected rat heart obtained in a small PET scanner for molecular imaging, see page 69. ISBN: 978-2-36873-008-9 Contents

Foreword 3

Introduction 5

Chapter I – Hadrontherapy 9 1. Introduction 11 2. Facilities in operation and planned 14 3. Accelerators 18 4. Beam delivery 24 5. Dosimetry 27 6. Moving targets 30 7. Radiobiology 33 8. Modelling 37 9. Treatment planning 41 10. Boron neutron capture therapy 46 11. Clinical programme update in particle therapy 53 12. Outlook 56

Chapter II – Medical Imaging 59 1. Introduction 61 2. From nuclear to molecular imaging 63 3. New challenges 70 4. Interfaces 84 5. Outlook 92

Chapter III – Radioisotope Production 95 Introduction 97 1. Properties of radioisotopes for nuclear medicine 98 2. Production methods and facilities 111 3. Examples and specific topics 128 Annexes 145

We you enjoyable wish reading! NuPECC members Working and Groups were topics. setup NuPECC forthree members the and Nuclear physics is a coin that has two sides: basic two basic research applications.Nuclear physics Without has and that acoin is NuPECC Chair NuPECC Bracco Angela incorporated, resulting in the report now the in at hand. resulting incorporated, steps necessary various the thoroughly have NuPECC liaisons followed discussed and particular in main sections: hadrontherapy, medical imaging and radioisotope and production –topics hadrontherapy, sections: are that imaging main medical to prepare this report. The draft reports were published on the NuPECC website and discussed draftwere NuPECC reports discussed the on published The website report. toand prepare this therapy.“Nuclear ThereforePhysicsthree report this for with initiated its Medicine”, NuPECC of society. health and wealth to the research there would be little to be applied; applications resulting from basic research contribute to applications beapplied; resulting research belittle there would at an open meeting in Paris on 18 Paris in November open meeting at an 2013.input The was receivedfromthe community abroad. and Europe pursuedin widely and actively l l l Foreword Modern medicine benefits tremendously from nuclear physics, both for diagnosis and fortremendously from benefitsdiagnosis medicine Modern forphysics, both nuclear Following the successful model of model previous conveners NuPECC reports, successful the were byFollowing engaged Secretary Scientific NuPECC Körner Gabriele-Elisabeth

Nuclear Physics for Medicine 3

Thus Thus it representsfulfill a contribution towards The presentThe reportone is initiatives of the Rutherford in the early 20 early the Rutherford in European Science Foundation. Foundation. Science European Nuclear physics methods find increased applica find physicsNuclear methods Physics –see Europe’ www.nupecc.org/ in for 2010 Nuclear Physics in Europe” in (see www. issued by NuPECC in 1994 and in 2003 with two two with 2003 1994issued by NuPECCin in and development to tied the intimately of new detec on society.impact of the committee expert of mission this the ing nupecc.org/pub/lrp10/lrp2010_final_hires.pdf nupecc.org/pub/impact_applications_interac physics progressed has new have ideas and pub/impact_applications_1994.pdf of nuclearphysics of indeed physics and itself. of these have found, and will increasingly find, find, increasingly haveof will these and found, tions_2002.pdf sciences life containment, change climate tion, diverse as as areas trans-disciplinary within tions accelerators techniques, tion to theoretical and the first discovery of the atomic of nucleus the by discovery first the beyond our daily experience there agreat experience is vari beyond daily our reports on ‘Impacts and Applications of and Nuclear onreports ‘Impacts science, cultural materials monitoring, and rity and simulation frameworks. A large number Alarge frameworks. simulation and as those in medicine which have which medicine considerable in those as and cancer therapy, cancer and environment space, secu and outside realm the well life, applications daily in heritage, arts and archaeology. Comprehensive archaeology. and arts heritage, energy, transmuta and processing waste nuclear of applications related and such techniques ety l l l Introduction launched by NuPECC after the successful publi thesuccessful launched by NuPECC after surveys on the impact of physics impact nuclear on the weresurveys cation of its latest Long Range Plan “Perspectives Plan cation Range of its latest Long While most nuclearphysics phenomenaWhile far are The developmentThe of nuclear physics since , respectively. nuclear then Since th century has been has century and www. and - ). ). ------(always indirectly but very often directly) devel butto often (always very indirectly focus on accelerator-based researchfocus in nuclear improve medical diagnostics and contribute and toimprove diagnostics medical issued in 2010, suggesting directions and astrat and directions 2010,issued in suggesting nuclear physicists to peer “inside” the nucleus can nucleus can the nuclear physicists to peer “inside” nection is: how nuclear physics can techniques deal and at a high level, to answer to these key level,to these to answer at and a high deal physics related on the and accelerator, detector, most appropriate therapeutic strategies. therapeutic appropriate most of nuclear physics provides fundamental supportof nuclearphysics provides fundamental not can Indeed opments only nuclear medicine. in questions. that further development physics nuclear of the further that to the requests of many specialist physicians, requeststo the of specialist many imaging isotopes suited for best used medical the report prepared bythis a group of distinguished that we havethat to issue thus and decided to focus those accelerators,by used those but techniques the body to study human health and diseases. diseases. and health human tobody study the inside agents these trace and to image be used and isotope-production technology contribute technology isotope-production and antee early detection of disease and to the select and of detection disease antee early to guar looking specialists, nuclear medicine and treatmentand be produced developed and with of the course include these and needs future and expert researchers, who haveexpert contributed agreat egy in the field, one important important onerecommendation field, the in egy to developmentsemerged leading of technologi life sciences. One important question in this con this question in sciences. One important life such as oncologists, radiologists, radiotherapists, radiotherapists, radiologists, oncologists, as such of current view to be has pursued in base skills concerns applications. In particular it stated was particular concerns applications. In cal interest. cal cancer therapy?cancer question specific It on is this In the last Long Range Plan of Plan NuPECC, Range Long last the In In a multidisciplinary vision, the knowledge the vision, a multidisciplinary In It is important to stress that laboratories to that stress It important with is - - - - -

Nuclear Physics for Medicine 5 Nuclear Physics for Medicine 6 These topics are interlinked but the underlying underlying the These buttopicsinterlinked are What do physicians do of ask nuclearphysics?What And what is the medical and physical point and of view medical what the is decided benefit. has to NuPECC put empha will which also contribute consider by also providing which in the three chapters. three the in on radioisotope production. third the and imaging laboratories, European in case the commonly is new developments nuclearmedicine from which for opportunities interesting advances, nological new infrastructures in Europefor produc the in new infrastructures particular, because of their cutting edge tech edge cutting of because their particular, of hadrontherapy, medical imaging and radioiso and of hadrontherapy, imaging medical tope production? technological developmentstechnological have his own their techniques and of particular improvements in of particular and techniques these be stressed in will that peculiarities and tory on hadrontherapy, first the the second on medical tion and study of radioactive beams offer in offer of beams radioactive study and tion require some consideration to are addressed and day. lives every saving This ratories are literally are fully dedicated to nuclear medicine. The to medicine. nuclear dedicated fully are advice to centres and other which able expertise each of topics these stressed others on well is the some extent in this booklet. booklet. this some in extent structive interaction with physicians is central. physicians central. is with interaction structive report. this in aspects onsis these chapters. On the other hand the influence of influence new the chapters. hand other On the gress made in radiation oncology in recent in oncology years radiation in gress made Paracelsus, a famous alchemist and medicus of medicus and alchemist a famous Paracelsus, Curies, the alchemists’ dream was eventually eventually was dream alchemists’ the Curies, for medicine.” for in medicines.” With the discovery of nuclear discovery the With medicines.” in physics, that it is for the making of new gold physics, it forthat is making the of alchemy, that it is for the making of goldof alchemy, it for making is that the us such is not the only aim, but also to con but also aim, not is only such the us therefore conclude: “Many have of said nuclear Today,try. we may Paracelsus, years after 500 thetransmutations by Joliot- artificial first the and Soddy and Rutherford by transmutation 16 early the - by physics nuclear radiochemis realised and and silver (andand elements’) other isotopes. For silver.and but For to not me is aim, such the sider what virtue and power may lie in these these power and in may lie sider what virtue consider only what virtue and power and may lie consider what virtue only In the footsteps of the alchemists the of footsteps the In The answers to these questions are various andare these answers questions various to The This report is organised into threechapters:into is organised report This A principal theme of ChapterA principal pro the 1 is In applying nuclear physics in medicine, con physics nuclear medicine, applying in In Life sciencesLife projects nuclear physics in labo th century stated: century

“Many have said ------With few exceptions required radionuclides the With with light and heavy ion heavy and accelerators. light with imaging parallel advances in instrumentation for instrumentation advances in parallel imaging advances.Developments medical in imaging ics been research involved always has medical in exploitation regard, of new this In future. the in contribution the see that One can results. imaging of the forissues hadrontherapy selectivity the are ideas and innovative techniques. innovative and ideas fuel essential the are radionuclides Indeed use. ical producing facilities modern role the important in an spectrometry, of playing is mass which imaging control hadrontherapy. in chapter quality is This nuclei (ions).therapy,frontier in radiation This nuclear physics experiments, sharing methods, methods, sharing physicsnuclear experiments, driven by the use of hadrons (particles subject of (particles hadrons use by the driven different strategies strategies forisotopes different producing for med production methods and their use for nuclear use their and production methods progressed point of over main The years. the medicine activities. They certainly provide this certainly They activities. medicine play amajor role. advances lead to further can and past the mous in making this enterprise surely one of the important one enterprise surely important of the this making or accelerators physics nuclear particle in facilities attention given is to new and Particular medicine. ous body parts using radioactive tracers radioactive have using parts body ous of physics nuclear to hadrontherapy been enor has of scientists and technical personnel for nuclear technical of and scientists out of accelerator research reactor and centres that this chapter to is emphasise howthis phys nuclear - to the strong force) strong to the protons as such atomic and techniques, and manufacturers. Emphasis is given is Emphasis manufacturers. and techniques, of proton dedicated and/or availability the ion new on-going developments.together with Key the productionthe of new isotopes radioactive come applications. nuclearmedicine all driving is that simulation interplayand to of the detector design technologies in the nuclear physics research will physics nuclear the research in will technologies be produced by artificial transmutation driventransmutation by be produced by artificial release of energy, the collimation of the particles, particles, of the release of energy, collimation the illustrated is worldwide, pursued and recognised reactors. It is important to stress that advances in advances in to that reactors. stress It important is radioactive beams. beams. radioactive accelerators, integration of the diagnostic and are not present in natural decay chains, so have decay to notare chains, present natural in somedescribes briefly in medical applications also Apointof major focus models. reconstruction and how the techniques for producing images ofhow for vari techniques producing images the have nuclear physics research as their main goal, goal, have main physics nuclear their research as sector with a very inspiring environment for new inspiring avery sector with from physicsspin-offs nuclear laboratories dealing centres play a key role in education and training centres play a key role education training and in The focus Chapterof isotopeThe is focus 3 radioactive In general, accelerator general, In research and reactor Chapter 2, devoted to imaging, illustrates illustrates Chapter devoted 2, to imaging, - - - Rather, it updated overview gives of how an fun way in nuclear physics facilities. As with previous with As nuclearphysicsway in facilities. Framework to be it important is Programmes, funding agencies and policy makers in research makers in agencies policy and funding damental nuclear physics nuclear research (indamental itsbroadest driven by the technical efforts currently under currently efforts technical by the driven mutual roles of fundamental and applied and nuclear roles of fundamental mutual community), physics nuclear the (beyond munity on developments in medicine. in developments on of latest developments the nuclear medicine in jects within Horizon 2020 that will enhance the enhance will that Horizon 2020 within jects booklet is not is intendedbooklet to be a position paper. research. engaged in and committed to nuclearphysics committed and pro in engaged sense) has had and will continue to havesense) impact an will had and has committee intends to inform the scientific com scientific the to inform intends committee As a final remark it is worth noting that thethat remarknoting is it worth a final As With this document the NuPECC expert the document this With - - - -

Nuclear Physics for Medicine 7

Outlook 12. 11. Clinical programme update in therapy particle 10. 9. 8. 7. 6. 5. 4. 3. 2. 1. Chapter I Chapter Conveners: Hadrontherapy Radiology Introduction planning Treatment targets Moving delivery Beam Dosimetry Accelerators Modelling planned and operation in Facilities 10.3 9.2 9.1 3.4 Microbeams 3.3 10.2 10.1 4.3 11.2 11.1 8.1 7.3 7.2 7.1 6.3 6.2 6.1 5.2 5.1 4.2 4.1 3.2 3.1 2.1 8.2 4.4 8.3 therapy capture neutron Boron Introduction

Introduction Introduction

RBE Introduction Introduction

Introduction The planning process treatment Beam featuresBeam for a centre hadrontherapy Beamline orientation inBeamline orientation the rooms treatment From the to accelerator the rooms treatment cells stem Cancer Introduction detection Motion organs moving Imaging tools forDosimetry hadron radiotherapy development Historical radiotherapy facilities hadron of development Historical Principle and interfacing methods delivery Beam Monte modelling Carlo in hadrontherapy Secondary neutrons Secondary Introduction

practice clinical in BNCT BNCT physics indications therapy Proton (Orsay, FAIR, Galès ELI) –Sydney (GSI) Durante Marco

34 30 30 38 33 33 48 53 53 46 46 25 27 27 37 24 24 24 37 31 41 41 19 19 18 18 14

9.4 11.4 10.4 9.3 7.5 5.3 5.3 3.7 3.7 3.6 3.5 10.5 11.3 7.4 6.4 2.3 2.2 10.6 4.7 4.6 4.5 6.5 8.6 8.5 8.4

Summary

Hypofractionation Future R&D Fragmentation Summary Current developmentsCurrent aspects assurance Quality therapies Combined Current status Current advantages and disadvantages Cyclotrons and synchrotrons: Motion mitigation strategies Future facilities Proton andion carbon facilities in operation challenges and Perspectives considerations Other performances delivery Beam images PET of Simulations

Conclusions

Perspectives Accelerator-based sources neutron indications ions carbon of Development Therapeutic neutron beams neutron Therapeutic

44 54 44 54 35 35 48 50 28 39 39 26 26 26 22 22 40 32 21 52 31 30 56 53 33 46 24 27 37 15 15 18 41 14 11

Nuclear Physics for Medicine 9

Two successive, comprehensive of the surveys Radiology l l l Introduction 1. for treating cancer [3]. cancer for treating Today, second the is cancer in this field. this in have which on impact our had alarge instruments, 1994in [1] [2]. 2003 and These havereports shown nuclear physics medicine, in ofimpact fundamental ogy and medicine and the intense collaborations collaborations intense the and medicine and ogy on “hadrontherapy” gives an updated view on the on the updated view gives an on “hadrontherapy” or more in radiation preciselyof ionising use of the through the development the ofthrough novel and methods between physicists, biologists and physicians and biologists physicists, between the very strong interface between physics, between strong interface biol very the cancer, wereagainst published by fight NuPECC the treatment still presents challenge. areal treatment still in article for foundation hadrontherapy his the with accelerators associated equipment and methods and highest cause of death in developed Its in of cause countries. death highest present spirit the chapter this In systems. healthcare current developments on the growing use of particle of developments particle use current growing on the 40 20 0 In 1946, accelerator pioneer Robert Wilson laid accelerator 1946, laid In pioneer Wilson Robert 1950 about therapeutic interest the of protons 1970 1990 - (protons, neutrons and light ions) for treatment of of ions) treatment for light and neutrons (protons, Loma Linda, California, in 1990. in 10,000 More than California, Linda, Loma integral dose delivered whole tolower the integral and body moreirradiation efficient of in and accurate ing ment treatmenthospital-based first of the in centre on physical (better ballistic accuracy) as well as as well accuracy) as on ballistic physical (better therapy modality based on nuclear particles on based particles nuclear therapy modality the worldthe from 1950 to 2015. the tumour, thereby sur dose to tumour, the reducingthe the biological reasonsbiological (especially for ions), heavy result Variousbon. turn-key now are companies offering rounding healthy tissue and thus leading to alower leading thus and tissue healthy rounding have protons been treated establish with the since clini cutting-edge advanced, intoan grown has have car heavier been treated with generally ions, early and advanced tumours. Today advanced and early tumours. proton therapy exponential growexponential of proton therapy centres around solutions for medical centres. Figure solutions for medical 100,000 Around modality. cal The benefitsThe of hadrontherapy based areboth Hadrontherapy is an innovative cancer radio- cancer innovative an is Hadrontherapy 2010 and 2015. and 1950 between world the in centres therapy proton of number the of Evolution 1.1. Figure patients worldwide

1.1 shows the the shows - - - - - 11 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 12 Nuclear Physics for Medicine – Chapter I – Hadrontherapy X-rays lose energy slowly and mainly exponentially X-rays exponentially slowly mainly and lose energy (Villigen, Switzerland). end 1980s of By the the it (Villigen, was already active in Russia, but it not was yet Russia, very active in already was moved is beam pencil where small avariable energy In the 1970s the European community was very very was community 1970s the European the In Figure Pion therapy was terminated, and PSI switched to switched PSI and Pion therapy terminated, was full flexibility in thetreatment,patient accelerator flexibility full is so sharp that new techniques had newto techniques be developed that so sharp is nary and transnational venture: its full development venture: its full transnational and nary popular in Western in Afew milestones Europe. popular cost of pionpossible production. high of because the a cost-effectivepatients that and treatment notwas project, apilot PSI much interested pions, with in partners. hadrontherapy interest in morbidity. Clinical more energy at the end of their range in matter – matter in range more end at of the their energy of tumours, exploiting the characteristic shape of characteristic the exploiting of tumours, ton therapy trial for ocular tumours. Proton therapy therapy Proton tumours. ocular for trial therapy ton Tounprecedented of target. the conformity allow an tumour, the reaching of slices different through the catunder fall These to whole treat the target. depositiondose The tissue. healthy surrounding the toreduced with damage beam, incidentthe particle the in region depth at a awell-defined to target makes possibleit peak Bragg The peak. Bragg the dosedeposition i.e. for hadrons, curve Bragg the toward its widespread current (see use 2, Section became clear that there was no clinical benefit to there no that was clinical clear became of energy the by adjusting be tuned can that body radiobiologists, engineers and IT experts, as well well as experts, IT and engineers radiobiologists, competencesrequires the of physicists, physicians, it that delivers precision fact resides the in treatment as collaboration between research and industrial research industrial between collaboration and as as they penetrate tissue, charged particles release particles charged penetrate tissue, they as of traversed. of matter depth While afunction as high-energy protons, building on their running pro running on their protons, building high-energy egories of passive scattering, where one or more or one where scattering, passive of egories largely driven and influenced by influenced physics. and nuclear driven largely system called “gantry”. called system delivery becoupled beam should isocentric to an scatterers to or spread used scanning, are beam, the The history been of hadrontherapyEurope in has history The Hadrontherapy epitome the is of a multidiscipli 2.2 ) are summarised below. summarised ) are - - - •  •  1996:  1991 1989 1999 1975 1969 1974:  1988 1982 1977 1973 1992 1990 •  Villigen therapy • Proton worldwide therapy • Pion Villigen 1980–1993:Villigen Vancouver 1979–1994: 2012 Los Alamos 1974–1982: Alamos Los

German proposals and projects: and proposals German Darmstadt Heidelberg: Sweden: Russia: France project: Since 1991:Since patients treated at 5,000 More than Curie Institut November The In 2006: old synchrocyclotron with a250MeV with old synchrocyclotron proton ambitious an programme launched officially the Centre 1991the between 2010 and treatment its cancer to extend the replacing accelerator agantry and Other European therapy projects projects therapy European Other (no ocular treatments) ocular (no

Active beam delivery beam Active Vertical Ocular treatments 72MeVOcular Depth passive beam spreadpassive beam deep seated tumours 230 MeV 230 deep seated tumours ring deflection cyclotron protons Large proposal same partners not funded not funded partners proposal same Large Launch of the project of the FranceLaunch Hadron for Creation Orsay of the Proton Therapy Uppsala Dubna Petersburg St. Moscow ITEP First proposalFirst Wannenmacher Zero proposal:not finished MeV 200 protons DKFZ and MPI Second proposal (Wannenmacher, Specht proposalIntermediate for EU (GSI) Kienle Heidelberg) Lorenz(DKFZ), (Radiology Centre (CPO), with ahospital unit in particle therapy particle in the Centre (Saint-Cloud)the René-Huguenin Gustave-Roussy (Villejuif), Institut the by BMBF by research and creation of infrastructures research creation and of infrastructures and the Paris Public Hospitals(AP-HP). Public Paris the and exclusive 201 of the use Mev proton synchrocyclotron, under the auspices the of a under synchrocyclotron, consortium comprising the Institut Curie, Curie, Institut the comprising consortium

/ : degrader Heidelberg: : patient shift

: horizontal magnetic magnetic : horizontal

230 patients 230 503 patients patients 367

• • • • • • • • • • • • • • • • • • May 1993 construction: Dresden joints FZ • Start • • • Austria: GSI Pilot project: Pilot GSI CERN: München: Ion beamHeidelberg Therapy HIT: start 2002 start ENLIGHT ENLIGHT PIMMS EULIMA EULIMA Neustadt and CNAO, and Neustadt Pavia (not active) IN2P3 Pierre Mandrillon At present the synchrotron is installed and and presentAt installed is synchrotron the New leadership Projekt Entwicklungs 2006 I+II+IIIDecember 1998: study Feasibility idea neutron of the the end 90s ofBy the the May 1993 project Austron proposed: was 1988 member became GSI Univ. MRC &Gray lab. Louvain, Catholique Main contractor Centre A. Laccasagne, Nice: contractor Laccasagne, CentreMain A. supported 1987October by EU Bruxelles start Members: MedAustron, TERA, CERN, CERN, TERA, Members: MedAustron, PIMMS was used for MedAustron at Wiener for used MedAustron was PIMMS End of project July 2008 after 440 patients 440 after ofEnd project 2008 July 2013: 1500 patients protonRinecker project 2002 proposal February positive construc 2003 decision by start BMBF September 1998 to Proposal BMBF New options: treatment 3Dscanner, biological treatment December 1997 start 2009 start treatment: ca. 1500 treatment: patients ca. treated start 2009 35 costs € total Mio Estimated Layout and technical part: GSI GSI part: Layout technical and Gruppe PEG Onkologie 2000 (Prague) CERN, GSI GSI (Prague)Onkologie CERN, 2000 patient treatment is expected in 2yearspatient treatment in expected is planning, in vivo PET in planning, medical part: Siemens part: medical treated the project the up to now tion attion Heidelberg authors Pötter, Auberger;Regler survived project but medical source the died spallation neutrons for source spallation

proton ion medical machine study proton machine ion medical The second proposal neverwas decided MedAustron: MedAustron: GSI, zur Hausen DKFZ) Hausen zur GSI, by BMBF but the partners started to started by but partners BMBF the called The atso GSI: facility the construct European light ion medical accelerator ion medical light European European network light ion therapy: network light European

- • TERA foundation, INFN, GSI and many local insti local many and GSI INFN, foundation, TERA Exhibition Exhibition will bepresented. have Accelerator also facilities will chapter, this adescription world ofIn the map facilities remains the community’s primary goal, goal, primary community’s the remains facilities it is also of paramount importance that existing existing that importance of paramount it also is in more than 20 venues 20 Europe more around in than infancy and in a clinical research phase with great research phase with a clinical in and infancy diation of healthy surrounding tissue. Fundamental Fundamental tissue. ofsurrounding healthy diation developing and optimising the next-generation next-generation the optimising and developing physicistsdoctors and now are together working delivery and dosimetry, including range control range including dosimetry, and delivery [1] [2] maximum efficiency associated with minimum irra minimum associated with efficiency maximum potential. [3] of hadrontherapy development centres their and used in the medical field for the early diagnosis and diagnosis the field forearly medical the in used research laboratories, conceivedtal mostly built and period 1995–2002 the shown in was which tutions, these structures. Hadrontherapyin its a field is structures. these therapy radiation (IGRT) image-guided tion in will medical diseases; other and treatment of tumours by academic research teams, to turn-key industrial industrial to turn-key researchby academic teams, research on radiobiology will bediscussed. research will on radiobiology and patient areanowadays are and target to ensure used study. under are Very dosimetry, and precise simu and are able to discuss global strategies. The strategies. revolu global able are and to discuss have an enormous impact in cancer therapy. While have therapy. cancer enormous in impact an While ensembles. Innovations precise on very new and evolved recent from fundamen in going decades, ers, clinicians and patients have and protocols to access clinicians ers, References lation and modelling of both beam characteristics characteristics beam of both modelling and lation centres research intensively collaborate that and cle accelerators and detectors are increasingly being cle accelerators being detectors and increasingly are Currently the largest community of scientists of scientists community largest the Currently interested hadrontherapy, in from different disciplines (http://enlight.web.cern.ch) disciplines State-of-the-art techniques borrowed parti from techniques State-of-the-art ESF. Nuclear Science in Europe: Opportunities Europe: Opportunities Nuclear Science in NuPECC, Impact and Applications of and Impact NuPECC, NuPECC, Impact, Applications, Interactions Interactions Applications, Impact, NuPECC, R.R. Wilson. (1946). Radiological use of fast of (1946). fast use Wilson. Radiological R.R. NuPECC Report of NuPECC NuclearScience. protons. protons. and Perspectives. Report and NuPECC Hadrons for Health Radiology

47 : 487–491. : , supported by CERN, , supported by CERN, 1994, ESF. 1994, 2003, 2003, ------13 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 14 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 1993. The rationale of using heavy charged particles in can charged particles heavy The using rationale of Theoretical and Experimental Physicsin Experimental (ITEP) and Theoretical Africa, nowadays called iThembaLABS, 200 MeV200 iThembaLABS, nowadays called Africa, University. He realised that by exploiting the high high University. the by exploiting that He realised Moscow, in of NuclearResearch Joint the Institute l l l Japan. At the National Accelerator National the At Japan. South Centre in were Cyclotron treated Harvard Laboratory, at the 1957 protons in Wernerwith started Gustaf at the Institute in Uppsala, Sweden. Uppsala, in Institute Dubna, the Leningrad Institute of NuclearPhysics Institute Leningrad the Dubna, Sciences, Chiba and the University the and of Tsukuba, Chiba Sciences, of Institute the Villigen, in Scherrer Institute facilities developed beam- for physics, nuclear with facilities 2.1 in Gatchina, the National Institute of Radiological of Radiological Institute National the Gatchina, in 2. 2. duce a dose distribution that is highly conformal conformal highly is that duce a dose distribution deuteron and helium ion beams from 184 iondeuteron the beams inch helium and dose peak) deposit (Bragg end at particle of the the protons have to been treat used patients cancer since of radiotherapy. of numbers patients Significant the Gustav Werner Institute in Uppsala, the Paul Paul the Uppsala, Gustav Wernerthe in Institute proton, Berkeley with in Laboratory Radiation the surrounding the sparing volume target to while the trajectory, absence the of dose beyond particle the at Harvard working time at that tor of FermiLab, Facilities in operation Facilities operation in by Robert R. Wilson, the subsequent founding direc subsequent the founding Wilson, R. by Robert radiotherapy was based exclusivelyradiotherapy based was on accelerator penumbra lateral produced sharp the by and range healthy tissue. Patient treatment started in 1954 Patient in at treatment tissue. started healthy to probe used can beams particle charged heavy of hadron radiotherapy facilities radiotherapy of hadron lines and treatment and rooms adapted needs to the lines synchrocyclotron. In Europe patient treatments treatments patient Europe In synchrocyclotron. cer radiotherapy was originally formulated in 1946 formulated in cer radiotherapy originally was and planned From 1960s mid-1980s to the the particle Historical development Historical - - - FermiLab, in 1990. It was the first dedicated clinical clinical dedicated 1990. first in It the was FermiLab, first scanning systems systems were thedeveloped in research scanning first Centre since 1989. (UK) cyclotron The used been has Center in Munich. in Center Scanditronix, operating at the Clatterbridge Oncology Oncology Clatterbridge the at operating Scanditronix, for fast neutronfor fast radiotherapy proton and therapy of facilities at PSI (Villigen, Switzerland) for protons at (Villigen, PSI facilities gantries. rotating three equipped with facility ions other than carbon and pions and carbon the were Of ions other than used. to improve expected thus is treatment outcome. The not included in these statistics. these not in included dedicated 250dedicated MeV proton developed synchrotron, by [1]. Treatments protons with accountfor over 85% patients treated with protonspatients (43 treated with 46% more than of the total, while treatments with carbon have carbon treatments with been while total, of the volume target and the with of dose distribution the installa the major The step next was tumours. ocular the MC60 62.5 MC60 MeVthe proton cyclotron, delivered by was first centres. The tors hospital-based in clinical trons and borontrons and neutron therapy capture (BNCT) are cases remaining the about 10% In in used cases. of the technique volume.This tumour the dosewithin the USA) of University a (California, Linda attion Loma been treated with hadrontherapybeen treated end by with of the 2012 respectively. More recently scanning beams haverespectively. beams More recently scanning improvement asignificant the in conformity of results and GSI (Darmstadt, Germany) for ions carbon (Darmstadt, and GSI and had ocular tumours. Patients treated with fast neu Patients fast treated with tumours. had ocular have to treat been used patients 1996 since 1997, and eye melanoma and is still used (2013) used still is eye and melanoma for treatment of started to be used on a routine basis in several clini in on to aroutine basis beused started cation of scanning beams, which allows “painting” “painting” allows which beams, cation of scanning construction and installation of accelera dedicated installation and construction cal facilities, such as at the Rinecker Proton Therapy Rinecker at the as such facilities, cal A new era in particle therapy started with the the with therapy started A particle new era in A major step in particle therapy appli the was A major particle step in Since its start in 1954, nearly 110, in its start Since 000 patients had patients had 000 000) 000) - - - - - Villigen, Rinecker Proton Rinecker TherapyCenter (PTC) Villigen, A report of the Corporate Strategic Intelligence A report Corporate of the Intelligence Strategic Proton of the to Therapy statistics According 2012. In three centres only carbon ion centrescarbon treatment2012. three only is In (CSIntel) perspectives market on and situation the were protons. patients opened with aretreating and 2013 of twoProCure half centres first the In wide. In Europe gantries are used to treat are used patients at gantries Europe PSI In Proton therapy 33 centres performed is world in October 2012 [2], 39 active lists proton ion and ther Cooperative Group [1] 39 proton ion carbon and for proton world, therapy published in the around 2.2 in München, Orsay, München, in Essen. and Prague Heidelberg, at Heidelberg. facility HIT at the only available is Essen in WPE the as well as Illinois and Seattle in the USA, Japan and Europe. A carbon ion gantry ion Acarbon Europe. gantry Japan and USA, the forused treatment (Hyogo, Heidelberg Pavia). and centres protonthree both are ion carbon and beams therapy centres were operationalend at of the beams with energies around 200 MeV 200 energies around are with or higher beams apy facilities with a total of 106 atotal treatment with rooms. apy facilities Chiba), and another in Gunma, applied (Lanzhou, 2.2.1 in operation in In 34 proton therapy centres worldwide proton worldwide centres proton therapy 34 In Proton gantries are available in 23 centres 23 Proton in availablein are gantries Proton and carbon ion facilities facilities ion Proton carbon and Hadrontherapy centres Hadrontherapy - - At the beginning of 2013 new 27 proton beginning the At therapy very sharp distal fall-off and penumbralateral of fall-off distal sharp very 60 MeV60 74 MeV: and (Germany), Berlin Catania Kraków (Poland),Kraków (Switzerland). PSI The advantage Europe and Japan presented is and Europe Figure in (PTCOG) web page [1]. page web (PTCOG) (Italy), Orsay Nice and (France), (UK), Clatterbridge for Europe and Japan are given in Figure 2.2. Figure in given are Japan and Europe for maps Detailed legend. figure the in indicated as treated patients of number the to proportional is spot the of size The worldwide. Figure 2.1. 2.3 is offering a dedicated a low protonenergy offering is accelera energies between proton use Europe with in beams commissioning proton and carbon ion therapy centres worldwide is is worldwide centres therapy ion carbon proton and of the lower energy cyclotrons is in particular the the of lower particular the cyclotrons in is energy or in the commissioning phase. In Europe five Europe In new phase. commissioning the or in the dose distribution. At the moment, the At no vendor dose distribution. the updated Proton on the TherapyCooperative Group tor Themap for treatmentof active of eye tumours. centres six tumours For treatmentused. of ocular tries are being installed or commissioned (Trento, installed are being tries 2.3.1 shown in Figure shown in centres around the worldcentres the around were construction under centres with C-235 cyclotrons and scanning gan C-235centres with scanning cyclotrons and construction facilities is published and regularly regularly and published is facilities construction The full list of currently operated and under operated and currently list of full The Future facilities Facilities in construction and and construction in Facilities Proton (red-orange) and C-ion (green) centres active active centres (green) C-ion and (red-orange) Proton 2.1 , and a detailed map of those in map in of those adetailed , and 2.2. - - 15 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 16 Nuclear Physics for Medicine – Chapter I – Hadrontherapy Rinecker centreMunich) on to Pencil in rely only Rinecker Kraków, Dimitrovgrad). Uppsala, Dresden, They will start operation 2013–2015. in start will future: laser driven p-beam (7). p-beam driven laser future: (6); p-beam conventional bunker: Experimental p.a. < 500 pat. capacity nozzle, (4); universal gantry isocentric room: Therapy (3). transport (2); beam system selection (1); 235 energy Proteus cyclotron transport: beam and accelerator proton Conventional Figure 2.3. in Dresden is again based on the IBA Proteus 235 IBA on based the Dresden again is in The Oncorayinnovations. protontherapy facility driven acceleratordriven ( the third in the world (after PSI in Villigen and the and world the in (afterVilligen in PSI third the cyclotron, but has already included room included cyclotron, for but already alaser- has The protontherapy in centre Trento (ATreP)is Many of these novel facilities present novel of Many these unique facilities Layout of the Dresden proton therapy facility. facility. therapy proton Dresden the of Layout Figure 2.3 ). very likely that one of the rooms will have one a diag that ofrooms the will likely very where bony the anatomy not is areliable surrogate to be closerbrought to shifter range the allow will Beam Scanning (PBS) a treatment as delivery Scanning Beam for the first time in this centre. This functionality functionality This centre. this in time first for the it will bepossible severalproton to choose among it will nostic on-rail CT available for patient positioning, availablefornostic on-railCT patient positioning, delivery time. Some studies suggest that relying relying that suggest Some studies time. delivery prior to dose treatment for available are immediate of tumour position, but also to more position, but also sophisticated of tumour of treatment where lower energies (below 70 MeV) on larger spot sizes may allow better compensa better may spoton sizes allow larger treatment and dosedistribution of the quality thus opening the door not only to treat indications door to not treat the indications only opening thus treatmentthe room prior to treatment. It now is in imaging tissue soft needthe for high-quality projectthe Trento in great emphasis placing is on quality dosimetric improving the thus patients, the a of such whereverification experimental first the in terms both of specifications available technical gives This ATrePtechnique. probablythe best PBS tion for intrafraction motion, and ATreP motion, and be fortion intrafraction will adaptive schemes, where the images acquired just adaptive just acquired where schemes, images the are needed but to not cover Last least, target. the hypothesis will be possible. The so-called ‘moveable be possible. The so-called will hypothesis snout’ is another interesting innovation available available innovation interesting another is snout’ the best compromise to spot between find sizes spotspot and position size accuracy. number of patients treated as indicated in the figure legend. figure the in indicated as treated patients of number the to proportional is spot the of size The Japan. and Europe in Figure 2.2. In addition to that, it is the first centrewhere first it the is to that, addition In Proton (red-orange) and C-ion (green) centres active active centres (green) C-ion and (red-orange) Proton - - According to the report of CSIntel [2], report to the ofAccording CSIntel 255 pro several have proposals other Europe, In been Arabia. Trust in Manchester and UniversityTrust London and Manchester College in Two to beoperational by centres 2017 planned are University Hospital. The location at the emerging Universitythe The locationemerging Hospital. at (NCPRT) been approved has new Aarhus the within worldwide by 2017, numbers is this by 2020 while www.icrsh.ro/ for scheduled is 2014. compact gantry IBA A with Hospital (UCLH). In the Netherlands several proHospital Netherlands (UCLH). the In Pencil Beam Scanning gantries, will be operational will gantries, Scanning Pencil Beam ket are stimulating active research development and ket stimulating are for protons ions), heavy and (see Romania http:// moment at is the uncer very offacility the future nuclear in extensive pursue basic studies will facility in Great Britain: at the Christie NHS Foundation NHS Christie at the Greatin Britain: to becompleted planned is end towards of the 2016. PTC Poland the Poznań, In stage. planning the in is 2015.in therapy tothe the programme, addition In new Aarhus University Hospital campus will enable Universitynew will Aarhus Hospital campus decided The radiotherapy to the quit business. planned in India, China, Korea, Taiwan Saudi China, and India, in planned to enter operation 2017. in planning to addition In proton therapy centre Petersburg St. at Center the biology. and medicine physics, of the National Center for Particle Radiotherapy Radiotherapy Center National of for the Particle first planned; being are patients per year of 2,200 by Varian to be built Russia Systemsof in Biological Institute International ofof the Medicine Nuclear Proteus two 235on IBA possessing cyclotron and ton therapy treatment rooms will be operationalton therapy treatment rooms will 2017. place in take treatments should Four locations treatmentton therapy atotal capacity centres with 2014 In Wiener Neustadt will in MedAustron tain. completed Siemens because it practically is though tion. tries. accelerators gan towards cheaper and smaller and treatmentdevelopments rooms. These the mar in protons for both tre planned ions). heavy and be completed. Nice acceptance of the In a super by Siemens, did not start clinical operation even clinical notby Siemens, start did and Maastricht. The site selection process will be The site selection will process Maastricht. and Groningen Delft, proposed: being Amsterdam, are 2.3.2 expected to increase to about 1,000 particle therapy to to particle increase aboutexpected 1,000 centre, rapid of currently and the easy construction submitted in Bulgaria (a synchrotron-based centre Bulgaria in submitted new Japan, centres and USA are several newin PTC completed in 2013. In Denmark, the construction construction completed the 2013. in Denmark, In 250 MeVconducting ProteusOne synchrocyclotron when possible, treatment and, adapta calculation The CCB facility in IFJ PAN Kraków, IFJ based also in PAN facility CCB The The Marburg particle therapy facility, built built therapy facility, particle Marburg The New accelerators New ), and Norway (also in this case, acen case, Norway), this (also and in ------MeV synchrotron, primarily developed in Russia developed Russia MeV in primarily synchrotron, Powered.Mevion Medical are Four systems such MEVION S250 is the world’ssuperconduct S250 the is first MEVION years been announcing a highly compact intensity- ahighly years been announcing Particle Acceleration Corporation)Particle for has several ProTom acompact comes market 330 into with the ing synchrocyclotron proton synchrocyclotron ing therapy from system [1] [2] modulated protonmodulated powered system therapy (IMPT) offers the synchrotron based CONFORMA 3000 3000 CONFORMA synchrotron thebased offers under installation in USA. Optivus Proton Therapy Optivus USA. in installation under by the dielectric-wall accelerator (DWA), dielectric-wall by the but it yet. used not has but been system clinically the remains in the development the in remains phase. and the Radiance 330 PT system. CPAC system. 330 PT (Compact Radiance the and and will be soon introduced for The customers. will and References Several new solutions are being proposed new solutions being are Several Therapy MarketReport (PTCOG) webpage http://ptcog.web.psi.ch/ webpage (PTCOG) Particle Therapy Co-Operative GroupParticle Proton Proton Intelligence, Strategic Corporate . CSIntell, 2012. . CSIntell, - 17 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 18 Nuclear Physics for Medicine – Chapter I – Hadrontherapy The feasibility of radiotherapy with heavy charged charged with heavy of radiotherapy The feasibility At the time Wilson proposed of heavy use the Wilson time the At l l l (about 230 MeV for 400 MeV/ protons roughly and without changing the techniques used to produceused techniques the changing without heavier ions carbon)with (essentially at present only Accelerators 3.2 3.2 3.1 facilities synchrotrons are applied, while for therapy while applied, are synchrotrons facilities in the human body) existed. The synchro-cyclotron, synchro-cyclotron, The body) human existed. the in heavier ions up to including nous cyclotrons are mainly used, although in some in although used, nous cyclotrons mainly are delivering beams with the required energy that were that required the energy with beams delivering of accelerators delivering availability on the depends protons and heavier ions started. Proton therapy Protontherapy started. ions heavier protons and proton therapy: in therapyparticle compact isochro protonsinstance first butlater the on in particles, the capability of (synchro-)cyclotrons capability the time. at that with Radiotherapy required. dose distributions the of accelerator for to produce types beams the tinct beams with the required characteristics. The histori The required characteristics. the with beams - therapy, dis of particle two led use and has to the amu foramu ions carbon needed are to reach location any were energies beyond requires that beam and well radiotherapy with experimental available time at the heavier ions, on the other hand, started in the 1970s the in started heavier hand, other on ions, the extent based on the accelerator types capable accelerator on based the extent of types started in the 1950s at synchro-cyclotrons, which which 1950s the at synchro-cyclotrons, in started is large to a situation This use. in are synchrotrons 3. cal developmentcal of accelerator technology, mainly capable of producing beams with the required energy required the energy capable with of producing beams accelerators no radiotherapy for particles charged cyclotrons isochronous bereplaced with easily could guided by the needsof by subatomic the physicsguided research Introduction Historical development 40 Ar, first and foremost foremost and first Ar, - - The first patient treatment The with protonstook place USA, built to make the first explorationstheinto first to the make built USA, It is relevant to mention that this technique is still It still is relevant is technique to mention this that Berkeley (Super-)HILAC, required yet another Protontherapy 160 MeV at the synchro-cyclotron facilities today. facilities in 1954 at 188 inchin Berkeley, at the synchro-cyclotron ions from helium to argon using a similar technique technique asimilar to using argon ions from helium wheel required modulator producing the energy ing dose-depth distribution, a collimator to conform conform to collimator a distribution, dose-depth pulsed beam with pulse period of 1–10 s. pulse with beam pulsed First patient 1957 physics In patients zoo. wereparticle first the opment of the heavy ion synchrotron, delivering a a opment delivering ion heavy of synchrotron, the the energies required to reach deep-seated tumours. energies requiredthe to reach deep-seated tumours. treatments were done at the Berkeley Bevalac with treatments were with done Berkeley at Bevalac the to avoid deposited dose being beyond tumour. the shape acompensator and tumour to the beam the increased by a strongly was beam of the size the ume tumours. brain more particular in tumours, tron (~100 Hz rate, low intensity, pulse energy) fixed Sweden. Uppsala, Werner in Gustaf the Institute at synchro-cyclotron 200 MeV the treated with at the the Tobiasat of al. et research radiobiological the based on the phase focusing discovered by Veksler focusing phase onbased the breakthrough in accelerator technology: the devel the accelerator in technology: breakthrough proton therapy of clinical majority at the used being and MacMillan, made it possible to pass the energy it made possible energy the to pass MacMillan, and at Harvard University,dedi at Harvard first the became which effects, and to achieve for proton and helium beams and to achieve for beams protonand effects, helium limit of the classical cyclotron, caused by relativistic cyclotron, caused by relativistic of classical the limit limited its application treatment to the oflimited static sophisticated scatter foil system followed system by arotat foil sophisticated scatter continued until 2002. until continued 1961cated in proton started therapy facility, and The beam characteristics of the synchro-cyclo the of characteristics The beam The stepThe towards heavier motivated ions, by volTo target to the dose distribution the tailor - - - - - • • • Austria), and GSI (Darmstadt, Germany), real Austria), (Darmstadt, GSI and University (Shanghai, China). In Japan three carbon carbon Japan three China). In University (Shanghai, Rhön Klinikum (Marburg, Germany) and Fudan Germany) (Marburg, Fudan and Klinikum Rhön Japan Europe to and develop dedicated synchrotrons (Pavia, Italy) and MedAustron (Wiener Neustadt, Neustadt, (Wiener (Pavia, Italy) MedAustron and with heavierin with ions haveeffort led to asignificant Gunma) by different Japanese manufacturers, while while Gunma) byJapanese manufacturers, different Germany), where patients have over 400 been treated for carbon therapy that are suitable for installation installation for suitable are that therapy carbon for ised by Siemens (Heidelberg, Germany), at HIT in a clinical treatment centre. In Europe design design treatment Europe centre. In aclinical in period 1997–2009. the in much techniques: more irradiation sophisticated on therapyprogrammes carbon established were also protons.ment with Subsequently extensive research trol of accelerators enabled has development the of Hyogo Chiba; and therapy centres were(NIRS, built for treat used the as to shape dose distribution the at NIRS (Chiba, Japan), whereat NIRS some 7,000 patients have been treated (Darmstadt, 1994, GSI since and lar for treatment the oflar radiation-resistant tumours several more construction. under are studies were made by CERN, realised at CNAO realised were by made CERN, studies The energy of the beam extracted fromsynchro a extracted the beam of Theenergy fromthe accelerator The narrow beam is actively sophisticated computerThe advent conhighly of in particu obtained results promising The very varying the primary beam energy. avari beam Instead primary the varying Neustadt, Austria), which is under construction. under is Austria), which Neustadt, Italy), (Houston, MDAnderson USA). It will with an energy analysing system consisting of consisting system analysing energy an with spot/raster the combination with scan in which HIT (Heidelberg, Germany),HIT CNAO, (Pavia, Harvard. Cyclotrons deliver a fixed energy beam, so is it beam, energy Cyclotrons a fixed deliver Switzerland) and GSI (Darmstadt, Germany)Switzerland) (Darmstadt, GSI and ning technique results in a volume scan. This This avolume scan. in results technique ning neered at (Villigen, PSI atresearch the facilities not possible to vary the penetration depth by penetration depth not the possible to vary of accurately tuned magnets. This so-called so-called This magnets. tuned of accurately technique has been developed has now is technique at and GSI be adjusted, ions of penetration the can the depth or basis on be varied apulse-to-pulse tron can treatment centres gradually is and to clinical replacing the scattering technique developed technique at scattering replacing the required value. required able thickness energy degrader in combination combination in degrader energy able thickness (Wiener MedAustron-facility at the beused also applied clini based at synchrotron being also even within one pulse. By using this technique technique this By using one pulse. even within spot or raster scanning technique has been pio has technique spot or raster scanning since the mid-1990s. the since It now transferred is being over by means scanned area to beirradiated the several magnets is used to tune the energy to the to the energy the to tune used is several magnets cal centres for carbon and/or proton therapy: and/or proton therapy: carbon for centres cal ------• • • 12 The use of hadrons, particularly protons,in radio use particularly ofThe hadrons, A large amount of data on the relative on of the data amount biological A large ventional radiation therapy, requires compliance compliance requires therapy, radiation ventional years for pre-clinical research in hadrontherapy. research in years for pre-clinical with stringent specifications on the distribution distribution the on specifications stringent with www.cenbg.in2p3.fr/microbeam2013/ with our experience and the data available in the the available in data the and experience our with Low-energy acceleratorsLow-energy have for been used many 3.3 3.4 following definitions and specifications in accordand specifications definitions following Table 3.1. Table reported is in cells of living irradiation necessary for positioning and visualising the cellu the visualising and for positioning necessary discoveries in radiobiology. The microbeam radiobiology. discoveriescom in The defined as for moreother defined conventional radioactive munity holds regular meetings: the 11 the meetings: regular holds munity microbeam-jp.org/iwm2015/ of charged particles. Complex imaging systems are are systems Complex imaging of particles. charged or Linacs (seeor Linacs Chapter https://www.gsi.de/ 7and of dose in order to achieve a highly conformal 3D conformal orderof dose in to achieve a highly therapy centre have must are: therapy. regard the introduce we should this therapies. In against therapy amajor fight is the innovation in by magnetic focusing. by magnetic (or where cells beam, it possible is single to target bio-pide and haveand new decisively contributed to fundamental achieved is either with delivery particle in accuracy active microbeam facilities employed facilities active for microbeam targeted held in Bordeaux (France) Bordeaux held in 2013 October in ( effectiveness (RBE) of charged particles has been has effectiveness charged particles of (RBE) lar or sub-cellular targets, and the sub-micrometre the and targets, or sub-cellular lar low-energy accelerators). micro the is case Aspecial literature. Increased selectivity ballistics of hadrons, of hadrons, ballistics selectivity Increased literature. sub-cellular structures) with apre-defined number with structures) sub-cellular specifications of a hadron beam is not yet as well is not specifications as of abeam hadron well yet a hadrontherapy centre a hadrontherapy collimators or, more frequently in the new machines, or,collimators more new machines, the frequently in compared with photons and electrons used in concompared photons in electronsused with and cancer. However,and level the definitions of the gathered low-energy Tandem, Graaf, der in van th The general characteristics that each hadron The characteristics general volume treated; treated; volume volume tissue to healthy betreated the and Microbeams started operation about started years ago, Microbeams 30 that surrounds it and high dose uniformity in in dose uniformity it high and surrounds that possible; as short as treatment times ability to treat most atdepth; cancers any ability high ability to discriminate between the the between to discriminate ability high Beam features for features Beam Microbeams will be in Fukui (Japan) in 2015 (Japan) in Fukui be in ( will for a database of RBE data including including data of RBE for adatabase ). A list of the current current of the ). Alist th meeting was was meeting http://www. ) and the ) and http:// ------19 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 20 Nuclear Physics for Medicine – Chapter I – Hadrontherapy • • • The minimum range required for a line dedicated line required range for a minimum The 38 cm in water. demanded in energy The equivalent 38 cm microbeam workshops (period from 2010 to 2013). Table courtesy of Dr Philippe Barberet, CENBG, France. CENBG, Barberet, Philippe Dr of two 2010 last 2013). to the from at Table courtesy (period reported workshops facilities the from microbeam constructed was list The cells. living of irradiation targeted for microbeams particle Charged 3.1. Table It is therefore necessary to define a beam Itof a beam had therefore is to define necessary In the case of lines devoted treatment of to the lines case of the shal In for a carbon ion beam is equal to 400 MeV/amu. to 400 for equal ion is acarbon beam depth, practical range defines the distance between between distance the defines range practical depth, point where reduced dose is the by It 10%. depends, of a beam ofof 250 abeam MeV protons approximately is to the treatment of deep tumours is 22 cm in water. in 22 cm is treatmentto the of deep tumours the along materials and energy beam on the usually, of input of protons beam the surface distal the and choicethe of accelerator to use. fortreatmentused the have in adecisive influence beam line (tools for tools line beam, beam forthe monitoring rate, field size, uniformity and symmetry of the field, the field, of symmetry and uniformity rate, field size, peak, of Bragg the modulation ofrons terms path, in adaptation range and beam modulation). beam The and adaptationrange range of penetration (range), depth adjustment of the dose energy protons 70 and MeV,energy 60 between whose range low tumours such as in the eye, treatments eye, require the in as such low tumours off. fall penumbra distal lateral and Europe Inside Europe Outside The required characteristics of the hadron beams the beams hadron of The characteristics required If one considers the dose curve as a function of afunction one as If considers dose curve the for fixed and orientable beam lines; andlines; orientable for fixed beam dosimetry; dosimetry; reliable control systems. reliable availability of treatment access rooms with availability high accuracy (≤ accuracy 3%)high absolute relative in and Laboratory GSI SNAKE Ion BeamCentre PTB CENBG RARAF JAERI SPICE/NIRS IMP IMP Location Darmstadt, Germany Munich, Germany Surrey, UK Braunschweig, Germany Bordeaux, France New York, USA Takasaki, Japan Chiba, Japan Fudan, China Lanzhou, China

- - Thereforetheusedwhen penetration be only it can thegreater solutioninconveniencelatter The has in 0.1–0.2 mm steps in water for beams with an energy energy 0.1–0.2 mm an water with steps for in beams ions protons. heavier than 3–3.5 cmis water.should the in beam of The range depth of the beam is no more than 4–5 cm. When When cm. no is 4–5 more of beam the depth than be achieved can by This 5 cm. than larger depths preferable aproperly with to energy reduce beam the on the dose-depth curve where reduceddose is the curve dose-depth on the steps of for at in most 5cm and 1mm of less than the SOBP.the in be variable should width SOBP The of to 95% flat part comparedthe in value to the points distal and proximal the between distance the of ions) case the it that deteriorates and geomet the (only it that produces fragments in neutrons light and be adjustable in steps of 0.2 mm in water for depths water for in steps depths ofbe adjustable 0.2 mm in ric characteristics of the beam (emittance ofbeam the increase).ric characteristics an absorber in front Shifter). absorber patient in ofan the (Range homogeneous dose throughout the tumour. This so- This tumour. homogeneous the dose throughout energy. energy. patient’s the order in entrance in body to deposit a or inserting beam of the energy the either changing enlarged by varying the particle energy upon energy particle the by varying enlarged lower than 70lower MeV than steps for 1to 2mm higher in and required are penetration itlarger depths highly is solution is always recommended in the case of using ofsolution recommended using case always is the in outside treatment degrader the shielded room. This called Spread-Out Bragg Peak Spread-Out (SOBP) Bragg called as defined is Ion species rarely p,He,Li C toU Si, Cl,I p, He, Li, Be, B, C, O, F, p toCa p, He p, He p, He He, C,Ne,Ar p p, He C The longitudinal width of the Bragg peak is peak of Bragg the width longitudinal The Energy range 1.4–11.4 MeV/u I: 05–2MeV/u Si, Cl:1–4MeV/u Li–O: 1–8MeV/u He: 1.4–10.5MeV/u p: 4–28MeV O: 12MeV He: 6MeV P: 4MeV 2–20 MeV 1–3.5 MeV 1–5 MeV Ar: 11.5and13.3MeV/u Ne: 13and17.5MeV/u C: 18.3MeV/u He: 12.5MeV/u 3.4 MeV 6 MeV Several to100MeV/u - • • • • vary from 2x2 to 15x15 cm from 2x2 vary Many factors, such as the intensity of the beam, beam, of the intensity the as such factors, Many In any case, it bepossible field should case, to the adjust any In field size requirements vary from 2x2 to 40x40 cm 40x40 tofrom 2x2 field size requirements vary arediameter andin mm 5 between 35 field sizes zontal and vertical beam, as those with the gantry, gantry, the with those as beam, vertical and zontal influence the maximum dose rate to the target. dose thetarget. rateFor to the maximum influence penumbra determined not is the only systems ing penumbra The is only 2mm. less than case, any in of 0.5 mm. accuracy overall an steps with of 1mm in needed. For horizontal beams used to treat diseases to treat used diseases Forneeded. beams horizontal due to the characteristics of the primary beam. Also Also beam. primary of the due characteristics to the mainly influenced by the divergencethe the by pencil influenced of mainly ment tissue the duespread to the in beam of the of extraction system and the beam scanning pattern. pattern. scanning beam the and system of extraction headof field neck,size requirements the the and the penumbra size at the maximum depth of treatdepth penumbra atthe maximum size the possible as and, small patient beas the should body tumours, treatment the of in ocular used beams, tal transport and the technique used to vary the energy, the to vary used technique the and transport ofefficiency beam the system, extraction beam the between the source and collimator. When using using When collimator. source and the between between 0.5 and 1 cm, so the following aspects aspects 0.5between following so the 1 cm, and properties optical by the determined is which beam, between distance reducingthe collimators, by using by the but also characteristics beam primary by the at different energy and quality with a FWHM of FWHM a with and quality energy at different penumbra lateral is the energy a variable primary For gantry. horizon arotating fixed with lines and should be taken into consideration: betaken should asuperposition uses of beams many beam scanning bereduced It can modulators. scatterers energy and contribution this be considered,should although collimator and skin and increasing the distance distance the increasing and skin and collimator passive In scatter be reducedcannot or eliminated. The field size should be different for fixed lines lines different fixed for be size should The field The lateral penumbralateral The (80%-20%)in entrance on It should be also noted that a system of an active notedof an asystem that It bealso should is obtained as asuperposition as of several beams; obtained is in the design of the dose monitor, of the design should the which in accu an of ±3%, orderin accuracy to achieve an during treatments. during principle, be deposited all at once; principle, bedeposited all the size of the beam and its position are two itsposition two are and beam of the size the be consideredmust This 0.5 cm FWHM. than besmaller also spot can beam of the size the dose needed in for local treatmentthe could, because high dosebeextremely rate can local the the dose deposited in every elementary volume elementary dose deposited every the in than a millimetre; amillimetre; than racy of 1%racy measurement doseof the of the in have a granularity and spatial resolution spatial of and less have agranularity each beam is needed; is beam each spatial parameters to be measured and verified parameterstoverified be measured and spatial 2 . For other lines of. For hori lines other 2 - - - - - . These systems, moreover,systems, These completelydecouple the of active number componentsThe relatively small view: the cost of construction and operation and up are cost of the construction view: From the beginning of its history in Berkeley the in of its history From beginning the Gy min Gy 3.5 fast (typically <40 m (typically fast inability to rapidly vary the energy of the extracted extracted of the energy the to vary rapidly inability cyclotrons for proton typical therapy it make in an These stability. good and controlled intensity ily ning. Moreover,ning. acceleration the because process is design of the scanning system and dosimetry tools. dosimetry and system scanning of the design ducting technology makes it feasible to significantly it makes feasible to significantly technology ducting medical field. Operating at fixed magnetic field and field fixedmagnetic at Operating field. medical may have systems consequences for scanning the passive degrader with an energy selection system. system. selection energy an passive with degrader made of graphite and are far from the treatment from the ofmade far are graphite and min mended to be10 Gy min of protons consequences has or ions for per spill the area rapid fluctuations intensity hand, other beam operation. Moreover, of supercon availability the to now significantly lower than for synchrotons. for lowerthan to now significantly tumours, higher dose rates required are (15–20 higher tumours, Gy beam, thus requiring external systems basedon a systems external requiring thus beam, timescale. adjusted on amillisecond be accurately can off on and rapidly. beam intensity The beam radiotherapy. In active scanning systems, on the systems, radiotherapy. active scanning In recommendedto 10 be 20 should dose rate interval rent hadrontherapy. in low used beam degraders The room. The productionbut easily of high neutronsis Cyclotrons produce costs. reduce operating and size and dosimetry equipment Acyclotron based used. dosimetry and cm 40x40 a field are sufficiently fast to allow varying the range with with range the allowvarying fast to sufficiently are typically acceleratorare patient. from They the acceleratorattractive economic from point an of limiting factor for high accuracy dosimetry. For dosimetry. syn accuracy factor for high limiting system using passive scattering poses no passive spe scattering using system significantly shorter than that of the typical respira typical thatthe of than shorter significantly is time 100 This ms. less than steps in of 5mm given cur the limited activation is the and shielded advantages and disadvantages and advantages cyclotron has been used for been the cyclotron used applications has in accelerators number the linear pulsed and chrotrons problemscific as compared to conventional X-ray choicebasedsystemactive efficient on forscan an cyclotrons make accelerator the characteristics of - eas and needed –if –high with continuous beams arelatively itsand has simple energy design constant The macroscopic time structure of the beam of macroscopicThe structure time The main disadvantage of the cyclotronthe is disadvantage of its The main Cyclotrons and synchrotrons: synchrotrons: and Cyclotrons -1 ). -1 .

For afield cm 5x5 2 energy at maximum energy, the at maximum energy sec) it possible the is to switch -1 . For treatment of ocular . For treatment of ocular 2 at 70 MeV it recom is ------21 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 22 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 10 mfor 30 protons mand respec ions, carbon and MedAustron (Wiener Neustadt, Austria). In Japan Austria). In Neustadt, (Wiener MedAustron Krakow (Poland),Krakow Uppsala (Sweden) Dresden and (Pavia, Italy) and is currently being installed at installed being (Pavia, Italy) currently is and Germany)(Marburg, by Siemens; a centre in Switzerland), acomplete at and PSI facil (Villigen, (Germany). HIT (Heidelberg, Germany) and Rhön Klinikum (Heidelberg, Klinikum Germany)HIT Rhön and Germany). more Several on based this systems Orsay (France), Trento (Italy), (Czechia), Prague Shanghai is under development. under is synchrotron The Shanghai Japan and USA the Europe, companies in Several 3.6 installed some 15 worldwide; Europe systems in installed ity with five treatment rooms at the RPTC (Munich, fiveRPTC treatment (Munich, with theity rooms at cyclotron isochronous asuperconducting installed design developed atdesign at have GSI been installed designed by a CERN-based collaboration and collaboration bydesigned a CERN-based 250 MeVdelivering protons, developed collab in degrader and energy selection systems. selection energy and degrader protons has been installed in Essen (Germany), Essen in protons been installed has mitigated this difficulty. The ability to vary the vary to ability The difficulty. this mitigated but arearound its dimensions limited, is machine macroscopic of the cycle of up which to 50% duty patient’s respirationactive treatment). (breathing of acceleration stabi the it not and is cycle easily oration with NSCL (East Lansing, USA) PSI and Lansing, (East NSCL oration with tively. The beam intensity of synchrotrons is tively. synchrotrons rather intensity of Thebeam their isochronous cyclotron delivering 230 MeV isochronous cyclotron delivering their tium of research institutes is operational is at CNAO of research institutes tium treatment of controlled cycle the by the techniques (2–4 cycle s).tory possible It to thus implement is built and commissioned by INFN and aconsor and commissioned by and INFN built been installed by different byJapanese manufactur different been installed need additional the for an eliminates energy beam the of weight The total aspill. within be changed recently been shown by NIRS that the energy can can energy the that recently been shown by NIRS accelerators and all other equipment. other all and accelerators complete with are routinely delivering systems and Tsukuba. Several more are under construction. Tsukuba.and more Several construction. under are ern computer-basedern have strongly control systems It has basis. on a spill-to-spill be changed can energy ers in Chiba, Gunma, Hyogo, Koriyama, Shizuoka Hyogo, Shizuoka Koriyama, Gunma, Chiba, ers in lised. As compared As tooperation cyclotrons the oflised. the beginning dueat to space effects charge limited synchrotrons for carbon and/or proton therapy have and/or proton therapy carbon for synchrotrons mod rather is complex,synchrotrons although cyclotron are currently being installed. being cyclotron currently are Varian Medical Systems (USA/Germany)Varian Medical has IBA (Belgium) has over has ten (Belgium) years last IBA the Synchrotrons produce a pulsed beam with a with beam Synchrotrons produce apulsed Synchrotrons for carbon therapy based on a on based therapy carbon for Synchrotrons Current status Current ------This indicates that substantial and roomcost for size thatsubstantial indicates This A clinical particle therapy facility requires very large large requires very therapy facility particle A clinical 5.6 T. This cyclotron, of which the has cyclotron,5.6 T.prototype which of This 230 MeV afield of proton with synchro-cyclotron (Loma Linda). (NSCL, TAMU, INFN-LNS, KVI) since the 1980s. the since KVI) INFN-LNS, TAMU, (NSCL, Varian(normal and (superconduct conducting) which is rather conservative in comparison with the the rather is conservative comparisonwhich with in In the USA synchrotrons for proton synchrotrons USA the In therapy have fields up to 5.3 T of the compactsuperconducting up of to fields 5.3 T 3.7 factor of between three (protons)factor three of between seven and (carbon) may a synchrotron for therapy carbon using facility investments in equipmentinvestments in (accelerator, beamlines, in a system with a footprint about twice as big as a a big as as about afootprint twice with asystem in this systems of first The compact avery system. in researchisochronous cyclotrons institutes in used operateing) at afield 2.4 T,of 1.7 and respectively, delivered a first beam, will be coupled to a comwill beam, delivered afirst market penetration of particle therapy.market penetration of particle To remedy pulse frequency of both machines is around 1 kHz, 1 kHz, around is machines frequency of both pulse resulting scanning, beam pencil with gantry pact by IBA/Sumitomo about since 2000 manufactured unit with two gantries basedon acyclotron typi gantries two with unit the developmentthe of a 250 MeV proton synchro- this situation the development the situation of morethis compact, for state-of-the-art than conventional higher times more significantly is operationthe of facilities such treatment room for conventional radiotherapy. The at commissioned several being currently are type been installed by Hitachi (Houston) by Hitachi Fermilab and been installed becoming the standard in proton in therapy. standard the becoming radiotherapy, compromises seriously which the treatment same the with radiotherapy facilities Also 200 M€. of excess in investment total a require reduction exists. are exploring possibilities to achieve this goal. to achieve this possibilities exploring are equipment manufacturers and research institutes research and institutes equipment manufacturers of state-of-the-art that expensive conventional than lower cost systems is essential. Both particle therapy particle Both lower essential. is cost systems locations in the USA. the locations in superconductor compact very technology. This sufficient for the spot scanning technique that is technique thespot scanning sufficient for capacity. Consequently, treatment the a are costs a while 70–80 M€, investmentof an requires cally cyclotron is mounted in the gantry, thus resulting resulting thus gantry, cyclotron the mounted is in cyclotron with a field of 9 T, using novel afield of 9 T,Nb using cyclotron with gantries, etc.) and buildings. Aproton therapy etc.) buildings. and gantries, The isochronous cyclotrons for proton therapy proton for cyclotrons isochronous The Also Sumitomo has started the development the started of has Sumitomo Also IBA has undertaken the development the undertaken has of aIBA Systems started Mevion Medical 2004 In Future 3 Sn Sn - - - While in the initial design (Cyclinac, CABOTO) (Cyclinac, design initial the in While 300 MeV/amu to sufficient treat carbon, 75% of USA. By combining fast acceleration fast (<300 ms By combining up USA. JINR (Dubna, Russia) has designed a machine deliv Russia) amachine (Dubna, designed has JINR while proton produced are while beams by accelerating IBA/JINR design proton of design about 250 MeV beams IBA/JINR delivering Italy) for by amachine Sumitomo and CERN) for both proton for both therapy. carbon and these CERN) In facility based on the IBA/JINR and INFN-LNS INFN-LNS and IBA/JINR on based the facility ity of this scheme, and higher gradient accelerating accelerating gradient higher scheme, and of this ity ies have (Catania, out been by carried INFN-LNS deliver a protondeliver post-accel is that or beam carbon acompact to cyclotron used isochronous is designs and Foundation (TERA al. et developed by Amaldi designs are being developed ARCHADE- being by are the designs molecular hydrogen ions. In the INFN-LNS and and INFN-LNS hydrogen the ions. In molecular ment of gantries. superconducting of high gradient C-band or C-band X-band gradient of accelerating high the S-band booster linac deliveredto a beam the booster linac S-band the the relevant cases, while IBA in collaboration with with collaboration in IBA while relevantthe cases, is cycle duty up to several seconds arelatively high of cycle extraction an energy) with to maximum treatment the Europe atand several locations in tons been developed has by ProTom International these machines as compared as synchrotrons to machines the these booster linac with a pulse frequency of 200 Hz. frequency of 200 Hz. apulse with linac booster stud therapy. Design carbon for considered being accelerators have repetition rate amuch higher atreatment to construct option. Plans attractive at aslighter extraction by stripping extracted are boron, and lithium of helium, beams deliver also 330 MeV the proton Exploiting achieved. maximum patient commissionedin now for is use and being T a3.2 a compact cyclotron with superconducting energy post accelerators therapy.energy for particle These independenterated cavity by an to avariable energy ions. light other of and carbon extraction 400 MeV/amuering can machines These carbon. for suitable accelerator radiosur also is this energy structures are under development. under are structures havethe tests First feasibil confirmed structures. for used conventional that than radius smaller currently used for carbon therapy make them a very for therapy avery used carbon them make currently company ProNova develop the recently has started USA-basedand a compact field while central gantry, chrotrons are also being considered being variable as chrotrons also are grate the linac into the gantry, requiring the use use the requiring gantry, into the linac grate the proposes to (TULIP) inte latest design the gantry, group (Caen, France) Catania. in and proton and gery imaging. The much smaller dimension and dimensionoffootprint The much smaller A compact (<6 m diameter) for pro synchrotron A different approach is taken in the designs thedesigns in approachA different taken is Fixed field alternating gradient (FFAG) gradient alternating Fixed field syn Superconducting isochronous cyclotrons are also Superconducting cyclotrons isochronous also are ------A design study for a system with multiple inde for with asystem study A design volumes, but this technique is still in its infancy. in still is technique butvolumes, this Livermore National Laboratory and is now being now being is and Laboratory National Livermore it possible to accelerate the particles in even smaller evenit possible smaller in to accelerate particles the type this for patient. The technology the around ing developed further for protondeveloped therapy further US by the [4] [1] [5] [3] [2] pendent extracted beams has been conducted has in beams pendent extracted proton therapy. proton of accelerator been pioneered has Lawrence at the than conventional synchrotrons, while retaining retaining conventional while than synchrotrons, to still smaller sized accelerators, in particular for accelerators, sized particular in smaller to still lead development under long run the may and in at pulse. each energy the to change capability the the RACCAM-project (Grenoble, RACCAM-project the France), while be produced in a 2 m long linear acceleratorbe produced rotat long linear a 2 m in an electron model of an FFAG of been electron model an has an (EMMA) are developing rapidly and might eventually make make eventually might developingare rapidly and high gradient pulses in a stack of insulating and and a stack of insulating in pulses gradient high have of FFAG to bedone before applicability the References synchrotrons in particle therapy can be established. beestablished. therapy can particle in synchrotrons still will testing prototype and R&D significant (UK).Very developed at Daresbury successfully company CPAC. acceleration based schemes Laser 200 MeV allow would protons disks, toconducting

The Dielectric Wall Accelerator, Dielectric The Wall based on very Several completelySeveral new accelerator schemes are 146: Accelerators”, World Scientific (2009). XII 81918-5 (1994). 81918-5 “Medical Applications of of Applications “Medical 2, vol. (RAST) M. Silari. (2011). Silari. M. Applications of particle of Reviews Hadrontherapy Eds., Larsson B. U. Amaldi, W. Scharf, O. Chomicki. (1996).W. O. Chomicki. Scharf, Medical “Accelerators Magrin, G. and U. Amaldi S. Myers and H. Schopper Eds., Springer, Myers Schopper Eds., H. S. and Accelerators and Colliders Medicine”, and Accelerators in in p. Radiat. Prot. Dosim Prot. Radiat. accelerators medicine. in Physica Medica Physica radiotherapy. in accelerators in Oncology in 488–513 (2013). 488–513 : 199–210. 199–210. : 440–450.

Accelerator Science and Technology and Accelerator Science , Elsevier Science, ISBN 0-444- ISBN Science, , Elsevier ,

. - - 23 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 24 Nuclear Physics for Medicine – Chapter I – Hadrontherapy The beam is transported fromthe accelerator transported is The beam “exit” systemis located downstream delivery The beam 4.2 4.1 l l l (normalised, 2σ). The beam is switched fromswitched is one 2σ). beam The (normalised, with the upstream system (ex: link with accelerator with (ex: system upstream the link with 4. 4. to the treatment rooms treatment to the for high speed of [1]) monitoring current for high the and of delivering charge acceleratorfrom the in is and ity assurance and then to the patient. It to the interfaces then and assurance ity down-stream target (ex:down-stream target feedback motion from the of irradiation is comparable with the duration of comparableduration is the of irradiation with etc.). beamprofilers. The beam stirrers, quadrupoles, of the organ of the patient). of the organ of the Beam delivery Beam to the treatment rooms by standard beamlines as as treatmentto the beamlines rooms by standard to a phantominstance for qual first in beam, the room to another via a dipole; the beam is thus only only thus is beam the room adipole; via to another available for one room at a time. This constraint is is constraint available for one This room at atime. acceptable during treatment hours because the time treatment time the because hours acceptable during physics nuclear in laboratories used (dipoles,also emittance could be in the range 2 to 5 pi.mm.mrad 2to 5pi.mm.mrad range the bein could emittance Principle and interfacing and Principle From the accelerator From the - “Standard” radiation therapy machines consist therapy radiation machines “Standard” 150 tons). constraints papers Many the describe 4.3 In the 1990s the first full 360° solution appeared, 360° full first 1990s the the In forcing the pioneersforcing the to innovate (seated position, ing factor for longer quality assurance experiments. assurance factor for longering quality ing around the patient (weighing between 80 and and 80 patient between the (weighing around ing diations (fromdiations highest/lowest few seconds between patient but preparation it alimit positioning is and of irradiation heads able to rotate 360° around a able heads around to rotateof irradiation 360° or opportunities associated with gantries (cost gantries associated with of or opportunities ticle therapy has faced a real challenge. The first The therapyticle faced challenge. has areal robotics solutions, specific immobilisation devices). immobilisation robotics specific solutions, of protons field of par the ions, or carbons rigidity horizontally positioned patient. Due the magnetic positioned magnetic the patient. Due horizontally energies to a 5 mm range change in less than 80 ms). 80 less than in change range energies to a5mm in the treatment rooms treatment in the lines is the capacity to quickly adjust the tune of the of the tune the adjust to capacity quickly the is lines several beam energiesseveral beam required for a patient’s irra systems (1960–1990)systems lines were beam on based fixed called “gantry”, a big mechanical structure rotat structure abig mechanical “gantry”, called The main specificity of particle therapy beam particle of specificity The main Beamline orientation orientation Beamline of the beam delivery systems. delivery beam the of Schematic of principle and interfacing 4.1. Figure - - - - - “scanning” techniques, which are expected to become expected are which techniques, “scanning” There are two general methods to shape the beam the shapeto beam two are Theregeneral methods 4.4 which was developed initially, and the more the and recent developed was which initially, Figure 4.3. Figure 4.2. interaction, to the tumour. The “scatterers” tumour. to spreadinteraction, the depth curve (the so-called “Spread-Out Bragg Peak”, Peak”, “Spread-Out Bragg (the curve depth so-called pact acceleratorpact gantry. the embedded is inside patient positioner recent to the ones where com the to the tumour: the “passive scattering” technique, technique, “passive the scattering” tumour: to the motion of achieved whereis the by the those part tumour using patient-specific The dose- using collimators. tumour homo intoawide beam Gaussian originally the future. near the in standard the beam in order to “shape” it, using particle–matter order particle–matter in to “shape”beam using it, considered, frombroad of range solutions still is principles). delivery beam Nowadays, a building, specific mechanical devices in the trajectory of the trajectory theof in devices mechanical specific geneously distributed beam that is shaped is that to beam the geneously distributed The The “passive” method [2] of consists putting Beam delivery methods delivery Beam Passive (left) and active (right) beam delivery system (courtesy of IBA). of (courtesy system delivery beam (right) active and (left) Passive et al. et (Pedroni gantry of kinds Different (a) ). (b) Gantry (patient enclosure) at Institut Curie. Institut at enclosure) (patient Gantry ). (b) - - “modulators”, rotating wheels of varying thickness. thickness. “modulators”, of wheels varying rotating “pencil” beam coming directly from the beam from the directly coming beam “pencil” The scanning technique is a kind of 3D scanning of kind of scanning 3D is a technique scanning The Finally, longitudinal compensators, devices specific longitudinal Finally, FWHM and minimum duration of per spot) duration 1ms minimum and FWHM SOBP) generated energy required then is using is transported to the patient to achieve small “spot” patient to the to achieve small transported is drilled for each field and each patient, achieve theand for achieveeach patient, field each drilled depositions of dose. The depth scanning is obtained is obtained scanning depth depositions The of dose. patientdose to the neutrons due to the produced by physical proprieties of charged particles: a thin thin a particles: charged of proprieties physical the treated volume. The main advantages advantages consist treatedthe volume.main The components. various the through passing beam the additional in dose it depositionthe that results and that it is not optimal in terms of the conformity of conformity of terms the in it notthat is optimal by modifying the energy of the beam (directly for of beam the energy the by modifying last conformal shaping of the beam just before just beam of shaping the the conformal last line (typical beam sizes at isocentre: sizes beam (typical 3–10line mm skin of the patient. The limits of this technique are technique this of limits patient. of The the skin synchrotrons or through energy selection system for for system selection energy through or synchrotrons cyclotrons) tumour. the of “slices” fordifferent the The active “scanning” technique exploits theexploits technique The active “scanning” - 25 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 26 Nuclear Physics for Medicine – Chapter I – Hadrontherapy The beam delivery system is the coreis system point develof delivery The beam vs high expectations in patients throughput linked linked patients throughput in expectations vs high 4.7 4.6 4.5 with the cost of the facilities, systems developed systems and cost facilities, of the the with Intensity Modulated Proton Modulated Intensity Treatment [3] describe Beyond the way to deliver the beam, the key the wayBeyond beam, the to the deliver Other issues are linked to beam delivery systems: systems: delivery to beam linked are issues Other System (model and method of commissioning), CT CT System (model of commissioning), method and fast beams vs uncertainties of physiological and vs uncertainties beams fast measurements. assurance quality for regular in a better conformity of the dose distribution to of dose distribution the conformity a better in nature of protons and carbon ions allows dynamic of dynamic protonsnature ions carbon allows and deposition. Besides the standards for conventional standards the deposition. Besides moving organs, advanced and innovative techniques advanced innovative and techniques organs, moving system delivery beam the in interactions particle associ the with belinked also must performances photon The reference techniques. papersIMPT, on beam. the monitor to countand used is ionisation chambers, mainly question concerns of dose performance the the opment therapy [5]; of particle particle charge the These com reliability. and safety and or upstream, tion protection of the patient and modelling of the of the protectiontion patient of modelling the and But these challenges. further and expectations the modern in factor used Index” “Gamma towards the trend is last to The converge criteria. important the are beams penumbras of the distal and lateral the absence the of patient-specific target, the accesso binations of new, innovative technologies can be be can technologies new, of innovative binations radiation oncology (field of 40 cm × 40 cm, 40 cm, (fieldaver oncology 40 cm × radiation of a much lowerries and are, neutron Constraints dose. ated system and procedures:ated and system Treatment Planning dose rateage of 2Gy/min of one litre) for atumour motion. towards organ sensitivity the and academic institutions. academic level risk. of asignificant associated with however, (speed, complexity the of number checks) has to confront certain compromises: very thin and and compromises: thin to very confronthas certain set by the industry vs research & development& research byvs industry the by set [6-7]. beam the sweeping promised But Eldorado the tools and method and on-site and scanner imaging, control software and IT systems mainly in the in mainly systems IT and control software context of high speed scanning techniques, radia techniques, speed scanning context of high In both methods, non-invasive methods, both In instrumentation, Perspectives and challenges and Perspectives Beam delivery performances delivery Beam Other considerations Other ------energy (163.9 MeV) [4]. MeV) (163.9 energy specific one at spots recorded all for position planned the from recorded position for each spot position and mean displacement from Displacement the planned position of the 4.4. mean Figure [3] [2] [7] [6] [5] [1] [4] References Accel. Sci. Tech Sci. Accel. 40: Meth Radiother. Oncol. Radiother. learning), (and still are http://ptcog.web.psi.ch/ http://ptcog.web.psi.ch/ Passive Scattering, Proton we TherapyThings have at PSI: learnt et al et Lomax A. Reference on Document Gottschalk, B. T. Haberer al et T. al et Furukawa (2009). Smith. Vision 20/20: Proton R. A. (2009). Schippers. delivery M. J. Beam et al et Li H. S54–S55. in spot scanning proton of therapy part as spot scanning in Med. Phys Med. assurance. patient-specific quality therapy. therapy. the NIRS fast scanning system for system heavy-ion scanning fast NIRS the radiotherapy. radiotherapy. archive_sw_and_docs.html Nucl. Instr. Instr. for ionsystem heavy therapy, Nucl. therapy: radiation for particle systems current status and recent and developments, status current Rev. 021703. . A330 Med. Phys. Med. . (2013). Use of treatment log files : 296–305. : Med. Phys Med. . . (2005). Modulated Intensity 02: . (1993). scanning Magnetic . (2010). Performance of 179.

36: 556–568. . 37: 5672–5682.

76:

. The primary quantity used in radiation therapy, in radiation used quantity The primary D l l l where where Practice published by IAEA (TRS-398) [1] publishedbyPractice IAEA for the proton for clinical techniques dosimetry Primary for the beam quality, Q quality, for beam the 5.1 instrumentation in nuclearphysics. in instrumentation ised dosimetry tools for tools hadrontherapy haveised dosimetry been delivery reference but the notis also only dosimetry proton ion heavy therapy, and including absorbed is determination of D determination referred is that reference to as ditions, dosimetry. dose to water, developed, frequently originating from research in frequentlydeveloped, originating Dosimetry - sys treatment and planning of treatment lines beam commissioning and of for testing tools acceptance, k and quality beam than other quality Q or specific dose ratewaterreference under in con tion chambers. tion the verification verification delivery.doseof the Therefore, special finally checks and assurance quality periodic tems, awater phantom: in tions N the uses InternationalCode of The established. are tocols by calibration of a dosimeter in standardised condi standardised of in adosimeter by calibration therapy international centrespro different between and ion beams are based on calorimetry but the on based are calorimetry ionand beams clinical beam is a direct determination of the dose dose of the determination adirect is beam clinical clinical reference instruments of choice reference ionisa are instruments clinical 5. 5. w,q The goal of dosimetry in hadron radiotherapy dosimetry of The [2]goal In order to standardise the reference the order dosimetry In to standardise Introduction

= M M Q q , corrected for the influence of quantities , corrected of quantities forinfluence the is the reading of dosimeter at the beam reading the is d,w

N

calibration factor in water determined water factor determined in calibration d,w,q D w . The basic a of output calibration 0

w k in external beam radiotherapy radiotherapy beam external in q,q . 0 q,q 0 is the correction correction the is - - - - - Watertight covers are available, which allow use of use Watertight covers allow which available, are The aim of relative dosimetry is to is relate of relative dose aim The dosimetry Ionisation chambers (IC),Ionisation chambers for reference dosimetry for hadron radiotherapy for hadron for the radiation quality k quality radiation the for 5.2 in water phantomsin nowadays are offered broadly dosimetry of proton and carbon ion beams, usually of proton usually iondosimetry carbon and beams, dose profiles properties as such beam (e.g. determine measurements since it is only the comparison of the itmeasurements since only is mum ratios, output ratios, mum A number factors others. and penumbras), maxi tissue percentage dose, depth of detectors radiation routinelyapplied relative is in theand air with of filled is ionisation chambers out of graphiteactive volume or A150 with plastic the chamber in water. For practically all chambers chambers water. all in chamber Forthe practically two dosimeter readings, one of them being in ref in one of being them dosimeter readings, two non-referenceunder dose under to conditions the built ionisation chambers cylindrical the are used by commercial companies. The most frequently The bymost commercial companies. ble (0.125 cm chambers reference conditions. In general no conversion no general In reference conditions. response corrected is atmospheric for the pressure. available with CE Medical or/and Medical CE available with FDA certificates. correction the lists market onavailable TRS-398 the cm 0.6 around 5.2.1 5.2.2 erence conditions. Relative dosimetry is used to used is erence Relative dosimetry conditions. legally prescribed practi by oncologist, a radiation legally coupled to the scanners working in air or in water or in air in coupled working scanners to the electrometer, IC an of and an are consisting clinics, reference therapeutic all in dosimeters used cally (0.02chamber cm coefficients or correction factors are required in are required factors correction or coefficients Dosimetry tools Dosimetry Reference dosimetry Relative dosimetry 3 (Farmer chamber), cylindrical thim (Farmer chamber), cylindrical 3 ). Frequently, active volume the 3 ) or plane parallel Markus Markus ) or parallel plane q . Since dose is a quantity a quantity doseis . Since - - - - 27 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 28 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 32 matrix; the area of each pixel is 5xmm area of is pixel each the 32 matrix; MPGD) on-going. are MatriXX and by PTW as Octavius detector 729, Octavius as by PTW and MatriXX MV X-rays radiotherapy. MV where the “729” stands for the number of fornumber cubic the ion stands where “729” the water supplied is phantom.adevice by Such IBA- awater phan in z-axis the along a detector with INFN group Torino in a INFN developed has built and Freiburg). One beam monitor is installed atFreiburg). the Onemonitor beam installed is Dosimetry under the name Zebra. An alternative An Zebra. name the under Dosimetry ionisation chambers, ableionisation to chambers, work profile beam as of a matrix is beams for tools scanning important the Peak monitor within moving Bragg thin the is to measure i.e. beam, of the range water the and in detector is placed on the beam line just upstream upstream just line placeddetector is beam on the determine profiles of charged particle beams since since beams profiles charged particle of determine diamond detectors or MOSFET detectors. MOSFET or detectors diamond dosimetry (2D 3D) and One of thedosimetry systems. pattern readoutpattern (Micro Detectors, Gaseous Pattern a micro ments based on with ionisation chambers pixelated parallel plateto be ionisation chamber pixelated parallel water. in monitors The or fordose distribution 2D proton ion and therapy compared as to conventional (thimble) miniature phantoms ionisation as such profiles is based on scintillators read by CCD on based scintillators is profiles of the last collimator toshape monitor beam the collimator last of the of the detector is 160 detectorof is the x160 mm offeredthe by (PTW,PeakFinder WaterColumn (multi-layer chambers of plane-parallel ionisation One solutionis aset consuming. time often too the beginning of the use of accelerators. use of the HMI At beginning the cham of ionisation Thematrix system. delivery the the protonthe at Orsay. therapy line Thesensitivearea developmentthe dimensional three and of two tom but is method for routine measurements this be performed can scanning by This peak. Bragg the used as amonitor as forprotonused the therapy beam bers is commercially offered by IBA-Dosimetry as as IBA-Dosimetry offered by commercially bers is and to measure the stability and reproducibility of reproducibility and stability the to measure and and the application of scanning beams stimulated stimulated beams application the ofand scanning the effectively has structure entire a way the that entrance of the sealed water column and the second the and water sealed ofentrance column the line. This system has been used among used others at been system has This line. segmented in 1024 square pixels arranged in a 32 x in segmented 1024arranged pixels square in solution dose measurements for is depth quick stopping powersame (range) corresponding the as chambers available in the matrix. New develop matrix. the in available chambers column. A single measurement a few takes A single minutes. column. chamber), separated by absorbing layers the such in diodes, dosimetric chambers, Markus chambers, cameras. Scintillation screens have to been used Scintillation cameras. The sharp gradient of depth dose distributions distributions gradientdose depth of Thesharp Therearefor some of dosimetry specific needs Another group of devices used to verify beam beam group of toAnother used verify devices One is to determine the depth dose distribution dose distribution depth the One to is determine 2 , with the anode anode the , with 2 . The . The - - - Real-time measurement of the 3D dose distribution measurement 3D of dose distribution the Real-time (neutron, protons heavier and fragments) are needed with aBaF with In order out-of-field the In to study invesand to doses Lynx, the 30 x 30 cm x 30 30 the Lynx, Berlin a system of a scintillator with CCD cam CCD with of ascintillator asystem Berlin fragments in carbon therapy) carbon in fragments to may beimportant 5.3 induced secondary cancers. induced secondary radiation- including ofincreased risk late effects, is mandatory especially for fast scanning beams and and beams scanning for fast especially mandatory is dose. additional order this in to estimate patients themselves in the are with interactions different types of secondary radiation. In hadron radiation. of secondary types different dose profiles of proton treatment.eyefor beams A doses in general, passive CR-39general, detectors as such in doses passive scattering beam lines and the scanning scanning the and lines beam passive scattering QA scanning of the for dedicated daily particularly ment quantifying the neutron the out-of-field dose and ment quantifying source of secondary significant principle only the beam systems, active scanning in produced, while profiles at IFJ PAN. IBA introducedthe IBA market on IFJ profiles at PAN. quantify for each specific beam line and collimator and collimator line forbeam specific each quantify orders of magnitude. Particle fluence measurements Particle orders of magnitude. therapy production the of neutrons (and heavier andscattered of secondary significance the tigate tracking calorimeters for the detection of for detection charged the calorimeters tracking tors have More been applied. advanced (but more to the challenges in experimental measurements. experimental in challenges to the beam delivery systems there are a number of filters there of anumber are filters systems delivery beam of terms out-of-field in lines beam In passive dose. beams. bulky) neutron detector systems include Bonner Bonner include systems detector neutron bulky) radiation additional tools may be necessary; espe may tools be necessary; additional radiation repainting techniques. Extremely high-granularity The out-of-fieldradiation. by several vary can doses and neutral radiation will be able to determine the the beable to determine will radiation neutral and is radiation secondary which in collimators and etch detectors and thermoluminescence detec detectorsthermoluminescence etch and 5.2.3 era has been used since 2005 to determine lateral lateral to determine 2005 since era been used has sphere systems, WENDI-2 detectors, as well as as well as detectors, sphere WENDI-2 systems, setting. The low dose areas are mainly an related to are The areaslow mainly dose setting. for used measurements is of system proton similar simulations play an important role in this field due field role this in important play an simulations Monte addition, Carlo In SRAM-detectors. small combination in signals timing for scintillators cil beam has been studied with a TOF-setup with using been studied has beam cil cially if the goal is to assess the contribution the from to is assess goal the if cially There is a fundamental difference between the difference between fundamental Thereis a At GSI the fragmentation of the carbon ion carbon of fragmentation pen the the GSI At R&D Out-of-field dose Out-of-field 2 -detector. For in-phantom measure For in-phantom -detector. 2 scintillator with CCD camera, camera, CCD with scintillator ------3D sensors (SINTEF) and Monolithic Active Pixel Active Pixel Monolithic and 3D sensors (SINTEF) without saturation effects. Various Si-pixel technol Si-pixel Various effects. saturation without Bragg-peak position as well as the lateral 2D dose 2D lateral the as position well Bragg-peak as Sensors (MAPS, Strasbourg). (MAPS, Sensors device will be able to cope with a large particle flux flux particle beable alarge to cope with will device identification particle tracking, performing device be asingle acompact Such detector will distribution. of the extremely large number of cells ( of number cells large extremely of the [1] [2] ogies are currently being studied, e.g. radiation-hard e.g. studied, being currently are ogies and energy (range) energy and It measurements simultaneously. References sizes are 5 are sizes absorbing layers. between sandwiched Typical pixel consists ofconsists (~50) many Si-pixel layers sensors of thin Absorbed Dose Determination in External Absorbed in External Dose Determination Phys. Med. Biol. Med. Phys. Beam Radiotherapy Beam (2010). for ion radiotherapy, beam Dosimetry 2000. No. 398, IAEA, International Atomic Energy Agency, Energy Atomic International C.P. Karger, O. Jäkel, H. Palmanas, T. Kanai C.P. Palmanas, Karger, H. O. Jäkel, μ m ×5 m m or 20

: R193–R234. 55: , Technical Series Report m m ×20 m m. Because Because m. ~ 10 14 ) the the ) - 29 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 30 Nuclear Physics for Medicine – Chapter I – Hadrontherapy l l l During dose delivery, precise monitoring of the actual dose delivery, precise actual of monitoring the During Cancer of organs affected by breathing motionsuch by breathing affected ofCancer organs ity assurance and adaptive and treatment schemes. assurance ity to befactored has and treatment intodedicated ing days, typically regarded interfractional. as typically days, permits precise 4D-dose recalculation useful for qual useful recalculation precisepermits 4D-dose patient control motion previously adapt can the and for strategies and motion compensation.plans volumetric imag motion tothrough has be assessed poor prognosis. The time scale of this motionis sec this of scale time poor prognosis. The optimised plan. The collected data during delivery delivery data during The collected plan. optimised Movingtargets onds, i.e. intrafractional. Other organs are affected affected are organs Other intrafractional. i.e. onds, 6.1 Introduction 6.1 as lung or liver causes a large fraction of all deaths by deaths of all fraction or liver a large causes lung as hadrontherapy range changes caused indirectly by caused indirectly hadrontherapy changes range e.g. by bowel motion with a time scale of minutes to of minutes scale by atime bowel motione.g. with cancer, and typically these cancers also show a very also cancers these cancer, typically and 6. C For successful treatment of moving organs, the the treatment organs, ofFor moving successful Besides the geometric motion of the target, in geometric in the Besides motion of target, the D - - - Treatment planning is typically based on based atime- Treatment typically is planning (WEPL). The 4D-CT due to high exposure captures captures exposure high due to 4D-CT (WEPL). The ferent have tissues to be traversed to beam by the motion can change the radiological depth when dif depth radiological the change motion can only a snapshot of breathing, and thus is not truly not is truly thus and asnapshotonly of breathing, 6.2 the motion also have to be considered. Also lateral have lateral motionthe also to beconsidered. Also to estimate the water-equivalent the to estimate length path be considered, the so-called interplay effect. This This interplay effect. be considered, so-called the have motion also to tumour and target between by soft tissue of either tumour or adjacenttumour organs. tissue byof either soft reach the target. This effect is especially severe in severethe in is especially effect This reach target. the resolved, quasi-static 4D-CT scan. A CT is needed is A CT scan. resolved, quasi-static 4D-CT ered dose. lung, where low-density lung tissue can bereplaced can where tissue low-density lung lung, causes severe, highly variable deviations ofdeliv variable deviations the severe,causes highly In scanned beam delivery, interference beam effects scanned In Imaging moving organs Imaging here shown for tracking (D). tracking for shown here motion compensation scheme, a with delivered is dose the (C); motion breathing monitored patient is positioned and his The (B). calculated is plan atreatment end-inhale); A2: A1: (panel end-exhale, 4D-CT a on based targets, moving of treatment Schematic Figure 6.1.

- - A widely applied strategy for tumour motion detec for tumour applied strategy A widely toforWEPL, explore CT the astatic is A possibility (perpendicular to the beam axis) may beam reduce to the dose (perpendicular with the patient. In-room MRI for high-contrast for high-contrast patient. In-room the MRI with Fluoroscopy maybe used for continuous tumour tumour continuous for used maybe Fluoroscopy theranostics imaging in real-time during treatment may offer during real-time in imaging images (particle radiography/tomography). Higher Higher radiography/tomography). (particle images patients. for pediatric particularly structures, ing afew mil is or 3D. 2D Achievable accuracy in non-ionising, real-time alternative uses implanted implanted uses alternative non-ionising, real-time delivery requires the design of a stable design requires holder the of the delivery treatment during dependent remote and imaging However, 2D. of 2–3 mm in accuracy documented atomic Low mate number up todeviations 82%. dosimetric critical documented with deviations, markersdense lead torange difficult-to-compensate main drawback is that image quality is operator- is quality image that drawback is main dose delivery. scanned in particularly but concerns, markersserious raise perturbation, of transponders is expected to expand to clinical to clinical to expand expected of is transponders 6.3 tion is widely debated, especially for lung tumours, tumours, for lung especially debated, widely is tion external by detected continuously transponders, detected are on markers, implanted which relies tion for adaptive treatment treatment. with Also under through the patient, resulting in range-dependent in resulting patient, the through with compatibility although opportunities, unique probe to applyultrasound asteady contact force beam maybe used for transmission measurements for maybe used transmission beam or multipleX-ray forby single localisation imaging rials together with specific implantation criteria specific together with rials real-time detection with millimetre accuracy. The accuracy.The millimetre with detection real-time be of would use. othermodalities repeated imaging, representative expected formotion trajectory the also related to marker migration and stability. The The related stability. and to markeralso migration additional dose delivered patient to the deserves additional body.application the for lesions in moving anywhere for motion maps. aprolongedand 4D-MRI 6.3.2 6.3.1 high energy particle beams represents beams a serious particle energy high electromagnetic receivers. Although typical appli typical receivers.electromagnetic Although limetres, especially if multiple views are used. A used. are views multiple if especially limetres, localisation without implanted markers, with a markers, implanted with without localisation specific attention for continuous imaging of mov imaging attention forspecific continuous challenge for application in hadrontherapy. in application for challenge prostatecations in are radiotherapy, cancer More futuristic solutions include the so called socalled the solutions include More futuristic motion detec Marker for implantation tumour Non-ionising alternatives include ultrasound for for ultrasound include alternatives Non-ionising Motion detection Motion Marker-based tumour motion detection Markerless imaging for target localisation target for imaging Markerless , where a low-dose, high energy particle particle , where energy alow-dose, high

the use use the ------The strategies for the realisation of the ITV differ differ ITV the of the strategies The for realisation by mar expanded be target can volume clinical The 4D-CT. In contrast to photon In 4D-CT. therapy, above- the A straightforward strategy is to is reduce ampli the strategy A straightforward The localisation of external fiducials with non- with fiducials of external localisation The which robust tumour motion can be achieved. motion can robust tumour which Point-based and surface-based external localisation localisation Point-based external surface-based and from consecutive 4D-CT scans between fractions. fractions. between scans from consecutive 4D-CT immobility verification has been verification has applied for years. immobility energies for patient-set-upionising correction and in the margins, for which several for strategieshave which margins, the in from taken often a volume target (ITV), internal and afrequent estimation ing verification of model in asnapshotin provide from information redundant detection requires the use of external/internal of external/internal use requires the detection to techniques detection Surface due to breathing. methods have methods level been proposed different of with learning machine as correlation well as polynomial of appropriatemisation preliminary detectors and making it comparatively simple to deliver. making On the have also mentioned to beincluded changes range patient-specificthus requir time-dependent, and motion monitoring and no additional hardware, hardware, additional no and monitoring motion other hand, the ITV increases the target size and and size target the increases ITV the hand, other on-line adaptation of correlation to parameters 6.4 tude of target motion. This can be achieved e.g. by bee.g. achieved can motion. This of target tude dose conformity, decreases the onethus big of the beam energies than those used for used treatment those are energies than beam been explored. Adaptive strategies update the ITV been Adaptive explored. ITV update the strategies rior–inferior motion of inner anatomical structures structures anatomical inner of motion rior–inferior required. Current studies are limited to the opti to the limited are Current studies required. abdominal motion is well correlated with the supe the correlated motion well with is abdominal advantages of particle therapy. particle of advantages 6.3.3 6.4.2 6.4.1 has been used for been used continuoushas motion and detection experimental acquisitions. experimental encompass intra-fraction breathing irregularities. encompass intra-fraction breathing linear correlation hysteresis. and Piece-wise linear/ linear Surface structures. moving of internal localisation substantially between scanned and passive and delivery. scanned between substantially correlation models, capable of interpreting non- interpreting of capable models, correlation capture the whole thoraco-abdominal skin surface surface skin whole the capture thoraco-abdominal complexity. All studies showcorrelation the is that studies complexity. All gins to encompass the target motion, forming the the to encompass motion, forming target the gins models The use of external surrogates for target motionfortarget surrogates use external of The The ITV technique does not require online not does require online technique ITV The Motion mitigation strategies mitigation Motion Motion reduction Motion External surrogates and correlation correlation and surrogates External Margins - - - - - 31 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 32 Nuclear Physics for Medicine – Chapter I – Hadrontherapy This potentially results in conformal target covertarget in conformal results potentially This To delivery, res beam - scanned counter interplay in variable errors are also averaged. errorsvariable also are For scanned delivery, the beam can beadjusted to can beam For delivery, the scanned use, also in combination, while 4D-optimisation is in the early research phase, so that the entries should be seen as the potential of this technique. this of potential the as seen be should entries the that so phase, research early the in is 4D-optimisation clinical while in already are combination, in gating as also well use, as rescanning and ITV techniques. mitigation motion the of weaknesses and strengths of 6.1. Overview Table Changes in WEPL are more difficult to compensate more are difficult WEPL in Changes increases the robustness of the method, as other as robustness method, of the the increases as such doseerrors. concepts of Several the exist, ing temporal exact on the depending variable, highly is different schemes effectively to different correlations break pre-com to use amotiondetect of phase a4D-CT putational costs are high. are costs putational incorpo phases, are computed 4D-CT plans on all concept. theranostics the with change potentially currently can WEPL puted in motion maps. Changes of the gating window only a certain fraction of the of the fraction acertain only window gating of the the apre-defined range, within is target the if only toring can either supply tracking vectors or eithersupply directly, can tracking toring motion. Motion beam to target the lateral track the breathing cycle is availablefor is cycle irradiation. breathing between motion and delivery. The rescanning also also motion delivery. The and between rescanning could this though from 4D-CTs, only be assessed rating tumour motion and WEPL changes directly. directly. changes motion WEPL and tumour rating treatment essence, In 4D-optimisation. research, is deliveredis Thebeam motionresidual gating. is and require a range shifter. Precise shifter. requiremotion arange and moni prostate in used cancer.as compression, balloons by rectal abdominal but also averaging of random dose errors, though inhomo averaging of random dose errors, though to averag leads of dose multiple times the a fraction correlation applying motions, spatial of two and the no specific Also by tracking. adequately addressed for complex not are also motionage that patterns 6.4.4 6.4.3 hardware is required for WEPL changes, but com changes, hardware required is for WEPL elongated treatment times, as depending on the size size on the depending as elongated treatment times, slice-by-slice, or breath-controlled volumetric, with to leads generally window. This gating so-called can be followed by adjusting the scanner magnets. magnets. scanner the befollowed by adjusting can canning or repainting can be used. As the interplay the As beused. can or repainting canning geneous fraction doses have doses geneous fraction to beaccepted. 4D-optimisation Tracking Gating ITV +rescanning Technique A different approach also resulting in a reduced approachalso A different resulting A promising alternative, but still in early stages of stages early in but alternative, A promising still Similar to rescanning, fractionation also leads to leads also fractionation to rescanning, Similar Interplay Motion compensation + – + ++ Robustness ++ ++ + – Conformity ------– using artificial inputs – for simulations. research artificial – using Time-resolved requires several dose calculation Several motionSeveral compensation strat detection and for moving targets is more is complex targets for moving due to interplay input parameters available often only after irra after often input available only parameters delivery has to be correlated to actual, measured to has be correlateddelivery to actual, positions and beam doseof timing The diation. [3] patient motion, which in turn has to be has mapped turn patient in motion, which [2] [1] precise re-calculations can be helpful for adaptive be helpful can precise re-calculations monitoring remains an issue of ongoing research. of issue ongoing an remains monitoring onto a 4D-CT for range estimation. This kind kind of This forestimation. range onto a4D-CT 6.5 treatment schemes and quality assurance, but also but also assurance, treatment schemes quality and tion. Robustness of both motion compensation of both Robustness and tion. for delivery passive delivery. Scanned especially use, and is only in the beginning of clinical implementa of clinical beginning the in only is and 6.4.5 egies are available, with gating and the ITV as ITV the and gating with areavailable, egies References comparatively simple options already in clinical comparatively clinical in simple options already Summary 13 Dose calculation Radiol. Phys. Technol Phys. Radiol. Biol Real-time tumour tracking in particle particle in tracking tumour Real-time S. Mori, S. Zenklusen, A.C. Knopf. (2013). Knopf. A.C. Zenklusen, Mori, S. S. M. Riboldi, R. Orecchia, G. Baroni. (2012). Baroni. G. Orecchia, R. Riboldi, M. (2011). Durante. M. Bert, C. Motion Current status and future prospects of multi- future and Current status Phys. Med. Med. Phys. therapy, particle radiotherapy: in dimensional image-guided particle therapy, particle image-guided dimensional therapy: technological developments developments technological therapy: Lancet Oncol perspectives. Lancet future and : 383–391. : . + ++ – + Delivery requirements 56 : R113–R144. . 6 : 249–272. ++ ++ + – Motion monitoring

.

- - - 7. 7. 7.1 The issue is even more severe with particle therapy,is evenissue The more severe particle with l l l where relative the effectiveness biological of (RBE) Biologically-optimised treatment plans are often often are plans treatment Biologically-optimised improvement of hadrontherapy compared to X-ray is plans biologically-optimised of implementation lead indeed to so on can and sensitivity individual normal tissue complication probability (NTCP), complication tissue probability normal discussed in radiotherapy [1]. Use of radiobiological [1]. radiotherapy radiobiological in of Use discussed parameters for tumour control probability (TCP), probability control tumour for parameters Radiobiology often hampered by the uncertainties in radiobiology. uncertainties hamperedoften the by physical of treatment the for a plan optimisation urement techniques now allow an unprecedentedurement an now techniques allow therapy.- meas repair and DNA Modern damage from different is beam the X-rays, depends on sev body. Radiobiology of charged particles goes, how goes, of particles charged body. Radiobiology ever, far beyond RBE and mayever, and represent beyond far RBE amajor patients’ the within change can and parameters, eral given tumour and for an individual patient. Clinical patient.Clinical individual for an and given tumour Introduction - - .2 7. values from experiments performed in the past 50 50 past the performed from in values experiments RBE is a complicated radiobiological concept concept radiobiological complicated a is RBE years with different ions always show ions different large vari a years with fractions, particle charge and velocity, and charge con oxygen particle fractions, ionising radiation induces a high fraction of clus fraction ahigh induces radiation ionising ( ions inducedby fast damage molecular into the insight dose, dose rate, dose per fractionation, number of dosenumber rate, dose, dose per fractionation, on several factors: endpoint, measured depending tered DNA damage, which is more difficult to repair to repair more is which difficult tered DNA damage, research topic in particle radiobiology [2]. radiobiology research topic particle in radiation. These effects are now the mainstream mainstream are the effects These now radiation. and triggers a different intra- and inter-cellular intra-and adifferent triggers and ance ( ance signaling cascade compared to sparsely ionising ionising sparsely to compared cascade signaling centration, cell-cycle phase. Data mining of RBE of RBE mining Data phase. centration, cell-cycle RBE Figure Figure 7.1 7.2 ). These studies show that densely show thatdensely ).studies These ). The spread in RBE values cannot RBE cannot values ). The spreadin Gisela Taucher-Scholz). of (courtesy Germany Darmstadt, in GSI at U-ions accelerated Cor by generated streaks damage DNA to 1(53BP1) protein suppressor p53-binding tumour the and (RPA) A protein replication the of recruitment the show pictures The cells. human in ions heavy of tracks along proteins repair DNA ofCo-localisation 7.1. Figure - - - 33 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 34 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 1.1 is used in clinical practiceplateau for both and 1.1 clinical in used is In fact, the increased RBE of slow protons increased RBE the translates fact, In SOBP may reduce complications field atedges. the for perhaps ions, heavy treatment abiological plan in an extension of the effective range of the protonof effective of extension range the an in been what done has escalation for Dose ing years. taking into account the increase in the distal proton distal the increase intoin account the taking less problematic is issue protons with RBE than the ues goesfrom 0.7 to 1.6 at mid-SOBP. Even though of val range the and increases, SOBP RBE the the of For proton aRBE beams, at experience NIRS. the ions, heavy using facility each performed are in trials be reduced repeat just by more vitroexperiments, in beam ( beam and sound value, although in the very distal part of part distal very the in although value, sound and as it is currently done at HIT and CNAO, following CNAO, and done at following HIT it currently as is spread-out (SOBP). peak Bragg is a reasonable This Figure 7.3 ). - - 7.3 RBE, i.e. using a flat SOBP in physical dose. Rather Rather in SOBP dose. aflat physical using i.e. RBE, (China)anddeep treated are for they superficial which may open new scenarios in hadrontherapy may in open newwhich scenarios It is now established that the tumour is a tissue, and and atissue, is tumour It now the is that established in hadrontherapy, patientsin have been reality but in that stem cells and stromal compartments play compartments a stromal and stem cells that clinics. the research measurements, on more RBE focusing than for correction any without C-ions with tumours Lanzhou several centres in treated and in safely and provideand novel applications in biology-guided should focus on the newly emerging radiobiology radiobiology newly emerging on the focus should There is a lot of emphasis on RBE uncertainties uncertainties RBEThere is a lot of emphasis on Cancer stem cells Cancer 1–30) and ions. ions. and 1–30) Rebecca Grün, GSI.) Grün, Rebecca of courtesy calculation and (Image model. biological the by predicted range increased the line green the and penumbra, distal the of azoom shows inset The dose. RBE-weighted prescribed the of 80% the is the line dashed black The model. LEMIV the with using correction the represents line orange RBE=1.1. conventional The the using SOBP physical corrected the indicates line dashed The therapy. proton in depth with RBE avariable to due extension range Biological 7.3. Figure ( photons to exposed cells for curves survival 855 includes currently ( database (PIDE) Ensemble Data Radiation Particle the from extracted are points Data ions. heavy to protons from ions, different indicate colours keV/μm water. Different as in given are values LET survival, 10% at calculated is RBE lines. cell vitro in on experiments published from (LET) transfer energy linear versus RBE 7.2. Figure www.gsi.de/bio-pide α / β ratio ranging ) which ) which 7.4 7.4 vitro studies show indeed that carbon ions show carbon more are that indeed studies vitro Radiotherapy is now towards is hypo going clearly Radiotherapy (up to 25–30 Gy). Treatment conven in technology dose/fraction(oligofractionation) high avery with (SBRT) hypof ion pushing and therapy both are with high-quality imaging and achieving greater achieving and imaging high-quality with fractionation. Stereotactic therapy radiation fractionation. body Recent in recurrencemetastasis. and local for both in recent years, improving tumour localisation localisation recentin improvingtumour years, increased effectiveness an of low-energyindicate decisive role in its growth and homeostasis. Cancer homeostasis. Cancer decisive and role its growth in makes it possible to deliver single high dosesto it high makes possible to single deliver from colon stem cells cancer protons eliminating in to destroy this compartment, which is responsible is which compartment, to destroy this - vas dose, high at very addition, tolerance In dose. advanced fact radiotherapy so much in has tional the dose to the normal parallel organs below the organs parallel normal dose to the the maintaining at and risk organs sparing tumours, ractionation toward the region of 1–3 fractions 1–3 of region fractions the toward ractionation reviewed ref. in [3] and mammary human cancer cells in vitro (studies vitro in cells cancer human mammary and Moreover, results pancreas cancers. and preliminary thereforeand ions heavy may represent tool ideal an ents, may become a dominant pathway for tumour may pathwayents, become for adominant tumour from colon stem cells than killing effective X-raysin supplying the cancer tissue with oxygen and nutri and oxygen with tissue cancer the supplying hypoxia, are resistant to and radiation stem cells cular injury, i.e. damage to the endothelial cells cells endothelial to the damage i.e. injury, cular This high-resolution collimators. using conformity Hypofractionation ). - - - - 7.5 vated above 10 [3], Gy per fraction the that and apoptosis rapidly acti is cell endothelial vascular Even though local control is generally very high with with high controlvery Even local generally is though (MSKCC, NY, USA) researchers, who foundthat with protonswith or ions. heavy few radiobiology studies specifically address the address specifically studies few radiobiology forme (GBM) or pancreatic cancer. However, very irradiation. In vitro experiments on GBM vitroexperiments have In irradiation. high research radiobiology at Particle effect. ising doses is needed to support and guide oligofraction needed is doses to guide support and myelinase is amajor is pathwaymyelinase for apoptotic the potential synergistic interaction of drugs and ion and of interaction drugs synergistic potential therapies to systemic con becombinedmust with of single fraction high-dose spinal SBRT, spinal high-dose fraction investiga of single used in many cancers, such as glioblastoma multi glioblastoma as such cancers, many in used Combined survival. increase and trol metastasis recorded pronecrotic institution same the from tors that vascular damage may be particularly effective effective may beparticularly damage vascular that response. In later clinical work use the involving laterresponse. clinical In radiographic change consistent with adevascular consistent with change radiographic the of range in responsedoses 18–24 after Gy, a radio and chemotherapy and radio protocols are already by the Memorial Sloan Kettering Cancer Center Cancer Kettering Sloan Memorial by the angiogenesis with C-ions even with atangiogenesis low suggest doses hadrontherapy.ation in of suppressed Indications hadrontherapy, in most malignancy radiotherapy hadrontherapy, most malignancy in suppression ( suppression stroma at high doses has been elegantly shown been elegantly has doses stroma at high ceramide pathwayceramide orchestrated by acid sphingo Combined therapies Combined Figure

7.4 ). Damage to the tumour tumour to the ). Damage contributes to cell death [3]. death cell to contributes vascular damage, which elicits radiotherapy, ablative stereitactic in used those as such dose, high very that hypothesised is it pathway, conventional DNA damage the to addition In exposure. following radiation high-dose death cell of Two modes 7.4. Figure ------35 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 36 Nuclear Physics for Medicine – Chapter I – Hadrontherapy visible in PET scan). This is clear clinical evidence clinical PETclear is visible scan). in This were assumed to play a role, this was hitherto not were hitherto to was play assumed a role, this Abscopal great for cure. cancer expectations with Darmstadt.) TU Reppingen, Norman of courtesy (Image radiotherapy. of success the for essential are T-cells 9, CD8 irradiation. by upregulated be can receptors Death neoantigens. 8, of expression novo de to and MHC-I of expression enhanced to lead can 7, Radiation granzymes. cytotoxic to sensitise proteins shock Heat 6, immunity. antitumour upregulationdependent of cell adhesion molecule also influences interferon-gamma Radiation-induced 5, tumour. the to T-cells effector attracting radiation, by induced be can Chemokines 4, radiation. by upregulated are immunity) (innate cells killer natural to cells stressed sensitising NKG2D-ligands, 3, success. therapy radiation in arole play 2, Cytokines expansion. T-cell consequently, and, activation cell dendritic through radiation, ionising by promoted is death cell Immunogenic cancer. 1, for therapy adjuvant Figure 7.5. fractions). In the CT scan four months after irra monthsafter four scan fractions). CT the In far from the irradiation field during radiotherapy field during from irradiation the far immunologically proven. 2012, March a mela In immunologically noma patient at MSKCC received adjuvant immune diation, disappearance of multiple metastases from of multiplemetastases disappearance diation, different drugs with C-io with drugs different [4] many years but although immune related effects immune years butmany although pal effects, and combined immunotherapy andand combinedimmunotherapy effects, pal radiotherapyment were concurrent with reported combination on the of indications provided useful observed in different animal models. animal different observed in formerly effects, of abscopal immune-mediated have been reported malignancy, for of a primary the irradiation field occurred. Changes in cellular in cellular Changes occurred. field irradiation the ticle therapy with immunotherapy (reviewed in in (reviewed immunotherapy with therapy ticle radiotherapy, by parti charged beenhanced can and molecular parameters indicate acomprehen indicate parameters molecular and - dis in therapy for one resulting year anti-CTLA4 her spinal metastasis (28.5 metastasis Gy,her spinal X-rays 6 MV 3 in ease progression, requiring focal irradiation of irradiation focal progression,ease requiring lesions of metastatic shrinkage as defined effects, later, including one completelater, response including (no cancer sive immune reaction against the tumour. More tumour. the reactionsive against immune cles ( cles cases of abscopal effects with anti-CTLA4 treat anti-CTLA4 with of effects abscopal cases ), which is now rapidly gaining access in clinics clinics access in now is ), which rapidly gaining These studies beg the question whether absco beg of studies These Equally important is the combination of the is par important Equally Figure Pathways where radiation can synergise with immune immune with synergise can radiation where Pathways 7.5 ). Carbon ions significantly reduced ions). Carbon significantly ns. ------in immune competent immune Arecent C3Hin mice. study ing immunotherapy and hadrontherapy. and immunotherapy ing cell dendritic with synergy showing system, this in [4] [3] [2] [1] models and a model of squamous cell carcinoma cell of a model and squamous models tumour rechallenge resistance which was depend was resistance which rechallenge tumour treatment approaches –anew, impressive very and encouraging outcome protocols forcombin encouraging future ent on CD8+ T-Cells and influenced by NK cells cells NK by influenced T-Cellsand CD8+ on ent References lung metastasis count in LM8 osteosarcoma LM8 mouse countin metastasis lung showed confer could ion heavy that irradiation Trends Med. Mol. 10: Cancer Cell Cancer Radiation Therapy. World Scientific Radiation 978-981-4277-75-4 , 2014. (2013). Immunologically augmented cancer cancer augmented (2013). Immunologically M. Durante, N. Reppingen, K.D. Held. Held. K.D. Reppingen, N. Durante, M. Kolesnick (2005). R. Engaging Fuks, Z. Durante.(2013). M. Loeffler, J.S. Charged Optimized (Ed.), Biologically Brahme A. particle therapy – optimization, challenges challenges therapy –optimization, particle treatment using modern radiotherapy. radiotherapy. modern using treatment the vascular component response. of tumor vascular the Nat. Rev. Clin. Oncol Clin. Rev. Nat. directions. future and 411–424. 8: 89–91. 19 : 565–582. ISBN: ISBN: . - - “Treatment planning”). A reliable estimation of the of the Areliable estimation “Treatment planning”). The well-known Monte Carlo (MC) codes FLUKA, MonteThe well-known Carlo (MC)FLUKA, codes The unique property of such particles is that thethat is uniquesuch particles of property The As described above in Section 7 ‘Radiobiology’, var above described 7‘Radiobiology’, Section As in voxel. For calculating RBE biophysical models like biophysical like models RBE voxel. For calculating l l l (voxel) is to calculate the energy and flux of primary (voxel) of primary flux and energy the to is calculate (Bragg peak). This makes makes possibleit peak).irradiate (Bragg This to LEM developed model radiobiology at or GSI the LEM Geant4, MCNPX, PHITS and SHIELD-HIT were SHIELD-HIT and PHITS MCNPX, Geant4, from NIRS can be applied (see can [1]from NIRS 7 Sections and fully used now in the field now the of used hadrontherapy in to fully initially designed for simulations in particle and and particle in for designed simulations initially killed beeffectively can cells of living ious kinds nuclear physics.nuclear - success of Howeverare them all 8.2 8.1 model propagationmodel of of protons, therapeutic beams (LET) is transfer energy linear their in maximum Modelling of biological dose from carbon ions it is important of dosefrom ions biological carbon it important is the target volume occupied by a tumour while while volume occupied target the by atumour the biological (i.e. biological RBE-weighted) dosedeliveredthe evaluating pointin Akey starting peak. Bragg the elevated relative into account their to take biologi by atherapeuticsub-volume ion to aspecific beam delivered to apatient doseis distribution biological by accelerated protons i.e. ions, or heavier nuclei. required for successful treatment. In calculations calculations treatment. In required for successful medium the in reached range end at of the their and 9). and this through propagating particles secondary and in hadrontherapy sparing surrounding healthy tissues (see tissues healthy 9 Section surrounding sparing cal effectiveness (RBE) cal close [1],to in particular, 8. 8. Introduction Monte Carlo modelling modelling Monte Carlo - - The MC models are especially useful for evaluating for evaluating useful areespecially The MC models As one can see in Figure see in one can As with these components. This includes also theesti also includes components. these This with fields created due to interactions of beam particles createdfields interactions due particles to of beam 2013. October in Reuters) (Thomson database Science of Web the from Estimated used. were codes/tools Carlo Monte respective where hadrontherapy, to related publications of number 8.1. Annual Figure fluctuations arelarge. fluctuations ing, especially in the last five years, with their total their total with five last the years, in especially ing, number approaching 900. They can be classified classified be can They 900. approaching number tissues. and neutrons materials orvarious ions in devoted to MC modelling in hadrontherapy in grow is devoted to MC modelling directly calculated from avoxel-based calculated 3D image, directly patient through range modulators, ridge filters, filters, ridge modulators, range patient through mation of the dose due to secondary neutrons and mation dose due of to secondary the the importance of low importance doses when event-by-eventthe treatment the room. in background radiation the beam delivery, one should simulate the radiation radiation the delivery, onebeam simulate should according to several majoraccording tasks. scatterers and collimators in the case of passive case the in scatterers collimators and coupled a biophysical with to model account for First, when the beam is transported to the transported is beam when the First, Second, the dose delivered be the patient toSecond, the can

8.1 , the number of number papers, the - - 37 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 38 Nuclear Physics for Medicine – Chapter I – Hadrontherapy validated and benchmarked Monte and codes/ Carlo validated MC modelling includes detailed simulation of simulation detailed includes MC modelling RBE and compared to the dose calculated by other compared and dose calculated to the RBE (e.g. analytical pencil-like beam) methods. In par In beam) pencil-like methods. (e.g. analytical Planning System (TPS) as a superposition of thin System (TPS) a superposition as of thin Planning MeV/mm 170 MeV protons and (b) 330 A MeV AMeV 330 (b) and 170 protons MeV crylate. Note the different dose scales in two panels. two in scales dose different the Note crylate. Instr.Nucl. Meth. B (2008). al. et Pshenichnov [I. results MCHIT/Geant4 8.2. Figure Some examples of modelling of nuclear reactions Some examples of modelling in the medium. The energy dueloss is to Theenergy ionisation medium. the in materials. dense such in multiple scattering enhanced as well as implants, in nuclei or prompt gammas to validate the range of range the nuclei or prompt to validate gammas nuclear reactions induced by nucleons nuclei and primary and secondary particle is calculated as a as calculated is particle secondary and primary vivo. in protons tissues human nuclei and in profiles beam of pencil alibrary beams, pencil-like patients’ body the in implants presence of metallic or for other quality assurance tasks (see tasks Section 9). assurance or for quality other tools for simulating the propagation of protons of propagation the simulating for tools ticular, such a validation may be necessary in the the in may benecessary avalidation such ticular, below. research Several groups (see [2,3]) e.g. have relevant to proton ion carbon and therapy are given lating the yields of unstable positron-emitting (PE) positron-emitting of unstable yields the lating channels are simulated by the MC sampling method. method. MC by sampling the simulated are channels reaction nuclear various at step each and calculated propagation particle of steps short during collection codes. help the of MC be created with can or validated environments by aTreatment clinical in calculated Third, since the resulting dose distribution is distribution dose the since resulting Third, Fourth, MC codes are indispensable for calcu MC indispensable are codes Fourth, Basically, in MC modelling a trajectory of each atrajectory MC modelling in Basically, 3 per beam particle, for 4 mm FWHM pencil beams of (a) (a) of beams pencil FWHM 4mm for particle, beam per

266 : 1094–1098] for spatial dose distributions in in distributions dose spatial for : 1094–1098] 12 C ions in polymethylmetha-

- - 12.78-cm thick water phantom. As one can see in water see one in 12.78-cm phantom. can thick As Therapy (MCHIT) [4]theGeant4 on based toolkit validated with experimental data for secondary for data secondary experimental with validated MCHIT [4].inside MCHIT dose the fraction total of The with sub-mm accuracy. The strength of a Monte strength accuracy.The sub-mm with was estimated as ~1%. This value is similar to the to ~1%. as estimated is similar was value This In particular, the effect of lateral scattering can can scattering lateral effect of the particular, In Figure Carlo model is that not only 1D depth-dose curves curves 1D not depth-dose that is only model Carlo Secondary neutrons are producedSecondary by proton and from their production points. In order In productionto evaluate points. from their of shielding and air tissues, surrounding in further is used here. The main task of anyis to task model of repro here. used is main The voxel-basedin Since phantoms. anthropomorphic improve of Geant4 models with fragmentation the However, obtained. is of relatively yields slow the neutrons produced AMeV by 200 neutrons below (with 150 energy MeV) at emitted not provide patient to a seriousthe hazard during distributions for proton given. is distributions beams carbon and deposition of energy distribution spatial duce the distance from the treatment from the site.was The model distance 8.3 model, and we conclude that there is still room to we and conclude theremodel, still is that in also and modulators range collimators, ments, ondary fragments and neutrons and essential. is fragments ondary of Monte research, the for model Carlo Heavy-Ion open issues. be mentioned some below keyonly topics with will of doses from secondary neutrons deliveredof from at doses secondary any one for a proton estimated should thus and beam the beam penumbra where beam contributionthe the of sec for than major achievements and of underlining aim the growing researchis field rapidly (see Figure this treatment. The MCHIT model allows calculation calculation allows model treatment. The MCHIT due to phantom specifically the is volume, which neutrons onof impact a patient, a secondary the treatment far the deposit very room energy can and propagate neutrons Such volume. treatment the butions in tissues. In Figure In tissues. butions in respect neutrons. to production of secondary and carbon nuclei in tissue-like materials and also also and materials nuclei carbon tissue-like and in a proton or acarbon-ion with simulated was beam especially evident for modelling radiation fields in in fields radiation evident for modelling especially large angles (20 angles large secondary neutrons producedsecondary nuclei, by carbon simple cubic (40 cm clearly be seen, which is much is stronger for which beseen, protonsclearly 3D dose distri but also calculated, be reliably can carbon-ion beams in materials of beam-line ele of beam-line carbon-ion materials in beams In order to illustrate general trends in this field field this in general trends orderIn to illustrate Secondary neutrons Secondary 8.3 12 C. The advantages of the MC method arethe The advantages MC of method C. , general good agreement with the data data the agreement good , general with o and 30 and 3 )

water phantom irradiated by irradiated phantom water o ) are overestimated) are by the 8.2 an example of such an 12 C beam in a in C beam 8.1 ) - - - - As demonstrated beams As by measurements with Bragg peak. The attenuation of the The attenuation of peak. Bragg 12 AMeV 200 by produced neutrons of spectra Energy 8.3. Figure et al et Mishustin I. [From model. break-up Fermi the with connected model cascade Binary Light-Ion the with obtained results MCHIT/Geant4 present Histograms axis. fragments are accurately reproduced areaccurately fragments by MCHIT 8.4 phantom, up to frag of70% undergo projectiles peak ( peak mentation before of Bragg reach the depth the they of 400A MeVof 400A but earlier producedbut (especially protons earlier fragments build-up of hydrogen, lithium, beryllium and boron and beryllium build-up of hydrogen, lithium, and alpha particles) propagate further beyond the particles) alpha propagateand further C beam in a water phantom at 0 at phantom awater in C beam Fragmentation Figure 8.4 12 ). ). C nuclei propagating in awaterC nuclei in propagating 12 C projectiles stop at this depth, depth, stopC projectiles at this Eur. Phys. J. D60 J. . (2010). Eur. Phys. o , 5 o , 10 o , 20 o and 30 and 12 C beam and and C beam o to the beam beam the to : 109–114.] - Biol. ( 10 10 15 13 would otherwise enhance the emission ofpar emission alpha the enhance otherwise would with (G4QMD) Dynamics Molecular Quantum the with Forin hadrontherapy treatment verification pos- is it Med. (seePhys. T.T.FLUKA (2010). al. et Böhlen Fermi breakup for model nuclear de-excitation Bragg peak. This is because of projectile fragments, fragments, is because of projectile This peak. Bragg Attenuation of of Attenuation 8.4. Figure and Fermi breakup models. breakup Fermi and 122 al et Haettner [E. data experimental – water. Points in nuclei carbon MeV 400A by induced reactions nuclear in legend) the see B, Hto (from fragments secondary include nuclear structure effects. Similar results results Similar effects. nuclearstructure include irradiation or 10–20 min afterwards. Since the Since or 10–20 afterwards. irradiation min in nuclear reactions induced byin therapeutic proton nucleus collision models, which may eventually may eventually which models, nucleus collision due to neglecting the cluster structure of structure cluster the due to neglecting 8.5 momenta of photons from a single annihilation momenta of photons annihilation from asingle model for nucleus–nucleus collisions and the the and collisions nucleus–nucleus for model modelling of production of PE one nuclei of thus is modelling tissue in positrons travel which afew millimetres on yields of nuclear fragments were obtained with were of with nuclearfragments obtained on yields of positron-emitting nuclei can beby reconstructed nuclei can of positron-emitting ticles in the fragmentation of fragmentation the in ticles is distribution depth-dose the dose, total to the to the Bragg peak. In contrast, the maximum of b maximum the contrast, In peak. Bragg to the close fall-off asharp with path beam the uted along of Examples calcu method. of key issues this the Precise dose. for planned the calculated tribution - dis the compared and tomographic with methods - The emis electrons. with before annihilate they reaction models. reaction a direction for further development of nucleus– for further a direction activity created by activity also well reproduced. At the same time the yield of yield the reproduced. time same the At well also and and nuclei carbon-ion Such low-energyand emit beams. helium fragments is underestimated, presumably underestimated, is fragments helium elsewhere [2,3]. Fragments nuclei, of target event are strongly correlated, a spatial distribution distribution event correlated,aspatial strongly are lated distributions of PElated nuclei distributions produced by protons sible to exploit production PE the of nuclei, unstable sion of characteristic pairs of annihilation photons of annihilation pairs sion of characteristic can be detected with a PET scanner during the the during aPET scanner be detected with can Figure O created distrib by evenly are protons tissues in C and C and N (9.97 min); C (with the half-life of 19.26C (with half-life the s); : 485–487], lines – simulations with MCHIT/Geant4 using QMD QMD using MCHIT/Geant4 with –simulations lines : 485–487], Simulations of PET images Simulations 12

12 55: C nuclei in tissue-like materials can be found befound can materials tissue-like C nuclei in C projectiles provide the main contribution provideC projectiles main the

11 8.4 5833–5847) set of its own nuclear with C, created in peripheral nucleus–nucleus created nucleus–nucleus peripheral in C, ). Since Li, Be and B fragments along along B fragments and Be ). Li, Since 14 O (1.18 min) and 12 12 C nuclei located is close to the C beam (black) and build-up of of build-up and (black) C beam . (2006). Radiat. Prot.. (2006). Dosim. 12 C. This indicates indicates This C. 11 15 C (20.39 min); O (2.04 min), O (2.04 min), 12 C, which C, 11 C and and C

+ - - - - 39 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 40 Nuclear Physics for Medicine – Chapter I – Hadrontherapy MCNPX and PHITS for yields of PE for nuclei PHITS yields devi and MCNPX Monte Carlo modelling of proton ion-beam and Monte modelling Carlo (p,n) reactions on carbon and oxygen. At the same (p,n) same At the reactions oxygen. on and carbon 15 FLUKA, Geant4, MCNPX and PHITS [3]. PHITS and MCNPX Geant4, FLUKA FLUKA, PE nuclei production by protons ions carbon and SHIELD-HIT and MCNPX with experimental experimental with MCNPX and SHIELD-HIT ing their theoretical description. theoretical their ing and theoretical between collaboration international description for of abetter especially codes, these in set-up a common irradiation in [2]. The nal nuclear reaction models of FLUKA, Geant4, of reaction nuclear FLUKA, models nal nuclear and atomic scales and radiation fields in fields radiation and atomic scales nuclear and data is reached, none of the existing codes/tools reached, is nonedata of existing the 8.6 projectiles agree better than for protons. A similar for protons. than Asimilar better agree projectiles two forthesecodes with calculated profiles production of PEinter nuclei. The of predictions tion of more detailed and accurate data on nuclear data accurate and oftion more detailed PHITS, Geant4, FLUKA, with obtained results tion improvetest and models. nucleus–nucleus collision more needed are time data for production of tile velocity. tile the media. While ageneralagreement of simula While media. the physics the between of processes at the links the reactions relevant to ion-beam therapy improv and ate from each other and from experiment. Therea is ate from from experiment. and other each approximations of cross measured for sections profiles for built-inproton using by activity beams experimental groups needed is experimental to foster collec the clear needclear to improve used reaction nuclear models for performed was protons, for only but comparison, of compared respect recently to modelling with have which velocities projec close to the collisions, can serve as an universal “best-choice tool”. A wide “best-choice Awide tool”. universal an as serve can cancer therapy is a powerful tool to establish therapycancer apowerful is gives most description accurate the of b measured O by nuclear beams in various light materials to materials light various in O by beams nuclear Two were GATE/Geant4 models, FLUKA, and Summary b + -activity -activity 11 C and and C 12 C + ------[4] [3] [2] [1] References Verhaegen. (2012). Monte calculations Carlo A. Mairani, G. Montarou, R. Nicolini, P.G. Nicolini, Montarou, G. R. Mairani, A. Lestand, L. P. Ferrari, Kurz, A. C. Gueth, Ty, D.R. Schaart, I. Buvat, K. Parodi and F. and Parodi Buvat,Ty, K. I. Schaart, D.R. 5507. Phys. Med. Biol. Med. Phys. Units and Measurements, Technical Measurements, Units and reports (2005). Neutrons from of fragmentation light International Commission on Radiation Radiation on Commission International and Agency Energy Atomic International Bohlen, I. Buvat, M.P.W. F. I. Cerutti, Bohlen, Chin, I. Pshenichnov, I. Mishustin and W. and Pshenichnov,I. Greiner. Mishustin I. Bauer, J. Robert, F. C. Seravalli, E. C. Robert, G. Dedes, G. Battistoni, T.T. Battistoni, G. Dedes, G. Robert, C. E. Blakely, Hendry, J. P.E. R. DeLuca, Phys. Med. Biol. Med. Phys. toolkit. GEANT4 Ortega, K. Parodi, Y. D. Parodi, Prezado, P.R. Sala, K. Ortega, Geant4 and FLUKA Monte codes. Carlo FLUKA Geant4 and Gahbauer, B. Michael, A. Wambersie A. Gahbauer, Michael, B. Stichelbaut, C. Kurz, J. Smeets, C. Van C. Smeets, J. Ngoc Kurz, C. Stichelbaut, Sarrut and E. Testa. E. and (2013).Sarrut of Distributions biological effectiveness in ion beam therapy beam ion in effectiveness biological ion GATE/ therapy: acomparison between nuclei in tissue-like media: a study with the the with astudy media: tissue-like nuclei in of positron emitter yields in proton in of positron yields emitter radiotherapy. radiotherapy. Relative Relative (Editors), Whitmore G. and secondary particles in proton in carbon- and particles secondary series No 461, 2008. Vienna, Phys. Med. Biol. Med. Phys.

58 : 2879–2900. :

57 : 1659–1674. :

50: 5493– , Treatment planning The treatment planning process is a crucial step in in step processis a crucial treatmentThe planning l l l which beam quality is used for used therapy is (photons, quality beam which Dose distribution comparison for meningioma patients. From left to right, IMRT with photons based on 5 fields, scanned proton proton therapy. scanned beam ion 5fields, on carbon and based photons with IMRT right, to left From patients. meningioma for comparison distribution 9.1. Dose Figure ing normal tissue and organs at risk which would would at which risk organs and tissue normal ing ning software runs on powerful computers. In the computers. In powerful on runs software ning distribution, tumour and organ specific parameters, parameters, specific organ and tumour distribution, surround the and tumour to the dose distribution the is to simulate deliveredaim to apatient. The particles, radioactive nuclides) radioactive treatment –the plan particles, control respectment to local outcome, with both or biological parameters, can be extracted in order in beextracted can or parameters, biological ogy and takes place prior to the first fraction being fraction being place prior takes first and to the ogy to enable the prediction of the best knowledge treat to knowledge best enable of prediction the the treatment overall oncol procedurethe radiation in result from an intended treatment. from Fromresult an dose this a so-called treatment planning system (TPS). system treatment planning a so-called treatment-relatedand toxicity. of These simulations 9.1 such a treatment are performed with the support atreatmentofsuch the performed are with 9. 9. In modern radiation oncology – irrespective of –irrespective oncology radiation modern In Introduction - - - - The treatment planning process consists of sev treatmentThe planning Consequently, the first 3D TPSs were used clinically Consequently, TPSs were usedclinically 3D first the in protonin therapy. beam later, Only by driven and dose distribution display of a TPS for of photon aTPS display beam dose distribution dose calculation was soon realised and pursued. pursued. and soon realised was dose calculation photon therapy. beam Figure opments in TPS made foropmentsmade proton TPS in therapy beam have of dimension and density, requirement and the of dimension for true three-dimensional (3D) and three-dimensional treatment planning of strong protons their physical selectivity and the these developments,these were introduced into 3D TPSs range sensitivity to tissue variations, both in terms terms in both variations, to tissue sensitivity range age of three-dimensional conformal therapy, conformal devel ofage three-dimensional and particle beam therapy. beam particle and 9.2 eral sub-tasks with strong mutual dependencies. strongmutual with sub-tasks eral set benchmarks for photonset benchmarks therapy. beam to Due The treatment planning process planning The treatment 9.1 illustrates a typical typical a illustrates - - 41 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 42 Nuclear Physics for Medicine – Chapter I – Hadrontherapy volume to be irradiated (planning target volume – target (planning volume to beirradiated (CT) is the basic imaging modality that serves treat serves that modality (CT) basic imaging the is which must be taken into account in creating an an creating into account in be taken must which provideswhich posior superior tissue contrast, soft most of selection the the Furthermore TPS. the with Before treatment planning, during which the which during Before treatment planning, PTV), organs at risk (OAR) and other structures at (OAR)risk organs structures PTV), other and formed using magnetic resonance imaging (MRI), (MRI), resonance imaging magnetic formed using for where pathologies tissue contrastCT softof the intra-observer uncertainties. The inter-observer The uncertainties. intra-observer is not sufficient, additional imaging series series are per imaging additional notis sufficient, treatment today’sin positions. In state-of-the-art devices are defined and individually casted for the casted for individually and are defined devices ment planning. This process defines the tumour, tumour, the the processdefines This ment planning. into account defini for taken is target metabolism cause usually they as orprostheses, implants, other fillings, dental present as patient, such the metals in the of attenuation effects potential position that is patient. Over recent immobili dedicated decades, or immobilisation aids positioning prior imaging beam particle In dose calculation. in modelling of it because enables calibration the ment planning optimal treatment plan. Structure segmentation is Structure treatment plan. optimal tion oncology at tion oncology present. Recent developments in radia in probably is uncertainty task, largest the is a medical which definition, target in uncertainties segmentation. for CT structure the co-registered then are to images additional All tion. tumour which (PET), in tomography emission tron geom patient and situation anatomic actual the betreatment related can beam devices to those treatment patient the in when imaging aspect tant However, purpose. same the serve they impor the for photon electron while and relevantthe particle, order in to ena imaging cross-sectional undergoes therapy this parameter is the stopping power the is parameter of therapy this beam therapy electron density.beam it the is ble of patient´s reconstruction the anatomy 3D in bilisation devices used in particle beam therapy beam particle in used devices bilisation radiation oncology practice, computer tomography tomography computer practice, oncology radiation attention needs to be paid to situations if there attention are toif needs bepaid situations appropriate incidence to needs on bebased beam dose calculations accounted for when performing as photon in therapyand rather beam are similar immo general, extremities). In abdomen, pelvis, head-and-neck, regions (brain, anatomical thorax, a manual process and as such prone such process as and to inter-a manual and actual radiation fields are designed, apatient designed, are fields radiation actual etry as intended treatment for as the session. Special etry several artefacts. In special treatment or special situations, In several artefacts. havesation devices been developed forvarious the cal parameters that are required are for that heterogeneity parameters cal grey-scale or Hounsfield units against various physi various against units grey-scale or Hounsfield CT Imaging in treatment that in positions implies Imaging CT Structure segmentation asub-process treat is in Structure ------50, 62 83),50, and electron 71)(Report proton and volumes of organs, and required minimum doses to required and volumes minimum of organs, 3D conformal radiotherapy with high energy pho energy high radiotherapy3D conformal with will not be considered adegree of as freedom will in CT information with functional information, have information, functional with information CT fraction and the total dose to be delivered, the treat dose the to be delivered, total the and fraction is the definition of treatment parameters. In this this treatmentIn of parameters. definition the is recommendations Several oncology. radiation in technology, of for multi use example the imaging definition in order to establish a common language a in language commonorder establish to definition given to focus volume particular the is documents prescribing, recording and reporting radiation reporting and recording prescribing, particle therapy facilities for proton and carbon ion ion carbon proton for and facilities therapy particle the particular in and information imaging modality patterns are determined by algorithms that are that by algorithms aredetermined patterns fluence particle which in ment optimisation, plan shape beam are parameters process. Optimisation or sub- organs to certain permitted doses maximum useful a clinically until optimisation undergoes plan treatment the and calculated dose is the parameters include directions, to beam ment select has planner particle aspecific or selecting treatments, modality observer uncertainties in target definition. For more definition. target in observer uncertainties on Beam Delivery). Foron Beam passively scattered beams, treatment process, the intent needs optimisation on Radiation Units and Measurements Units (ICRU) and on Radiation therapy that are based on synchrotrons, combined ontherapy based are synchrotrons, that However, upcoming the treatment planning. with ICRU of these all A commontreatments. theme in Commission International the years, forty than of PET,use complement which pure morphologic ton beams. In contrast, scanned beam delivery is is delivery beam scanned contrast, In ton beams. on based mostly is optimisation treatment plan passively scattered i.e. methods, delivery beam two (tumour)target structures. into treatment as to such betranslated parameters decisions doseper on the medical totion making addi feasible. is In on indication, depending type beam (Report 78) (Report beam therapy. based on inverse planning or computerisedbased on inverse treat planning processis This etc. weight, beam incidence, beam (see beams pencil Chapter 4 scanned and beams address the specific issues issues of photon specific the address (ICRU Reports and size, spread (SOBP) size, and out Bragg length, peak this In obtained. is acceptableand dose distribution on these consider Based and tolerance of doses OAR. motion, of treatment robustness against aspects plan has defined and published recommendations defined has for human intelligence and a manual trial and error and trial amanual and intelligence human similar to treatment plan optimisation in standard standard in to treatment optimisation plan similar species, like protons, ions, ions carbon species, like or helium contributed significantly to reducing the inter- to the reducing contributed significantly chapter or selection combination the of particle The next step in the treatment planning process treatmentthe in step planning The next Treatment plan optimisation differs between the between Treatment differs optimisation plan - - - - - TPS. However,TPS. developments current are rendering Effects like multiple Coulomb scattering, nuclear scattering, like Coulomb multiple Effects field per field optimisation, and the simultaneous simultaneous the and field per field optimisation, nine elementary pencil beams per dimension. per beams pencil elementary nine with results calculation beam pencil the (d) and GATE simulation (c) criterion. 2%/2mm the using map, γ-index (b) calculation. beam pencil the in account into taken were sigma initial the of times 20 to Longitudinal energy deposition (E water. (a) with areas grey light the and air with area white the bone, with filled was area grey dark The depth. 5cm at inserts thick cm 3 two with phantom awater 150 at MeV/A, hitting σ=2mm with Figure 9.2. interactions and fragmentation can be included, be included, can fragmentation and interactions acompositein treatment plan. the general, treatment the intent.In specify turn in driven by dose, organ and volume parameters which volume which and parameters organ bydriven dose, often subdivided in sub-beams or elementary pencil pencil elementary or sub-beams in subdivided often spots and beam treatment fields of all optimisation in terms of be classified can methods optimisation the highest accuracy in dose calculation in the pres the in dose calculation in accuracy highest the have These models models. therapy beam pencil are beams, ray tracing algorithms are also used in the the in used also are algorithms ray tracing beams, passive scattered with For dose calculations beams. species. of irrespective particle speed, high and bility flexi high been shown accuracy, to sufficient deliver albeit only in a(semi-)empirical in only albeit To manner. achieve beam state-of-the-art for in particle TPSs algorithm ence of tissue heterogeneities, pencil beams are heterogeneities,ence of beams tissue pencil single field uniform dose optimisation i.e. dose (SFUD), optimisation uniform field single The most commonly applied dose calculation The appliedmost dose calculation commonly Energy deposition of a Gaussian helium ion beam beam ion helium aGaussian of deposition Energy dep ), lateral energy contributions up up contributions energy ), lateral - - RBE models for scanned beams used in TPS are TPS in used beams for scanned models RBE fore.g. protons effects, a genericfactor of RBE 1.1 is For the latter, RBE is included via LET dependen LET via included is For latter, the RBE for the same endpoints. Although very elegant in in elegant very Although endpoints. for same the ions. Current carbon like particles LET for high its concept, this model suffers somewhatfromthe suffers model its concept, this developed at GSI. The LEM model is an analytical analytical an is model LEM developed The at GSI. mostly built on the Local Effect Model (LEM) Model Effect Local on the built mostly parameters are alpha-beta are parameters ratios of aphoton beam input endpoint. The basic and type cell per fraction, dependencies on dose for accounts RBE that model ionfor carbon therapydifferent practice in very is applied frac most commonly irrespective of organ, therapy. beam particle of pencil beam algorithms for dose calculation in in for dose calculation algorithms beam of pencil tionation and energy. The situation is differs greatly greatly differs tionation energy. and is The situation Figure In outdated. models these approaches are used in clinical practice to include practice to include approaches clinical in used are for Monteachal and simulations Carlo algorithm effects also need to be modelled during dose cal during also need to be modelled effects limited knowledge of alpha-beta knowledge ratios forvari the limited protons, as such rather pragmatic particles, low LET suitability the geometry,illustrating thus lenging scanned beam delivery and passive and scattered delivery beams. beam scanned cies obtained from historical neutron data, while while neutron from ciesdata, historical obtained (see Chapterculation 7on For Radiobiology). also beam pencil comparison a typical shown is between In addition to the physical dose, radiobiological physical radiobiological to dose, the addition In 9.2 a dosimetric adosimetric - - - - - 43 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 44 Nuclear Physics for Medicine – Chapter I – Hadrontherapy Treatment assur involves several quality planning verification in one verification or in a morehomogenous points imaging using verified priortreatment to delivery Methods to perform patient-specific,Methods treatment- Radiotherapy (IGRT). Some IGRT concepts in in concepts IGRT Some (IGRT). Radiotherapy Geometric factors of influence like organ filling filling like organ Geometric factors of influence immobilisation device, patient are rotations, device, etc. immobilisation intensive task which exceeds the scope of this intro scope of the exceeds this intensive which task distributions. Assessment for parameters clini the distributions. there at are risk, organs and tissues doses to normal device. The frequent use of imaging tools to verify to tools verify frequent The imaging device. use of to treatmentduction planning. plan-related QA range from experimental dosimetry plan-related dosimetry QA from experimental range Potentialperformed sources intended. of as errors therapy beam on based are pre-positioning particle ment delivery beam room the combined and with is a rather complexandprocedures. This workload posi table position as such or gantry parameters, RBE dose on in uncertainties of effects motion, and needs to be dose distribution resulting the pleted, or anthropomorphic phantom to independent dose dose independent to phantom anthropomorphic or are, requirefor These attention. that other aspects respect endpoints with clinical and types tissue ous those used in photon therapy, in used beam mostthose the i.e. the TPS to the delivery unit, human errors, or short human unit, delivery to the TPS the control quality and assurance quality to periodic system IT of an database to transferred are the tion, patient and organ robustness against their and terns toxicity. to based imaging devices mostly located in the treat locatedthe mostly in devices based imaging treatment related parameters and beam geometry ance aspects. First of all, a TPS needs to needs besubjected aTPS of First all, aspects. ance as well dosesas on tumour focus criteria that ance accept clinical the Besides reviewed. and assessed and uncertainties are incorrect data transfer from transfer incorrect are data uncertainties and located CT outside treatmentand the a room with Guided Image correctand called patient is geometry 9.3 equipment. These can be planar or volumetric be equipment.planar X-ray can These practice. clinical require attention in aspects eral pat scanning time, delivery estimated example, status, patient diameter, patientstatus, the position in specific, QA task is to verify that dose delivery is thatdosedelivery is specific, task to QA verify subsequent treatment to patient the rooms. transfer called Patient Record Verifycalled and System. common dose volume applied. are parameters to acceptance of atreatment similar are cal plan comings in the dose calculation of the TPS itself. itself. TPS of the dosecalculation the in comings A treatment-plan-related, and also patient- also and treatment-plan-related, A patient as specific far is QA concerned,As sev If a treatment plan is accepted, the underlying underlying the accepted, is atreatmentIf plan Finally, after a treatment been com a has after plan Finally, Quality assurance aspects assurance Quality ------where treatment plans are adapted accordingly to where adapted are treatment accordingly plans In such a setting, combined modality treatments combined modality asetting, such In Improvements respect to dose calculation with LET particles, ion beam therapy thus offers ideal ion therapyoffers beam ideal thus particles, LET Developments in treatment planning and dose cal and Developments treatment in planning from temporal changes in anatomy. in from temporal changes of Examples imaging techniques. In contrast radio to current In techniques. imaging is certainly an issue; however, issue; an cur with speed gain certainly is optimisa ofinclusion treatment robustness in plan in parallel rather than in synergy. In recent In synergy. years in rather than parallel in deformable dose accumulation. and registration dose painting is called technique deliberately. This prompt based rays. reconstruction Dose gamma offer new options but also require further research further offer also new optionsrequire but on PET imaging of beta activity distributions or distributions of activity beta on PET imaging tion strategies. Monte Carlo based dose calculation Monte strategies. tion dose calculation based Carlo workflowandimprovethe to accuracy. delivery or emitters beta as such traverse tissues, human products interaction when particles utilising tion treatments need to address the challenges arising arising treatments challenges need the to address trend towards beenthere aclear closer has collabo therapy photon and therapy were beam developed therapy heterogeneous practice, doses are delivered of radio-resistanttumour selective boosting the beam therapy as a complementary treatment option. option. treatment complementary a as therapy beam strategies. for dose painting brushes rent relevant general concepts in hardware also is doseverifica situ or in techniques re-calculation research issues that impact TPS development TPS research impact that issues are has which communities two ration these between algorithm implementation dose cal pursued, is algorithm GPU-based which concern in speed, algorithms art QA methods in particle beam therapy. beam particle QA in methods art and development. and For combined example, modality representaccurately situation. anatomic the and together with scanned beam delivery and high high and delivery beam scanned with together and 9.4 like image guided adaptive radiotherapy (IGART) guided image like single particle detection as mentioned as detection above particle are single sub-volumes that can be visualised by molecular by molecular sub-volumes be visualised can that standard radiotherapy departments invest in proton invest in radiotherapy departments standard culation have focused on various aspects to facilitate to have facilitate aspects on various culation focused research state-of-the- topicscurrently rather than certainly been influenced by the fact that existing thatexisting the fact by been influenced certainly culation accuracy, biological modelling and the the and accuracy, modelling biological culation Another general trend in radiation oncology is is oncology radiation general trend in Another From a historical point of view particle beam beam From point of particle view a historical Current developments Current ------[5] [4] [3] [2] [1] References – Threshold Doses for Tissue Reactions Doses – ThresholdReactions for Tissue Therapy Williams and Wilkins, Philadelphia, 2007. Philadelphia, Wilkins, and Williams Recording, and Reporting Proton-Beam and Reporting Recording, Charged Particle Radiotherapy Charged Particle Prescribing, Prescribing, Measurements, Units and 2007. Radiation in Normal Tissues and Organs Organs and Tissues Normal in Radiation of Effects Late and Reactions/Early Engineering, CRC Press 2011. book, Engineering, Publication 118, 2012. Publication StatementProtection, on ICRP Tissue International Commission on Radiological on Radiological Commission International Radiation on Commission International (editor) H, Paganetti Physics Therapy Proton T. F. Kooy, and M. H. DeLaney, Proton Radiation Oncology: A physicist’s- Radiation Goitein, M. Series in Medical Physics Biomedical Medical and in Series in a Radiation Protection Context, ICRP Protection ICRP Context, aRadiation in eye view eye , ICRU Report 78, Bethesda, USA, USA, , ICRU 78, Bethesda, Report , Springer, New York, 2007. , Lippincott Lippincott , , 45 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 46 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 10. 10.1 80,000 ionisation events the ionisation place inside take 80,000 l l l 10 Boron neutron therapy capture (BNCT) adual is Artistic description of BNCT. The BNCT. of The description 10.1. Artistic Figure fragments destroy the tumour cell. cell. tumour the destroy fragments it a absorbs thermal neutron. reaction The high-LET short-range charged into the tumour cell, nuclear undergoes reaction when it can selectively hit the tumour cells, sparing the the sparing cells, tumour the selectively hit it can nuclei (see Figure of the high-LET nuclear reaction fragments, about nuclearreaction fragments, high-LET of the they induce an exothermic nuclear reaction in reaction nuclear exothermic in an induce they region irradi is tumour the value, maximum the tumour/ the patient. When injectedinto the tem, therapy. First a a First therapy. Boron neutron capture therapy capture neutron Boron the surrounding cells. BNCT is therefore a cellular BNCT therefore is acellular cells. surrounding the radiation therapy. Unlike traditional radiotherapy, radiotherapy, traditional Unlike therapy. radiation a minor biological effect on living cells. However, cells. living on effect biological a minor neutrons neutrons. Thermal have thermal ated with healthy-tissue healthy-tissue - sys the circulatory through or specificity,is locally, surrounding healthy tissue. healthy surrounding cal damage. The nuclear reaction does not damage The damage does notnuclear reaction damage. cal B-doped living cell giving rise to severe rise biologi giving cell living B-doped Introduction 10 10 B concentration ratioreached has 10.1 B carrier, with high tumour-cell tumour-cell high B carrier, with ). Because of the short range range short of). the Because 10 B atom, previously previously B atom, 10 B - - 10.2 1990 to today, cancershave many been treated using 1950s by Sweet and by BNL Farr Brownell at the and - dis cancer. The brain patients with in Reactor MIT (BPA) accumulated preferentially selectively is and 10 10 with apoor prognosis, havewith undergone BNCT, in benefits. evident clinical with BNCT therapy, other combination oralone in with from diagnosis (0% vs. 20% in no-BNCT BNCT in vs. (0% 20% vs. from diagnosis increase of the overall survival rate after 30 months 30 months rate after survival overall ofincrease the therapeutic scheme the producedin asignificant of augmented the metabolism via cells into tumour many cases in combination with chemotherapy combination with in (such cases many of 38% after 24 months from the date of diagnosis. diagnosis. datefromthe 24 of months of after 38% tion of morbidity) and a recovery in overall survival oftion morbidity) arecovery survival and overall in associated a cancer form oftoma brain multiforme, but results different reporting treatment modalities, to: i) absence transporters of of specific tumour and ii) no difference in concentration ii) and no ofdifference tumour beam radiotherapy,beam inclusion EBRT). The of BNCT recognised effect from a clinical point of viewpoint of (reducfrom clinical a effect recognised accumulated selectively into tumour cells by sev cells selectively into tumour accumulated as Bevacizumab or Temozolamide or with external or Temozolamide Bevacizumab external as or with were attributable outcomesappointing trials of these the Hospital General by using Massachussets at the first The comparison cells. to normal in acids amino head neck and were cancer treated a by BNCT with eral mechanisms. For borophenylalanine example, mechanisms. eral clinical trials with BNCT were initiated in the early early the BNCT were in with initiated trials clinical group). Moreover, from 1999, about 165 patients with BNCT+EBRT in 30% vs. no-BCNT in 0% and group B is the isotope widely used for this purpose, being being purpose, for used this isotope the B is widely B between healthy and pathological tissue. From tissue. pathological and healthy B between - glioblas 1994,Since patients atwith 227 least BNCT in clinical practice BNCT 10 B in the the B in - - 10.2Figure BNCT, from forcolon example liver can metastases *  10.1.Table Operative BNCT centres 67 Isot. Radiat. Appl. malignancies. neck and head recurrent for therapy capture neutron al et Kato [from BNCT without and with treated cancer neck and head recurrent with patients of plots 67 Isot. Radiat. Appl. patients. glioblastoma diagnosed newly the for therapy capture al et Kawabata [from BNCT with treated not and treated glioblastoma diagnosed newly all for survival overall the of plot Kaplan–Meier side, Left 10.2. Figure organs. ture concerning glioblastoma and neck and cancers. glioblastoma concerning ture have proven undergone BNCTespe with effects, cially in the case of relapse in brain or other distant or distant other of brain relapse case the in in cially Centre Helsinki, Finland Helsinki UniversityCentralHospital, Ibaraki University ofTsukuba, Tsukuba City, University ofTokushima, Tokushima Medical School,Kurashiki University, OsakaandKawasaki University Research Reactor, Kyoto Osaka MedicalCollegeandKyoto Taipei, Taiwan Taipei Veterans GeneralHospital, Buenos Aires Instituto deOncologíaAngelH, GM: glioblastoma multiforme; CM: cutaneous melanoma; AA: anaplastic astrocytoma; HN: head and neck cancer; Men: meningioma; meningioma; Men: cancer cancer; thyroid neck AT: and head HN: anaplastic astrocytoma; anaplastic AA: melanoma; cutaneous CM: multiforme; glioblastoma GM: More than 50 patients with cutaneous melanoma melanoma cutaneous patients 50 with More than Many other type of have cancer been treated type other Many by shows some recent litera from the data . (2009). Survival benefit from boron neutron neutron boron from benefit Survival . (2009). : S37-42]. survival Kaplan–Meier : S15-18]. side, Right . (2009). Effectiveness of boron boron of Effectiveness . (2009). States Europe Japan Japan Japan of China Republic Argentina Neutron source Centre, Espoo FIR-1, VTTTechnical Research Agency, Tokai, Ibaraki JRR-4, JapanAtomicEnergy search Reactor, Osaka) JRR-4 (KyotoUniversityRe- KURR University, Hsinchu,Taiwan THOR, NationalTsing Hua Bariloche AtomicCenter - - - Table 10.1 BNCT (see Table ity of suitable neutron beams and the problematic the of neutron and suitable ity beams scarce availabil the that to underline important is is very aggressive and is histopathologically char histopathologically is and aggressive very is number ofnumber BNCT treatments. tron beams producedtron beams by research nuclearreactors. It tissue surrounded by anaplastic cells. The latter is latter The cells. by anaplastic surrounded tissue acterised by the presence of small areas of necrotic areas presence by the acterised of small the access to nuclearreactor centres limits heavily and lung tumours. lung and cer, and others under investigations, such as breast as such cer, investigations, others under and conversely less aggressive than GB, although its although conversely GB, lessthan aggressive carcinoma of head neck the and region. The former glioblastoma multiforme (GB) or squamous cell cell (GB) squamous or multiforme glioblastoma Most of the treated tumours with BNCT are with Most treated of the tumours Nowadays, six centres are treating patients with patients with centresNowadays, treating are six Neoplasm GB andHN GB GB GB, HN,CM HN CM andAT ). All of these centres neu of these use ). All patients* N° oftreated 31 HN 2 AA 50 GM 4 AA 20 GM 23 124 HN 7 Men 3 AA 30 GBM 10 3 AT 7CM

- - - 47 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 48 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 10.3 v) trials. lack of the randomised which it decays immediately to its state,ground it decayswhich immediately weakness. The main advantage is its ability to act is advantage ability its The main weakness. invasion. vascular or lymphatic without In fact the two charged particles emerging from emerging particles charged two the fact In Boron is a metal with two stable isotopes: two with Boron ametal is Q-value is +2.79 MeV. The reaction proceeds two by is shared between the a the sharedis between a sufficient that providing atumour, destroying in iii) the necessity of a multidisciplinary team (nuclear team of necessity iii) amultidisciplinary the environment; location clinical outsideii) the their or with deep,or besuperficial it can particular in ium ions, respectively. ions, ium directly and specifically on the tumour, both pri both tumour, the on specifically and directly data about histological characteristics of treated characteristics about histological data pathways. In the 6.3% of cases the Q-value energy Q-value the 6.3%of energy cases the pathways. In prognostic importance, with afavourable with impact prognostic importance, (i.e. aselective metastasis) or secondary with mary patterns, histological show can melanoma different prognosis; for example poorly-differentiated lesions oncological subjects. The main weaknesses of BNCT weaknesses main The subjects. oncological of survival overall on the and of life quality on the together, may result in an improvementtogether, an may in result patient in transfer) and short range, which is smaller than the the than smaller is transfer) which range, short and energy (linear nuclearreactionthe have LET high two selective molecules for for molecules selective two chemistry, dosimetry, sophisticated technology, be best suited as an adjunctive treatment, used in in treatment, adjunctive used an as suited be best biology and medicine); and ofbiology only iv) availability the reaction leaves the reaction are 9 µm and 5 µm in tissue for a tissue in 5µm and 9µm are ion (0.84 MeV). lithium the and The average ranges cell. tumour the in of boronamount accumulated is are: i) the small number of number neutron suitable are: i) beams; small the cutaneous malignant Similarly, available literature. and and head and neck cancer cannot beretrievedhead neck and cannot from cancer the Unfortunately, have five-year scarcely survival. the alter variously can characteristics histological energy is shared between the a the shared is between energy MeV a0.428 ray. gamma emitting The remaining effect on the neoplastic cells. Moreoverthe on neoplastic effect cells. has also it lithium ion (1.01lithium MeV). 93.7% the the of In cases survival. surgery, chemotherapy, EBRT, when used which, cell diameter. cell including modalities, other with combination Therefore, as things currently stand, mayBNCT stand, currently Therefore,things as and therapystrengths targeted many has This The reaction cross section is 3837 barn and the and The 3837 crossis reaction section barn 11 BNCT physics BNCT B (80.1%).therapythe The exploits nuclear 10 B(n, a ) 7 Li. This reaction is very effective effective is reaction very This Li. 7 Li ion in an excited an from ion state, in Li particle (1.78 particle MeV) the and 10 B delivery in tumours; tumours; in B delivery particle (1.47 MeV) particle particles and lith and particles 10 B (19.9%) (19.9%) B - - 10.4 15.7% of the natural metal and it ahuge thermal- has and 15.7% metal natural of the These electrons, the energy of which range from range thewhich of energy electrons, These X-rays Coster-Kronig or and Auger While electrons. 7.94 MeV. When 79 keV to 6.9 MeV, leave orbital the vacancies in ( Neutron therapy capture quan (NCT) needslarge 157 g GdNCT kind of therapy: gadolinium, which is a metal of ametal is which of therapy: gadolinium, kind Since these molecules are already used in photody in used already are molecules these Since from the reaction point, Auger and Coster-Kronig and Auger reactionfrom point, the dro-closo-dodecaborate interesting results in mice skin-melanoma studies. studies. skin-melanoma mice in results interesting healthy surrounding the than cells for tumour ity investigation in order advan its potential in investigation to assess 69%. remaining the for conversion electrons internal it leaves neutron cross capture (225 section kbarn). therapybe envisaged in can (PDT),namic use their new drugs, based on a phthalocyanine molecule molecule based on a phthalocyanine new drugs, drugs are under investigation. For instance, two two For investigation. areunder instance, drugs produces high energy g energy produces high molecule enriched with 36 36 enriched with molecule of fivestable isotopes. The the lanthanide series. The natural metal occurs as occurs metal The natural series. lanthanide the tity of thermal neutrons at the tumour site. So neutrons tumour at of the thermal tity respect to BNCT. with tages experimental preliminary under still is technique as contrast used already indeedaretoxicity. They reaction point. Since reaction Since point. a BNCT+PDT therapy. a agents in MRI (magnetic resonance imaging). This This (magnetic resonance imaging). MRI in agents of about cascade 10 Auger energy an the electrons, high energy density should give to should high-LET- rise density energy high energy less than few tens of nanometres from lessthe than energy have which of <1electrons, energy keV, release their The electrons. orbital-levelhigher by filled are that electron shells enriched with 40 40 with enriched like biological damage. Gadolinium chelates and chelates and Gadolinium damage. biological like The decay rather is high. released by asingle locally sources clinical investigations: BSH ( BSH investigations: clinical Two nowadays are forcells. available drugs to have designed affin abetter adrug with cell cryptates could be used as carriers with very low very with carriers as be used could cryptates para-borophenylalanine -rays and fast electrons transport the energy far far energy the -rays electronstransport fast and Gd(n, Another element been proposed has Another for this The proposedThe therapy, more properly called 10 B has to be carried into or close to the target into or target close to to beB has carried the Accelerator-based neutron Accelerator-based neutron g 158 ) , ought to exploit reaction capture , ought the 158 Gd in an excited The an state. in Gd Gd, which has apositive has which Q-value ofGd, 158 157 Gd atom de-excites by emitting Gd atom de-excites by emitting 10 Gd B atoms and on a porphyrin B atoms on aporphyrin and 158 Na

absorbs a thermal neutron, neutron, thermal a absorbs -rays 31% and time of the Gd decay can give decayGd to rise can C 2 157

10 9 Gd isotopeGd represents H B 10 12 mercaptoundecahy B, haveB, produced 12 H

10 11 BNO SH) BPA and 158 Gd decayGd 4 ). Other Other ). - - - - - ~ 270 mb within the first 50 keV. first the ~ 270 mb within 2.25 MeVAt there 1980s. Nowadays, apparently most the advanced 10mA vacuum-insulation tandem accelerator tandem of the vacuum-insulation 10mA Therefore, low-energy high-intensity particle accel particle high-intensity Therefore, low-energy 30mA RFQ (radiofrequency RFQ quadrupole), was 30mA which E 92.5%, 92.5%, (d,n) investigation. under reactions also is trans waste nuclear for (accelerator-driven system Natural lithium is a metal with two isotopes ( two with ametal is lithium Natural It is used in its natural or in its isotopic or in form its natural It in used is Legnaro (Italy) in the framework of the ADS project (Italy) framework the ofLegnaro ADS in the Budker Institute (Russia); Institute 2.4MeVBudker iii) the 30mA far, only nuclear reactors nuclear supplyfar, quanti only can large is a broad resonance, which takes the cross abroadis the section takes resonance, which iv) 3MeV University the at the Dynamitron 5mA p(5MeV)a ofcore the +Bebe will it 2012and in neutron of 8.8×10 yield neutron 87.6 is energy keV. However, order in to neutron 10 of more intensity source of than an mA) necessary for performing BNCT in reasonable BNCT in for performing necessary mA) of handling difficult makes which point, melting neutron keVmean 38.3 is energy maximum the and power tests high passed mutation). It successfully project neutron the is source 5MV based on the or lithium targets, although the possibility to exploit possibility the although targets, or lithium nuclear SOREQ the Israel, In (UK). of Birmingham developed di atLaboratori the Nazionali originally 7 threshold ofthreshold 1.88 MeV. reac this of Thepeculiarity tive LINAC. tive of neutrons,ties have but they several drawbacks. time (less than 1hr). (less than time proton (about high currents the with 10 target this of 2.5ton MeV beams give proposed, are a which resonance of advantage the MeV,take at 2.25 pro up mb. to 580 Therefore,the yieldneutronis very up rapidly increases to itscross is tion that section tively low energy. neutrons ofto fast produce of quantities rela large the Argentinean Commission of Atomic Energy; of Atomic Energy; Commission Argentinean the of accelerator tandem-electrostatic-quadrupole based on a liquid-lithium target (LiLiT) and the the and (LiLiT) target onbased a liquid-lithium high for protonhigh At energies over just threshold. the exploit (p,n) neutron reactions by using beryllium exploit (p,n) neutron beryllium reactions by using erators have been developed for BNCT the since lithium target. Aproblematic low target. the drawbackis lithium centre is designing a 2.0 MeV a2.0 centre 10 superconduc designing is mA cyclotron of Kyoto (Japan); ii) university 2.5MeV the Lithium Li(p,n) reaction was developed at SARAF (Soreq Li(p,n) reaction developed was at SARAF p = 1.9 MeV neutron the 1.5×10 is yield The A high-power accelerator-based neutron source source neutron accelerator-based high-power A Particle accelerators are designed to mainly acceleratorsParticle to designed are mainly Other running projects are: i) 30MeV the running 1mA Other 7 6 Li(p,n) Li 7.5%)Li point at 180.54 amelting and °C. 7 Be has aQ-value has ofBe -1.64 MeV and 11 mC -1 on a thick natural natural on a thick 10 mC -1 , the the , 14 7 7 s Li Li Li Li -1 . ------Thermal neutrons also cause capture reactions that capture cause also reactions neutrons Thermal Applied Research AcceleratorApplied Research Facility, Israel) a as MeV protons ~2.5×10 is ( (n), neutron the production proceeds of which Natural beryllium is a metal with only one isotope only with ametal is beryllium Natural (Q-value= + 2.125 MeV), which leaves2.125(Q-value=MeV), + which 10 Competing nuclear reactions for NCT. for is the two-body reaction two-body the is isotope dissipates a peak power areal density of 2.5 kW/cm power density apeak dissipates areal proton beam with a radial gaussian distribution distribution gaussian protona radial with beam BNCT. forin device con prototype use LiLiT The produced by the Be target holder and by the beam beam holderproduced by the and target Be by the photon per neutron produced. rays More are gamma mC give data aneutronmental of 3.5 yield ±0.3×10 proton 3 MeV. than energies bigger Recent experi through the formation the compound of the nucleus through of afull-scale feasibility tive demonstrate the values temperature elevation. The yieldneutron for 1.91 (~200 lithium thick) of liquid °C) supported by a the reactionThe more is point. the important reaction copper), in less than gives to target tude rise which decayto the of for becomes which relatively significant tron yield, excited states of through 2.057 is MeV. energy threshold the However, the both three-body reactions three-body (p,p’n)both (p,p’) indirect and reactions are usually pointed out. The main one pointed main The out. reactions usually are resonant neutron float on apeaks continuous neu and good thermal conductivity, it more is thermal good and suitable accelerator-based BNCT neutron source basedon a of volume 0.5 peak density and MW/cm are not useful in the frame of the targeted therapy, targeted of the frame the in notare useful reaction exothermic dueare to the hydrogen in beryllium (about 8ordershydrogen beryllium of magni in energy (1.67energy MeV) of stable any isotope. Therefore, The negativeQ-value exchange. is -1.85 MeVand excited state at 3.56 MeV. due yield, gamma The liquid-lithium jet target, using a10-13 using 2MeV jet target, mA, liquid-lithium swelling with the risk of risk blistering. the with swelling sigma ~10sigma mm. (> of ahigh-velocity sists 4m/s) jet (1.5 vertical mm since they transport the reaction energy far from far reaction the energy transport they since assembly. shifter concave wall. Recent beam tests show that the target show target tests Recent the concave beam that wall. Beryllium 9 B, but it can also proceed through direct charge charge direct proceed through but also itB, can Be). Because of its high melting point(1278Be). melting of itshigh Because °C) The gamma-raysThe producedthe by neutron source A drawback is the very low permeability of low very permeability the A drawbackis With the expression the With -1 for E for 9 Be also has the smallest neutron binding neutron binding smallest the has also Be p =5 MeV. =5 6 Li to the ground state, is about is ground state, to the 0.1Li 10 9 n s 9 Be(p,n) 9 Be, can occur. Hence occur. the can Be, Be(p,n) -1 mC 9 -1 B several nuclear B severalnuclear 9 . These conserva B that proceeds proceeds that B 9 Be(p, 6 3 Li in the the in Li with no no with a ) 6 Li Li 12 2 - - - - -

49 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 50 Nuclear Physics for Medicine – Chapter I – Hadrontherapy The energy shifter, called also beam shaping assem shaping also beam called shifter, energy The All the (p,n) the reactions produce neutrons, which fast All MeV MeV). at threshold 2.36 and 0.73 MeV. Elastic and radiative reactions are the most radiative reactions impor the and are Elastic (TRIPS) injects into the accelerator (RFQ) ahigh- accelerator intothe injects (RFQ) (TRIPS) (Q-value –0.158 MeV at threshold 0.17 and MeV). 10 where, including within healthy cells. Similarly, the the Similarly, cells. healthy within where, including gives to a0.59MeV rise which proton a40keV and Schematic layout of the INFN BNCT irradiation facility for shallow tumours. shallow for facility irradiation BNCT INFN the of layout Schematic 10.3. Figure key reaction neutron nitrogen is capture 31 fast neutronsfast have to lower to in be shifted energies ion ranges in tissue are ≤11 are tissue ion in ranges every but it occurs µm, intensity proton beam, which is accelerated proton is intensity which and beam, bones. of irradiated is interest in must be thermalised in order in to becaptured by the bethermalised must order to ensure that the tissue between the skin and and skin the between order tissue the that to ensure thermal neutron sourcethermal for BNCT. source The then analysed by a 90° magnet. The proton magnet. by beam a90° analysed then neutron fast beam. original the them. able is to completely tumour thermalise the MeV). 0.54 at threshold generate which of g abackground tant, the since interactionpoint, from the far energy the bly (BSA), is a stack of different materials, which which bly (BSA), materials, astackof is different reactions are possible. reaction ray of to 2.2MeVa gamma rise of energy. The other appropriately shape, energetically and geometrically, geometrically, and energetically shape, appropriately hydrogen neutron capture capture neutron hydrogen scattered fast neutrons.scattered Moreover, fast nuclear other carbon ion. This reaction does not actually transport transport does notreaction actually ion. This carbon Neutron beam shaping beam Neutron B atoms and thus be useful to therapy. The original to therapy. The original beuseful B atoms thus and P(n,p) With fast neutrons fast reactions other openWith up. Figure 31 40 Si (Q-value –0.709 MeV at threshold and Ca(n, 10.3 40 Ca(n,p) shows the conceptual design of a design shows conceptual the a ) 37 Ar (Q-value +1.748 MeV), which which +1.748 MeV), (Q-value Ar 40 K (Q-value –0.529 MeV and 16 O(n, 1 H(n, a ) 13 C (Q-value – 2.216 g ) 2 H, which gives which H, 14 14 N(n, N(n,p) -rays and and -rays a ) 14 11 C, C, B - - - 10.5 After having defined the three energetic groupsthe defined for having After weight depend on the neutron source spectrum. A A neutron dependweight on the source spectrum. IAEA figures of merit for shallow and deep tumours. tumours. anddeep of merit forshallow figures IAEA BNCT facility which exploits the Li(p,n) exploits the reaction which BNCT facility Shallow tumours D Φ Φ tumours Deep D Φ Φ D D Since in BNCT only thermal neutrons use are thermal BNCT only in Since ful, undesirable radiation, which releases energy releases energy which radiation, undesirable ful, for shallow and deep tumours. deep tumours. and for shallow in healthy tissues upstream and downstream of downstream and upstream tissues healthy in impinges the beryllium target, which is in the in is which target, beryllium the impinges needs smaller BSA than a facility which exploits which afacility than BSA needs smaller malised, emerges from the BSA to treat superficial to emerges treat superficial BSA from the malised, of thumb” to achieve such a minimisation are the the are to aminimisation achieve such of thumb” the tumour site, has to be minimised. The “rule The “rule site, to has be minimised. tumour the the following fluenceand absorbedrates dose following ratesthe (E thermal neutron Be(p,n)the reaction,higher of because the and size BSA The melanomas. skin as such tumours and fast (E fast and energies latter. of the centre of the BSA. The neutron beam, fully ther fully The neutron beam, centre BSA. of the . . . . n (epi+fast) g g epi epi th th n (fast) /Φ /Φ / Φ 10 ≥ / Φ Therapeutic neutron beams neutron Therapeutic epi epi th tot / Φ th 9 ≤ ≥ 10 ≥ cm

≤ ≥ 0.9 / Φ

n n 2×10 epi epi

≥ 100; Φ 2×10 <0.5eV), epithermal (0.5eV 10keV) recommends neutrons, IAEA -2 ≤ 2×10 th th 9 s cm -1 ≤ 2×10 -3 -3 Gy cm Gy Gy cm Gy -2 s -1 -3 epi Gy cm Gy -3 / Φ Gy cm Gy 2 2 fast fast 2 ≥20 2 n <10keV) <10keV) - - Although a precise AD assessment needsa a precisecomplex AD Although 0.13 dose-rate), RBE-Gy/ is (advantage-depth ADDR value of which is 3.6 in the simulation, and on the on the and simulation, the 3.6 is in ofvalue which the depth in tissue at which the dose to to which at the dose tissue (AD),in the is depth which with 40 ppm of 40 with dose components the also are doses, total the with BNCT facility, well illustrate the AD concept applied AD the illustrate well BNCT facility, Clearly, the AD value depends on the tumour-to- on the depends value Clearly, AD the tumour equals the maximum dose to the healthy tis dose the maximum equals tumour is supposed to be different for the two tissues. If we tissues. two the supposedis for to bedifferent design, the two figures of merit do not allow for of allow meritpropdo not figures two the design, min at 2.6 cm of depth, in healthy brain tissue. The The tissue. brain healthy in cm atof 2.6 depth, min dose due biological-effective to 4 the Only plotted. sue. point of To at view) agiven depth. to treat atumour to the charge particles emerging from the capture capture from the emerging particles charge to the respect ratio with tumour-to-healthy-tissue RBE tissue absorbedtissue doses) 1. less than is (the therapeutic gain the ratio of tumour-to-healthy- depth advantage tool to is the know auseful end, this tumour tissue experiences the same dose-rate same experiences the tissue value tumour dose biological-effective rate, called maximum the 3, together In Figure dose. biological-effective to the reaction, the value of which is 2.8 in the simulation. simulation. the in 2.8 is of value which the reaction, approach (Monte together with simulations Carlo receive would at 9.8 tumours Deeper cm of depth. and healthy-tissue healthy-tissue hypothesise that tumour cells have been charged cells tumour that hypothesise erly assessing the possibility (from dosimetric possibility the the erly assessing lower dose than the healthy tissue maximum dose. dose. maximum tissue healthy the lower dosethan centration 11 of that only shows figure ppm. The In Figure 10 Figure In However, although useful for neutronHowever, source useful although In other words, AD is the depth behind which which behind depth the is otherwords, AD In 7 Li ions, emerging from the 10 from the emerging ions, Li 10 10 .4 B concentration ratio (BR), the the (BR), ratio concentration B B, being the healthy-cells healthy-cells the being B, , Monte Carlo simulations of a, Monte simulations Carlo B capture reactions, reactions, B capture 10 B con B He He - - -

values in different parts of the tumour, making the making tumour, the of parts different in values 2 cm and epithermal neutrons epithermal 2 cm and for deeper depths. However, BR-values, for neutrons small epithermal inserted into the patient A vivo intothe for monitoring. in inserted value. ADDR of apoorthe knowledge implies different neutron sensitivities, for measuring the neutronfor different measuring sensitivities, microdosimetric data, radiobiological data and 10 and data radiobiological data, microdosimetric mini detector made of two mini TEPCs, one with one with TEPCs, detector mini of made two mini gas-proportional tissue-equivalent with monitored 10 the to calculate used is method, neutronthemal fluence, activation by measured with ionisation chambers two uses which method, to use quasi-thermal neutrons for depths less than neutrons quasi-thermal less than to for use depths tres diameter have been constructed, which can be be can which havetres diameter been constructed, D the absorbedD the total dose and value. ADDR the it since determines therapeutic plan, complex. rather plan treatment 10 the that 10 deep as tissue. as soft cm in treat tumours and healthy tissue. If it is not, AD can have can different it not,AD is If tissue. healthy and healthy tissue RBE could be critical for a successful for a successful be critical could RBE tissue healthy BR-valueshigher (about 4), or more can they than For 4-5cm. deeper than treat tumours can hardly concentration assays in the tissues), a thumb rule is is concentration tissues), the rule in assays athumb counters (TEPC). Mini TEPCs of afew millime TEPCs counters Mini (TEPC). the monitoring Therefore, different. is components Dosimetry andDosimetry microdosimetry gests the use of the well-known twin-chamber twin-chamber ofwell-known the use the gests The RBE at different depths in a phantom can be can ina phantom different depths RBE at The protocoldosimetric BNCT The actual [1]sug These considerationsassumption theare on based Moreover, radiation different of the RBE the n /D B concentration is uniform both in tumour tumour in both uniform is concentration B g ratio is poorly related to RBE. That ratio poorly is related to RBE. (labelled (labelled products capture-reaction high-LET the for but tissues two the for same the are which biological weighting factors, appropriate by multiplied been have doses physical The tissues. two the both to line components are common The dose-components. black- different the out point lines Different Pisa). of University 2002, a.a. cycle, XIV thesis, PhD spettro, di traslatori materiali originali esu tensione acceleratore compatto a bassa un su BNCT, basata la per sorgente neutronica da fusione una di Studio (J.Esposito, phantom ahead in depth the against tissue, brain healthy glioblastoma tumour and in rates dose effective simulations of biological- Carlo Monte 10.4. Figure reference 3, page 410). page 3, reference (See 1.35 respectively and 3.8 is which of factor weighting n /D B dose. However,B dose. 10 g ratio. The ther ratio. The B in figure), the the figure), B in B - - - 51 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 52 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 10.6 Therefore, any tumours can potentially respond to potentially can Therefore,tumours any Therefore promicrodosimetry as for a dosimetry, As with conventional with therapy, radiation As BNCT can (PET). Future clinical researchto on bebased has (PET). clinical Future BNCT therapeutic possibilities, clinicians need need clinicians possibilities, therapeutic BNCT BNCT. If in the past many efforts haveBNCT. efforts aimed many past been the in If functional imaging, such as magnetic resonance magnetic as such imaging, functional inter-comparisons and randomised studies. Only Only inter-comparisons studies. randomised and is the characterisation of the histological pattern pattern of histological the characterisation the is imaging (MRI) or positron emission tomography tomography emission positron or (MRI) imaging ness of neutron treatments or indirectly by testing by testing ness of neutron treatments or indirectly neutron sources that are necessary for a neutron BNCT in are necessary sources that have breast as such new tumours become atarget, different radiation components radiation anddifferent relative biologi metric tools is mandatory. is tools metric acceleratorsparticle able are to provide intense the protocols, mentation clinical of more successful tissue. to healthy damage minimising measurements effective. microdosimetric make monitor the RBE for cells with and without 10 without and with for cells monitor RBE the of neoplasms for directly stratifying the effective the stratifying of neoplasms for directly these issues. these vivo concentration in the of boron-transporters by two drugs with good performance are already avail already are good performance with drugs two microdosi theoretical and of experimental use the for sources neutron of completion quick the and tion tumours, therapy,tion treat infiltrating BNCT can tocol for to BNCT beimplemented has order in to tumour specificity could expand potentiBNCT expand could specificity tumour by W. Sauerwein and colleagues [3].by W. colleagues and Sauerwein accelerator-based BNCT. accelerator-based neutron progress. The sources in is Moreover, soon. and beyond conventional radia head-neck and recent in skin years cancers, at brain, damage. cell endothelial and ofage DNA, nuclear dam inducing by achieve its therapeutic effects 10 without other the and applications can be found in the recent the in befound bookapplications edited can More important towards deeper tumours. alities However,able. new 10 inter-comparison. Therefore,clinical significant any scientific community should support the support coordina should community scientific neutron daily-accessible and suitable a sources in clinical environment. The construction of several environment. The construction clinical implethe allow would environment. This clinical mesothelioma, pleural cancer, osteosarcoma, lung, cal effectiveness, which needwhich to be effectiveness, monitoredcal for The More details about BNCT principlesMore BNCT and details In order to exploit the large spectrum of order spectrum In to exploit large the Different accelerator-based neutron sources have sources accelerator-based neutron Different Conclusions 10 B carrier aspect is less important, since less is important, aspect B carrier B carriers with still higher higher still with B carriers B in the cathode wall, can can wall, cathode the B in B [2]. [2]. B ------[3] [1] [2] References Neutron Capture Therapy Capture Y. Neutron Nakagawa. L. Evangelista; S. Altieri; S. Bortolussi; N. N. Bortolussi; S. Altieri; S. Evangelista; L. Protti; I. Postuma. (2013). Postuma. I. Protti; Microdosimetric W.A.G. Sauerwein, A. Witting, R. Moss, Moss, R. Witting, A. Sauerwein, W.A.G. Binns, P.J., al et Binns, and Isotopes and P. V. D. Moro; Colautti; Chiriotti; Conte; S. facility of LENA reactor. of LENA facility Springer-Verlag 2012. Heidelberg, Berlin dosimetry exchange for boron neutron neutron boron for exchange dosimetry measurements. measurements. measurements in the thermal irradiation irradiation the in thermal measurements capture therapy,capture absorbed I: dose part , in press. , in . (2005). An international . (2005). international An Med. Phys Med. Applied Radiation Applied Radiation . 32 : 3729–3736. : . 11. 11. 11.1 1980s recorded 60 to more recently than PSI on the l l l (LET) along their path. If the ballistic properties are ballistic the If path. their along (LET) (p), neutrons (n) become or has ions, heavy one of (IMPT); accurate dose-calculation methods (Monte methods dose-calculation accurate (IMPT); website to dedicated protons We alone. summarise Hadrontherapy, i.e. radiation therapy using protons protons using therapy radiation i.e. Hadrontherapy, QA (gamma-prompts, PET). on-line innova These Carlo) progressively that replace less sophisticated Clinical programmeupdate ing; pencil-beam scanning (continuous or by spots), scanning pencil-beam ing; place of formerin nuclearphysics prototypes; not far different for most particles, i.e. protonsi.e. and for most different particles, not far dose to the tumour volume, along with maximal maximal with volume, along tumour dose to the development of isocentric rotating gantries that that gantries rotating isocentric of development patient set-ups for protons); (mainly guided image of new clinical indications, from a few in the early early the from afew in indications, of new clinical ones vivo (ray-tracing, in beam), with pencil along of “conventional” photon (X-ray) therapy: introduc tures; ii) biological aspects, due to an increased due to an ii) aspects, tures; biological the management of cancer, since it deals with two two management of with the cancer, it since deals approaches attractive most and sophisticated the in tions havetions exploration the considerably stimulated oftion compact commercial dedicated accelerators evolution technological the paralleled has therapy transfer energy linear ahigh related with tissues, below the clinical experience accumulated in proton in accumulated experience below clinical the by heavier represented ions, nowadays almost of the optimisation allows that aspects, ballistic radiotherapy track (IGRT), mobile target including interposed effectiveness radiobiological on (RBE) able to proton generate modulated intensity therapy easier and arrangements, sophisticated beam allow exclusivelyinterest by ions. The carbon for particle i) oncology: of radiation modern aspects essential light ions, the biological advantages are only shared only are advantages biological the ions, light sparing of surrounding normal anatomical struc anatomical normal of surrounding sparing in particle therapy in particle Introduction - - - - • • • 11.2 Protons, whose clinical experience exceeds 100,000 100,000 exceeds experience Protons, whose clinical patients worldwide, have proven two advantages in i) Delivering an escalated dose to a“radio- to dose escalated an i) Delivering resistant” tumour process, situated close to, or to, close situated process, tumour resistant” be found in recent articles and textbooks [1-4]. textbooks and recent in be found articles and carbon ion therapy. Detailed information can ion carbon and therapy.can information Detailed settings: abutting a radiosensitive organ: aradiosensitive abutting 80% overall survival (OS), eye-preservation, survival overall 50% 80% years) protracted make and occur, follow-up can (CS) have explored been extensively the since CS, and ≥ 75 GyEq in CH. Late failures (i.e. >10 failures Late ≥75 CH. and GyEq in CS, GyEq esp. uveal melanomas, malignancies, Ocular Optimal dose has been setto dose has about 70 GyEq in Optimal for p) for Skull base and cervical canal low sarco grade canal cervical and base Skull Spinal, para spinal and sacral sarcomas/CH sacral and are spinal para Spinal, introduction of biological agents in metastatic metastatic in agents of biological introduction necessary. particularly challenging conditionsdue to the challenging particularly of remain presentations. particles But charged mas: chordomasmas: (CH) chondrosarcomas and by most groups: approx. control 95% local (LC), being administered to a maximum of 50–60 of 50–60 to amaximum administered being re-irradiation. represent the main indications in the proton the in represent indications main the and sometimes salvage programmes including p p including programmes salvage sometimes and late 1970s. Recent advances have concerned the literature, with highly hypofractionated doses highly with literature, cord the and/or and proximities, cauda equina permanent LC. achieving in importance crucial genetic profile of these malignancies, and theand these malignancies, genetic profile of Proton therapy indications Proton therapy . Remarkable results have. Remarkable results been reported (i.e. Physical dose x estimated RBE of 1.1 RBE xestimated dose (i.e. Physical - 53 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 54 Nuclear Physics for Medicine – Chapter I – Hadrontherapy • • • 11.3 The clinical experience has involved has experience approxi clinical The Biologically, maximal increased RBE is observed in observed is in increasedRBE maximal Biologically, mately 15,000 patients worldwide, mostly in Japan. Japan. mately 15,000 in patients worldwide, mostly ii) Improved sparing of normal tissue from from tissue of normal ii) Improved sparing radiation effects: effects: radiation indications ENT sites, or rectum/bowel in pelvic sites, in sites, in pelvic in sites, or rectum/bowel ENT In adults, protons adults, haveIn proven for beneficial impor particularly is advantage this children, In It is interesting to mention long not It that interesting only is Head neck have and long been carcinomas also facilities became available. Nowadays available. indi became these facilities of efficientfollowed introduction the polychem mate surgical frequent interposition of metallic in the mind of many investigators. Actually RT of investigators. Actually many mind the in improved studies. despite dose-escalation niques (see introduction). development has of Monte calculations Carlo The dose-distribution. in duces uncertainties marrow that make them attractive in chemo- in attractive them make marrow that malignancies has also been recently addressed. also has malignancies that tumours pediatric of improvement matic management much safer. their made Remarkable multiple anatomical organs, such as parotids in in parotids as such organs, multiple anatomical protons, to reduce expect one long can term otherapy programmes made RT almost obsoleteotherapy RTmade programmes almost not has been definitely gliomas of malignant terms ofterms improved But physical dose-sparing. term side-effects can be spared using particles, particles, using be spared can term side-effects development. mid-1980s,under the In dra the of organs exquisite due to sensitivity the tant, bone-air cavities, in sino-nasal sites. This intro sites. This sino-nasal in cavities, bone-air be achieved using modern dose-delivery tech dose-delivery modern be achieved using on mucosa bone acute toxicity and but also potential The youngsters. in maturation brain results haveresults adenoid been achieved esp. in cystic These lead to a severe path. beams’ the in rial radiations combinations. It is also important to important combinations. Itradiations also is risk-reduction of radiation-induced secondary along with sparing of critical structures, can only only can structures, of critical sparing with along when proton popularity in evenand gained has remained crucial in most clinical situations, situations, most clinical in crucial remained has interposition of due to the challenging highly stress that optimal “conformality” to the target, target, to the “conformality” optimal that stress selection of patients. Further improvements ofFurther selection patients. sequelae, esp. those affecting bone growth and bone growth sequelae, esp. affecting those carcinomas, approaching 80%. But the outcome But the approaching 80%. carcinomas, C-ions beachieved (see using could below). clinical benefits still remain partially unknown. unknown. partially remain still benefits clinical becations considered should a priority. Using Development ions of carbon ------11.4 The The Japanese haveC-ion derivedtheir experience There are also C-ion also Thereareunder development projects in Austria (Wiener-Neustadt),Austria France and (Lyon and variations are observed according to tissue-type, to tissue-type, observed are according variations 20–25000 new cases per year in countries such as as such countries per in newyear cases 20–25000 Recent evaluation by the French byRecent the evaluation group ETOILE Heidelberg, 2009), and Italy (Pavia,Heidelberg, 2009),2012), Italy and been has LET particle, which was applied was to slow-growing, which particle, LET France, Italy or Germany.France,exceed Italy These values by first randomised trials are also being conducted. being also are trials randomised first Caen). from formerly tested neutrons (n), high- aneutral far the current capacities current of the hadron-therapyfar pro intrinsically radio-resistant, hypoxic, and/or hypoxic, radio-resistant, intrinsically in Lyonin protons that assessed C-ions and be could X-ray with perspectivein particles therapy. The in skull base CH, a benefit confirmed ina recent abenefit confirmed CH, base skull in not in the plateau the not located where in upstream, normal non- operable malignancies, administered with with administered non- operable malignancies, due to the excessivedue to the reported on toxicity healthy dose (compared X-rays), with help put might that patients respectively. representwould This about but nor cutaneous, not ocular (generally melanomas of particles), that make further intensive physical of particles), further make that of origin). Prostate mucosal have carcinomas also multivariate analysis; 50% OS, in selected cases selected cases in OS, 50% analysis; multivariate 70–85% been reported has LC outcome further: tissues, related with poor dose-distribution. On poor dose-distribution. related with tissues, of pancreatic carcinomas, known for their usual usual for their known of pancreatic carcinomas, unusually high doses per fractions. These included These per doses fractions. high unusually dosetion of (not the types to mention alternating highly them makes This interposed. are tissues and located, is where tumour peak, the distal the tiated more recently in Germany (Darmstadt, 1997,tiated more (Darmstadt, Germany recently in beneficial in approximatelyand 12% beneficial 5% of cancer onbased more “conventional” of fractionation the ini experience, European The explored. been largely biological and clinical endpoints, and fractiona and endpoints, clinical and biological radio-resistant). Unfortunately, neutron clinical clinical neutron Unfortunately, radio-resistant). another hand, the C-ion the dose-profile hand, another somewhat attractive in the most challenging tumours. But tumours. most challenging the in attractive and sarcoma/glioma histological subtypes (= subtypes sarcoma/gliomaand histological and biological research necessary. biological programmes and experiments were discontinued in the mid-1990s, the were in experiments discontinued lar indications, with the hope of improving their hope the of their improving with indications, lar substantially reduced over few years, past the substantially lethal outcome; 80% in unresectable spinal/para outcome; unresectable in lethal 80% similar to protons has stimulated interest to protons for simi stimulated has similar (slow prostatic and primaries salivary, growing), spinal sarcomas; 80% in some in series of sarcomas; aggressive 80% spinal grammes. For protons, facility costs have costs For protons,beengrammes. facility Perspectives - - - - X-ray evaluations, highly suitable in the context of the in suitable X-ray highly evaluations, C-ions, it will remain for a long time beyond for along the time remain C-ions, it will dramatic technological progress, for both. As for As progress, for both. technological dramatic [1] mote advanced research programmes. relatively them “accessible” to major can making [3] [2] [5] [4] the exceptionthe of centres few dedicated able to pro References scope of most oncological groups, with hopefully scope hopefully of most groups, oncological with cer centres. This might favour might comparative cer p vs centres. This 10: Verlag, 2012. Heidelberg, Proton and Charged Particle Radiotherapy Charged Particle and Proton Carbon IonTherapy Carbon Jönsson, B. Glimelius. (2005). Proton Glimelius. Jönsson, therapy B. Francis, 2012. Francis, Lippincott Pub, Philadelphia, 2008. J. Lundkvist, M. Ekman, S.R. Ericsson, B. B. Ericsson, S.R. Ekman, M. Lundkvist, J. U. Linz (Editor),U. Therapy Linz IonBeam J.S. Loeffler, M. Durante.(2013). M. Loeffler, J.S. Charged Proton and and T. Proton Ma, Charlie Lomax, C.M. T.F. Kooy (Editors), H.M. DeLaney, particle therapy – optimization, challenges challenges therapy –optimization, particle of cancer: potential clinical advantages and and advantages clinical of potential cancer: Nat. Rev. Clin. Oncol Clin. Rev. Nat. directions. future and cost-effectiveness. 411–424. Acta Oncol Acta . CRC Taylor Press, & . 44 : 850–61. 850–61. : . Springer . . - - 55 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 56 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 12. 12. • X-ray therapy a consequence is of basic nuclear phys for numberof the country leading the USA, Asia. l l l However, the current phase I/II clinical results results However, clinical I/II phase current the Despite heated the debate cost/benefit on the ratio, Outlook for hadrontherapy positive if increase may largely for hadrontherapy by presently are affected those including hypoxia. Patients with the highest priority priority highest the Patients with hypoxia. including medicine evidence-based of advocates Strict ics. for research facility of aclinical construction the ing not necessarily lead to improved clinical outcome. lead to improved not necessarily clinical particle treatments based on the tumour genetic treatments tumour on based the particle patients eligi most and of pediatric the melanomas, protonsdistribu ions.superior The heavy and dose proton therapy centres, now is contemplat seriously or resistant to conventional treatments (renal cell toma), and by including benign diseases, where diseases, benign toma), by including and to further breakthroughs in the future. future. the in breakthroughs to further lead can and past, therapy the been enormous has in mucosal uveal and bone large and sarcomas, tissue due to to resistant histology, radiation tumours general in and or recurrent tumours, unresectable organs, of critical proximity in localised tumours hadrontherapy in tion compared to conventional background. ble for radiotherapy. The of eligible patientsnumber research could expand the indications for charged indications the research expand could hadrontherapy is rapidly expanding in Europe and and Europe in hadrontherapy rapidly expanding is local control Moreover, sufficient. local is radiobiology support the rationale of the therapy, rationaleof forsupport the the especially contend improved an that does dose distribution - glioblas liver cancers, and pancreas carcinoma, prostate, breast) incidence (lung, high cancers with in evidence emerges from trials current clinical chordomas/chondrosarcomas soft base, of skull the genetic background and/orgenetic background microenvironment, local The contribution of physicsnuclear to hadron Accelerator physics treatment the made possible. - - - - - • • • • Medical physics is tackling the problem the of range physics tackling is Medical Real-time measurement 3D of dose distribu the Real-time Next steps hereNext development the are of smaller Nuclear physicists developing are novel detectors Beyond protons ions carbon there and room is and transport of beam Biophysical modelling for of developments ions other use such the in for ab and of treatment plans, for benchmarking radiography.and particle for verification range determine the Bragg-peak position as well as the the as well position Bragg-peak as the determine ment duration. duration. ment play between beam and target movements. target and play beam A between possible solutions problem to the inter of the planning. Monte Carlo methods are largely used used Monte arelargely methods Carlo planning. water- and motion tumour incorporating phases, promising alternative where is 4D-optimisation, of charged and neutral radiation can be able to can radiation neutral of and charged or moving targets, such as non-small-cell lung lung non-small-cell as such targets, or moving treatment of tumours close to critical organs organs close to critical treatment of tumours the concerns in one main of the uncertainty, ularity tracking calorimeters for detection the calorimeters tracking ularity and beams scanning for fast important is tion 4D-CT computed are treatment plans on all but much oxygen reduced scattering), lateral rescanning methods. For high-gran example, methods. rescanning already a major part of the treatment plan with treatment ofwith the amajor plan part already and cheaper accelerators and beam delivery cheaper delivery acceleratorsand beam and as He (similar biological effectiveness as effectivenessprotons, biological Heas (similar protontherapy. in issue an initio effects is essential for isessential next-generation effects treatment directly. changes length path particle equivalent ling of relative effectiveness is biological ling (RBE) dose distribution. 2D lateral systems (gantries), also able (gantries), treat to shortenthe systems also cancer. Gating, rescanning, and tracking are tracking and rescanning, cancer. Gating, carbon ions, and is increasingly also becoming becoming also increasingly is and ions, carbon modeling of radiation action. The The model action. of radiation modeling - - - - - Therapy (ENLIGHT), which for Therapywhich over (ENLIGHT), 10 has years ULICE, ENVISION and ENTERVISION, with with ENTERVISION, and ENVISION ULICE, 2020. is hadrontherapy in R&D of 80% than More years will be to develop links with these companies: these with be to develop links years will One of the important challenges of the coming coming of the challenges One important of the know-how and expertise, etc. Many fields explored fields Many etc. know-how expertise, and fully led several EU FP7 grants such as PARTNER, PARTNER, as such grants led several EU FP7 fully conventionalfeedback in X-rays radiotherapy using therapy have researchfor can particle significant ideal platform to continue this research in Horizon research platform in toideal continue this involved hadrontherapy represented in well is in different disciplines (physics, biology, engineering, engineering, biology, (physics, disciplines different development therapy Europecan and of particle medicine) therapy (see interested particle in http:// ments. or electrons, which still covers over still or which 95% electrons, of treat the total funding of over be can funding total 24 M€. ENLIGHT the the European Network for European LIGhtthe Ion Hadron today achieved by commercial companies. companies. commercial by achieved today represented network for in essential scientists an and so forth. The European scientific community scientific community European The so forth. and accelerators, in detectors, extensive expertise and enlight.web.cern.ch lead this field with existing and future facilities, facilities, future and existing with field lead this collaborations, evaluation programmes, share of of share programmes, evaluation collaborations, (possibly useful against very resistant, hypoxic resistant, very against (possibly useful Nuclear physics will play amajor roleNuclear physicsthe in will for boron neutron capture therapy). capture neutron boron for tumours) and neutrons (produced at accelerators accelerators at (produced neutrons and tumours) for details). ENLIGHT success- for ENLIGHT details). -

57 Nuclear Physics for Medicine – Chapter I – Hadrontherapy 58 Nuclear Physics for Medicine – Chapter I – Hadrontherapy • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • List ofList Contributors Jean-Louis Habrand,France–medicalconsultant Jan Dobeš,CzechRepublic–NuPECCliaison Jürgen Debus,Germany–medicalconsultant Jacques Balosso,France–medicalconsultant Thomas Haberer, Germany Annalisa Patriarca, France Alejandro Mazal,France Adam Maj,Poland–NuPECCliaison Claas Wessels, France Christian Graeff, Germany Giacomo Cuttone,Italy Guido Baroni, Italy Samuel Meyroneinc, France Sydney Galès,France–convener Stephanie Combs,Germany–medicalconsultant Sytze Brandenburg,Netherlands Igor Pshenichnov, RussianFederation Igor Mishustin,RussianFederation Dieter Röhrich,Norway Frauke Roellinghoff, Belgium Pawel Olko,Poland Hamid Mammar, France–medicalconsultant Dietmar Georg,Austria Enrico Fagotti,Italy Laura Evangelista,Italy Marco Durante,Germany–convener Ludovic Demarzi,France Paolo Colautti,Italy Lucas NorbertoBurigo,Brazil Marcus Bleicher, Germany (Chapter I) 2. 2. 5. 5. 4. 3. 1. Chapter II Chapter Conveners: José Manuel Udias Conveners: Medical Imaging Introduction Interfaces Outlook challenges New imaging molecular to nuclear From 2.1 3.2 3.1 4.1 3.3

Nuclear imaging techniques design Detector Quality controlin hadrontherapy Quality CT spectral towards counting: Photon Simulation and reconstruction

(Madrid) –David (Madrid) Brasse

84 63 79 70 74 2.2 4.2 3.4 (Strasbourg) imaging Preclinical spectrometry Mass Nuclear medical imaging using using imaging medical Nuclear β + γ coincidences: γ -PET 82 63 87 84 63 92 70 61 59 Nuclear Physics for Medicine

“A century ago, the living body, most of the like “A living the ago, century Roentgen captured an X-ray captured an Roentgen wife’s of his image From the words of Bettyann, Holtzmann and Kelves and Holtzmann From words the of Bettyann, finger – her wedding ring ‘floating’ around a white a around ‘floating’ ring – her wedding finger l l l Introduction 1. from nuclear medicine where single photon wherefrom- nuclear medicine single emis in living organisms. Molecular imaging originates originates imaging Molecular organisms. living in impressiveis years fifteen achievements last of the material world, was opaque. Then Wilhelm opaque. world, was Wilhelm material Then poses began with Georges de Hevesy in the 1930s. Georges the Hevesy de in with began poses probably imaging. emergence the of molecular observe complex processes biological early at the level processes biological subcellular at the quantify mathematicians and chemists physicians, ogists, through to the present to the progress day, has through amazing tomography (PET) imaging techniques are used to used tomography are techniques (PET) imaging bring their expertise to observe, characterise and and characterise to observe, expertise their bring One most of the imaging. medical been in made for of ever”. changed vision range bone our –and stage of a disease or for therapeutic follow-ups. of adisease stage emission positron and (SPECT) tomography sion The use of radioactive tracers use pur of The radioactive for medical Multidisciplinary by definition, physicists, biol physicists, definition, by Multidisciplinary - - The detectors used in SPECTin nowadaysdetectorsusedThe look quite theBerkeleycyclo at discovery of technetium The SPECT rapidly became the most frequently SPECT the rapidly used became SPECT, which essentially depends on the collima on the depends SPECT, essentially which for PET imaging as an invaluable tool in the clinical clinical the invaluable tool in an as for PET imaging detectors does not impact overall image quality in in quality detectors image not does overall impact machines in 1968 pushed the discipline forward. forward. 1968 in discipline pushed the machines modern clinical practice, PET remained, until very very until PET practice, remained, clinical modern well are of photomultiplierpled tubes, to amatrix overlapped with the other imaging techniques occa techniques overlapped imaging other the with tron and the announcement of the first SPECT first of announcement the the tron and tion stage. stage. tion performance of most intrinsic The technetium-99m. cou crystals, inorganic iodide Sodium technique. routine is due to the combinationroutine due to is the of several factors, recently, shadow. the in story success current The adapted to image the 140 keV the adapted to image photons generated by emission-scanning technology all over world. the all technology emission-scanning similar to the ones used at the beginning of this of this onesbeginning at to the used similar such as CT and MR moved under the spotlight of moved MR spotlight and the CT under as such modalities imaging anatomical sionally, but while PET began at the same period as SPECT and has has SPECT and as period same at the PET began growth over the last ten years. ten last the over growth aconstant sustained has scanners PET of number the that and choice preferred the now PET/CT is how seen be can It cameras. PET of number Figure 1. Evolution in the the in Evolution - - - - 61 Nuclear Physics for Medicine – Chapter II – Medical Imaging 62 Nuclear Physics for Medicine – Chapter II – Medical Imaging “technetium”-like isotope for PET mandatory. was With a half life of almost two hours and ideal physi ideal and hours two of almost life ahalf With Johannes Czernin from UCLA, at the 2003 annual annual 2003 at the from UCLA, Czernin Johannes with other chapters of this booklet. chapters other ofwith this and developments clinical in software ware and DGN meeting, commented “PET/CT that DGN meeting, atech is field of nuclear imaging. It focuses on devel new It focuses imaging. field of nuclear for success of the PET.CT with The combination future prospects of medical imaging, mostly in the the in mostly imaging, prospects of medical future ing a new era, where technical improvements will improvements where anew era, technical ing will factor a determining also was modalities imaging played fact role.in The arather minor need for a nical evolution revolution”. led has nical to that a medical not but compete rather complements with other preclinical studies as well as interface applications interface as well as studies preclinical physics Differentcover sections community. hard revolution”, evolution on based medical atechnical ple for SPECT, already imagers cardiac dedicated exam an role. As important increasingly play an promoted oncology. tool in dominant PET the as opments innovations brought nuclear by and the of-flight PET and the combination with MRI will will MRI theof-flightwith andcombination PET patient at compounds the radiolabelled of providing improvementof which has detector performance in take full advantage of solid-state detectors. Time- full take isotopethe of choice. However, it requires awell- bed. Finding the clinical niche in which PET does which in niche clinical the Finding bed. as described by Thomas Beyer. by described Thomas as established network of cyclotron facilities capable network ofestablished cyclotron facilities continue to challenge researchers:continue “PET/MRI to challenge a is properties for PETcal imaging, This chapter highlights state-of-the-art and chapter highlights This SPECT and PET imaging techniques are enter are techniques PETSPECT and imaging 18 F rapidly became F rapidly became ------A typical state-of-the-art commercial clinical PET state-of-the-art commercial clinical A typical Tracers emitting gamma rays by the Tracers areimaged gamma emitting Molecular imaging using radioactive tracers makes tracers radioactive makes using imaging Molecular l l l PET about procedures, takes 15 minutes. Sophisticated algorithms distil 3D images out of 3D the images distil algorithms Sophisticated 2.1 images taken at different angles around the aroundobject. angles at different taken images isotope aradioactive decays that emission bying the 2. 2. needed for quantitative imaging. Scanners come with come with Scanners needed for quantitative imaging. patient size, the axial length of 20–25 cm amatter is length axial the patient size, aprecision accurately, very measured with of about photons radi by the emitted positron annihilation tomography). computed emission photon of limiting the costs. Nowadays, all PET scanners are are PET scanners Nowadays, costs. all the of limiting a patient’sotracers in are body. times detection The 2-dimensional by combining object obtained is of an of apositron by apositron-emission imaged are tomograph. In tomography, a 3-dimensional image image tomography, 3-dimensional a In tomograph. of “camera”. types Tracers distinct ofuse two contain typically of the order of a million events per second. order of the of amillion typically From to molecular nuclear resolution Awhole body of obtained. are about 4mm a collection of sophisticated data and image analy image and of data sophisticated a collection of attenuation the correction determination accurate 2.1.1 huge data set thus recorded. Images with a spatial aspatial with recorded. thus set Images huge data of rates Data asecond. large: are abillionth half sis options for specific scan procedures and clinical and clinical procedures optionssis scan for specific the with scan the detect individually that crystals scintillation of small a few tens of thousands contains scanner when positioned on arotating and, images sional 2-dimen to It take used is camera. gamma so-called combined with a CT scanner for a quick, easy and and easy for aquick, scanner aCT combined with gantry, allows tomographic imaging (SPECT: tomographic imaging allows gantry, single imaging The scanner bore scanner The of about by determined 70 is cm Nuclear imaging techniques Positron emission tomography emission Positron 18 FDG tracer,FDG one most of common the - - - - The physical characteristics of SPECT scanners have SPECTof scanners The characteristics physical In recent years, commercial systems for clinical recent for clinical In commercial systems years, First systems allowed the integrated but sequential integrated but the sequential allowed systems First During the last decade there has been a growing theredecade been a growing has last the During PET and MRI without quality loss in either imaging either imaging loss in quality without PET MRI and full-body scans. These systems allow simultaneous simultaneous allow systems These scans. full-body 2.2 ical workflow are well-developed important workflowfeatures. areimportant ical well-developed clin the in integration and of use Ease investigations. ing”. The necessity of understanding biochemical biochemical understanding ing”. The ofnecessity colli by the resolution determined image largely are not changed much not over The changed few decades. past the processes at the molecular level have processes molecular at the stimulated Collimators detector. the of front in positioned mator modality. and most forpossible, recently first for headscans integrated systems havetruly fields, made magnetic optimised quite a while ago. Nevertheless, SPECT SPECT Nevertheless, ago. awhile quite optimised remains NaI, material, scintillation used originally onance imaging) scanner have scanner become available. onance imaging) use combining a PET and an MRI (magnetic res- MRI aPET an and combining use research interest in the field of “molecular imag field researchof the interest“molecular in are rather simple mechanical devices that were that devices ratherare simple mechanical and because sensitivity adequate mainly for task, the 2.1.2 2.1.3 example ease of use, stability and reliability. and stability ofexample ease use, scanner developersscanner have rapid of the use made pro silicon-based photosensors, insensitive are to silicon-based which combination of PET and MRI. The development The combination of of PET MRI. and gress in electronics and computation, and electronics improving for gress in imaging Preclinical imaging Preclinical Single photon computed tomography computed photon Single PET combined with magnetic resonance resonance magnetic with combined PET - - - - 63 Nuclear Physics for Medicine – Chapter II – Medical Imaging 64 Nuclear Physics for Medicine – Chapter II – Medical Imaging very weak. In fact, the injected activity in a mouse amouse in injectedactivity the fact, In weak. very Major efforts are devoted towards obtaining higher higher aredevoted Major efforts towards obtaining (FWHM). A resolution better than 1 mm (FWHM) (FWHM) 1mm Aresolution than better (FWHM). whereas a state of the art clinical scanner has aspa has scanner clinical whereas astate art of the mouse, of the forbrain the be necessary would Functional molecular imaging investigations are investigations imaging molecular Functional field of research is often called “preclinical imaging”. imaging”. “preclinical called field of is often research for brain receptor investigation is typically not receptorfor brain typically is investigation imaging of the rat brain requires a spatial resolu ofrequires rat a spatial the brain imaging is are where These fields the technology illustrated. Finally, animals. applied as to small imaging), down to the cellular level, so as to obtain results results tolevel, obtain so as cellular todown the performed on small animals, such as mice and rats, rats, and mice as such animals, performed on small merging the allow that techniques multimodality namely, techniques, positron imaging molecular of molecular information with anatomical details, details, anatomical with information of molecular on patients [Massoud Ghambir, and 2009]. The study beforedirect models human on simplified tion of less than 2 mm full width at half maximum maximum at half width full 2mm oftion less than dimen the because scanners, for clinical those than tomography (magnetic resonance (CT) MRI and tial resolution not better than 4 mm (FWHM). (FWHM). 4mm resolution not than tial better both in hardware and software, especially for in-vivo for especially hardware software, and in both requirements resolution on spatial are much higher evolving. rapidly and easier to handle instrumentation. instrumentation. easier to handle and instrumentation, technological in advance great a 2.2.1 emission tomography (PET), single photon emission photon emission (PET), single tomography emission smaller than those of human beings. For example, beings. of those human than smaller sions of even rats and more much clearly are of mice PET/CT; as such SPECT/CT be PET/MR, and will state-of-the-art for most technologies diffuse the resolution cheaper spatial and sensitivity, higher This mice. rats and e.g. animals, on small studies computed tomography (SPECT), X-ray computed greater than 5–10greater there arelimita than Further MBq. imaging This chapter givesThis overview ashort of the In addition, the available radioactive signal is is available signal radioactive the addition, In Present technology for small animal PET PET animal small for technology Present - - - - MA-PMTs have undergone of aseries improvements (see ( (see which have been partly triggered by needs of the triggered havewhich been partly with characteristic times of the same order same of the of times the characteristic with wire anode structure), to structure), second anode generationwire (square- fine anode granularity. And finally, with the third the with finally, And granularity. anode fine fast throughput is desired. is throughput fast in the active area dimensions (up active areadimensions the in to 5cm inside) nates photon of the via interactionobtained are designs make use of rotating planar detector pairs detector pairs planar of rotating use make designs matrices of scintillators. In this case, the coordi the case, this In ofmatrices scintillators. ments is usually based on a miniaturised structure structure on based aminiaturised ments usually is matrix of 16×16matrix elements pitch. on a3mm anode an with structure dynode metal-channel on the high-granularity position-sensitive PMT. position-sensitive high-granularity the on most In scanners. of choice for most preclinical detector elements small with scanner of aclinical the centroid of the light produced by the crystal produced centroidthe crystal by light of the the by calculating i.e. technique, “light-sharing” the ter sampling and image uniformity, but it severe has uniformity, image and ter sampling volume of injectedsolution maximum ontions the to about 90%). These 5 cm tubes are based on theareto about on 90%). based tubes 5 These cm led to the this community: imaging molecular the requirements on PET scanners for small animals animals requirements onfor PET small scanners processes studied are required dynamic when fast round shape, (up to 10 acrossed cm and diameter, and it produced field. and has copious this research in and especially in the active-to-total the area ratio in (up especially and high-sensitivity instrumentation is especially especially is instrumentation high-sensitivity ers tubes (MA-PMT)ers tubes have photodetector been the evolution MA-PMTs from early on based atypical limitations in terms of dynamic imaging and if very very if and imaging of terms dynamic in limitations solutions MA-PMTs the coupled are to pixilated surrounding the animal in a small bore ring. Other Other bore ring. asmall in animal the surrounding above of the put has stringent All time. scanning shaped metal-channel dynode structure) with a very avery with structure) dynode shaped metal-channel generation been there agreat has improvement ~ 10% blood volume). of total the a consequence As The design of most small-animal PET instru PET of most design small-animal The High-resolution multi-anode photomultipli multi-anode High-resolution Figure 2 Figure Figure 3 Figure ). The latter configuration offers abet configuration ).latter The ) over the last twenty years, many of many years, ) over twenty last the opposite one. in time coincidence with the four heads, where each one is with configuration detectors arotating of Example Right: rings surrounding the animal. in arranged are detectors the where geometry, ring Left: scanner. PET animal construction of a small- the for configurations Two 2. different Figure - - - - These photodetectors will definitely not only only be not definitely These photodetectorswill X- Y-coordinate and to strongly so adopted, as is (APDs) are used for the parallel readout pix of(APDs) the forparallel used are the where matrices of small-area avalanche photodiodes photodiodes avalanche where of matrices small-area read-out. anode To be independentwould single In this case a matrix (either amatrix case assembled or mono this In However, these two figures are often mutually mutually often are However, figures two these ilated matrices of matrices ascintillator. ilated detector so close to the target, there is a significant there asignificant is detector target, so close to the developed DOI information. to obtain prototypes are produced are prototypes or proposed by research forreadoutmethod the of of matrices scintillators. physics. energy However, high product in order in opposed, i.e. increasing one could cause the reduc the one cause could increasing i.e. opposed, scintillator, deposited a monolithic in light of the the simpler often of formethod both resistivechain used for clinical scanners, but they will replace will but they scanners, forused clinical the scintillator pixel (no-coding error). (no-coding pixel Typical scintillator the readout, of complexity the cost and the to limit have ASICs dedicated end, been implementedthis tion of the other. Every year, new small-animal PET other. oftion the Every year, new small-animal of PET imaging. challenge the is sensitivity tion and photon of the absorber beat thickness should the so of spot, the dimension the spot also and light the block detector. These photodetectors so-called the being characterised and studied by groups. many studied and characterised being by measuring, with high precision, centroid the high of with by measuring, resolution, and thus many techniques have techniques many resolution, been thus and reduce of number output the channels. as to infer depth of interaction(DOI) depth to infer as information. coupled is one matrix to one to scintillator the as Hamamatsu H8500 the with used currently are and heads should bepositioned should heads and object, close to the have become more alternative and an attractive examples of this solution are PET inserts to MR, to MR, solution PET are inserts examples of this least one attenuation length at 511 oneleast attenuation length keV. the With lithic) of photoconductors granularity same the with contribution of the parallax error to the spatial error spatial to the contribution parallax of the centre the to be used reconstruct of mass also could The simultaneous improvement resolu spatial of simultaneous The MA-PMTs The best readout for method modern To maximise the efficiency of PET systems, PET PET ofsystems, efficiency To the PET maximise More recently, semiconductor photodetectors So-called silicon photomultipliers (SiPM) are photomultipliers silicon So-called - - - - Anger camera, a very high resolution to down afrac high avery camera, Anger By using large detectors such as aconventional detectors as large such By using SPECT configuration, e.g. thallium-doped sodium sodium thallium-doped e.g. SPECT configuration, of are two imaging animal for small SPECT systems Steve Meikle for the detection of medium energy γ rays, are only γrays, only are energy offor detection medium the for a good detector reso for SPECT, spatial high i.e. iodide (NaI:Tl) Anger camera, equipped with aspe (NaI:Tl) equippediodide camera, with Anger - sys resolution spatial the increases of imaging the new horizon in dedicated instruments for high- instruments dedicated new horizon in detectors with direct γ-ray direct conversiondetectors with CdTe as such mance. At the same time, some fully engineered some fully time, same the At mance. main types: the first one makes use of the clinical the clinical use oneof first makes the types: main mation, originally derived from the coded aperture derived coded aperture from the originally mation, solution pin the is appliedmost collimator widely here the used, are lead or as tungsten such medium overlapping projections of iterative use by the esti tors, following PET scanner technology. PET scanner following tors, tive technology as compact high-resolution gamma compact as high-resolutiontive gamma technology However, obtained. is oftion amm sensitivity the the object of theontodetector. tem by magnification of arrays where regular clinics, to the contrary type: ration. To overcome this problem, multi-pinhole multi-pinhole To problem, ration. overcome this ahigh-density holes or hexagonal square, in round, resolution nuclear imaging and such solid-state such and resolution imaging nuclear and CdZnTeand have been proposed. The requirements 2001.approach in Barrett proposed by Harry group The number ofincreases. the pinholes as of 2.2.2 SPECT systems SPECT hole (or one collimator, multi-pinhole). this With lution, high energy resolution, and good efficiency resolution, efficiency good and energy lution, high systems based on compact, high resolution detec on based compact, high systems releasedcommercial are products. as scanners solid-state detectors provide alterna apromising solutions implemented, are magnifi but large the cial collimator; the second the one of consists dedicated collimator; cial cameras. Semiconductor detector technology is the the is Semiconductor detector technology cameras. cation produces projections large may that overlap low be very configu because could of pinhole the groups offering or promising even perforgroupsor better promising offering As for the second type of small animal SPECT, animal of small for second the As type In both cases, the main feature is the collimator collimator the is feature main the cases, both In Present technology for small-animal small-animal for technology Present in 2002 has solved has problem the 2002 in of www.hamamatsu.com. site: web Hamamatsu the from Images MA-PMTs. structure) multi-anode with H8500 Hamamatsu (right, generation third and structure), crossed-plate anode with R8520 Hamamatsu (centre, generation second structure), anode wire crossed- with R2486 Hamamatsu (left, generation Figure 3. Example of first first of Example ------65 Nuclear Physics for Medicine – Chapter II – Medical Imaging 66 Nuclear Physics for Medicine – Chapter II – Medical Imaging very high resolution, to down tensof and microns, high very within in the range of the necessary high spatial spatial high necessary of the range the in within which provideswhich X-ray a3D map local of the attenu widely used techniques of noninvasive diagnosis, of noninvasive techniques used diagnosis, widely Computed tomography (CT) one is most of the ise the entire animal in one shot. in animal entire the ise improvement the is imaging of sensitivity, always next generation of PET systems for small-animal generationnext of PET for small-animal systems mal can be performed in less than one minute. This This one minute. less than beperformed in can mal resolution spatial closeto itsintrinsic the pushing of a140.5path keV CdTe in about is mm. 2.4 conversion detec state photodetector. solid direct A by solutions scintilla on based fulfilled partially mm. In this case, the main challenge is to is increase challenge main the case, this In mm. obtain ultrahigh-resolution systems able systems to visual ultrahigh-resolution obtain the sensitivity and especially the field of view field to the of especially and sensitivity the and efficiency tor quantum offershigher a much the and low resolutionthe energy of scintillators tors/photomultipliers PET, in due to as especially resolution, whereas its intrinsic efficiency does resolution, efficiency not whereas its intrinsic relatively low (25–35%) the efficiency of quantum almost reached of of a fractions its resolutionalmost limit 2.2.3 ation properties of the scanned patient. Dedicated patient. Dedicated ation properties scanned of the a large field of view so that a scan of the entire ani the entire of thatscan a view so field of a large energy resolution and its granularity is now is well resolutionenergy its granularity and limit. On the other side, small-animal SPECT has SPECT has side, small-animal other On the limit. last decades, with the main goal of obtaining a of obtaining goal main the with decades, last scanners for small animals have been built in the the have in been built animals for small scanners create asevere free mean the DOI contribution, e.g. The major concernthedevelopment for the of Small animal CT imaging CT animal Small - - - - - with a typical pixel size of com micron, used size 50 is pixel atypical with with PET images for providing anatomical informa anatomical for PET providing images with Feldkamp algorithm, but iterative are methods algorithm, Feldkamp field. CT scans have mainly been used in connection in connection used been havescans CT mainly field. for calculating the PET the However, attenuation. for they calculating Figure 4 presentedis Figure in CTs Spiral are a cone-geometry configuration. in X-ray small by avery using obtained is with tubes noise reduction. Hence dose limitation and increase increase and noise reduction. Hence dose limitation phy studies, are the main topics of research in this topics of this main research are the in phy studies, X-raymedium (30-50 energy kVp). detec A large obtaining the requested resolution, i.e. the quantum requested the quantum resolution, the i.e. obtaining the construction and the use of the CT. of the use can the and This construction the control detectors kept are the strict during under in misalignments that is performance design the panel CMOSflator a CCDs tor, magnified as such spot ( focal anode tungsten tion to be combined with functional imaging and and imaging functional totion be combined with being increasingly applied. The main issue with with issue Themain applied. increasingly being be done with various techniques, with and without without and with techniques, various be done with The entire geometric magnification. high bined with an animal CT is the high dose that is needed is dose that for high the is CT animal an ard way of reconstructing the image employs image the the ard way of reconstructing implemented. for issue obtaining One critical also have also gained importance as a means of investi ameans as importance have gained also shoot mode and in continuous mode. The stand The continuous mode. in shoot and mode speed of the examination, for instance for angiogra for instance speed examination, of the of amouse image CT Atypical phantoms. special CT clinical in as rotates animal system the around gation gation CT for small animals can operate step and can in animals forCT small in the field of molecular imaging. field of the molecular in se per . ~ rendering. volume image CT image, CT PET/ (F18-), Fused image PET CT, right: to left from a mouse: Figure 4. 10 micron) low and to Typical CT image of of image CT Typical ------180 degrees. Within a certain relaxation time, the the time, relaxation acertain 180 Within degrees. very useful tool both in the clinical and the preclini the and clinical the in tool both useful very MRI (magnetic resonance imaging) has become has a (magnetic resonance imaging) MRI RF pulse (the so-called B1 (the energy field)transfer pulse so-called can RF increase can source to produceimage MR the RF Hence, in-vivo MR imaging requires that the SAR is is SAR the requires that Hence, in-vivo imaging MR http://www.weill.cornell.edu/research/cbic/facilities/mri_7tesla.html from: (Taken animals small for system MR Figure 5. Atypical for a human subject. However, subject. for ahuman of interaction the the ionising, so that it can be considered it so that can non-harmful ionising, netic field in a certain direction. This phenomenon direction. in a certain netic field to study radiation electromagnetic uses MRI niques, districts within the subject. Such radiation is non- is radiation Such subject. the within districts describes this phenomenon (specific SAR this the describes is magnetic moment will return to its stable equilib return momentmagnetic will moment amagnetic possess μ phenomenon one nucleus, of can the of magnetism To limit. the below understand asafety maintained of rotation is called “spin” and causes the nucleus to “spin” the causes of and rotation called is times T1 and T2 gives an insight to the distribution distribution to the insight T1 gives T2 an and times moment magnetic its flip nucleusto will the that external field An (B0). external of an direction the electri amass, with analogy of amechanical think object. power of of an mass absorbed per unit RF the that temperature body. ofthe the The quantity rium position. The themeasurement rium of relaxation rotation, mag rotation generates the itself asmall according to the energy received, typically by 90 or by 90 received, energy to typically the according absorption rate), W/kg as in measured defined and 2.2.4 spatial resolution in 3D. Like other imaging tech resolution imaging other 3D.spatial Like in centre of gravity of the charge is not on the axis of notcentre is axis charge on of of the the gravity the If its axis. around rotating and charged cally high a with very and tissues soft contrast between excellent with produceimages can MRI fields. cal MRI small animal imaging animal small MRI , which aligns along along aligns , which ) - - - - - The strength of the magnetic field may vary from field vary themay 0.5 magnetic of Thestrength MRS is its sensitivity, still in the micromolar range, micromolar range, the in its sensitivity, is still MRS MR, is of is great help forPET the orMR, SPECT image (morphology) behavior and hydrogen of the (i.e. of In any case, it is obvious that the information from information it the obvious is that case, any In Functional imaging such as PET SPECT are as such and imaging Functional PET/CT is the diagnostic instrument of choicePET/CT for instrument diagnostic the is 31 favoured by high field systems, which allow for allow a which systems, favoured field by high ferent atomic nuclei provides insights to functional ferent atomic nuclei to functional provides insights phenotypic characterisation, and for angiogenesis ing the same bed for the animal such as in PET/ in as such bed for same animal the the ing intrinsically non-morphological techniques. Hence Hence techniques. non-morphological intrinsically advent field the the of With (i.e. ies. and high 9.4 T) to confined research primarily are preclinical in dynamic visualisation of tissue perfusion, and many many and perfusion, of tissue visualisation dynamic membrane studies, creatine and lactate quantitative quantitative lactate creatine and membrane studies, been has MRS and more.step-upfrom The MRI nucleus frequency of under the Larmor match the modalities are executed one after the executed are other, oneshar after modalities of multimodalities, types there two are imaging, mal ani field of the small in Also most investigations. stud but not pharmacokinetic pharmacodynamic, tinuously growing: examples are translation studies studies examples translation are growing: tinuously bore of clear >30 adiameter tem has cm. example of a7T An cost apparatus. ofto the the to 9.4 application to of the course and Taccording of types nuclei ( different using water)the (physiology). body the in The phenom the so-called “tandem configuration”, where the two where configuration”, the “tandem so-called the to apply volume proper error. corrections for partial needed are images sites anatomical needed, is target required in analogy to the clinical area, where area, a clinical to the analogy required in a morphological imaging technique, such as CT or CT as such technique, imaging a morphological and biochemical information: for instance cell cell for information: biochemical instance and analysis. More more and are integrated systems analysis. small on information quantitative when addition, to mandatory often is information anatomical response fMRI. and for tumour especially attention, spectra, proton high-resolution shimming advanced comparedas to PET SPECT.MRS and the Thus, 2.2.5.1 2.2.5 higher signal to noise ratio. The identification of dif to noise ratio. The signal of identification higher enon of magnetic resonance can beinvestigated resonance enon can of magnetic localise precisely position the radiotracer. of the In localise studies, etc. The limit of MRI and even more so MRI of of limit The etc. studies, 5 Figure shown in is from Bruker system resolutionspatial (100 micron or less) for rodents. capable technique high a very ofsatile providing ver avery is MRI imaging, study. animal For small studies of the mouse brain have mouse of brain the been great receiving studies 1 with studies P) with an appropriateP) frequency to an operating with RF The impact of MRI in molecular imaging is con imaging in molecular impactMRI The of Multimodal approach Multimodal PET/CT SPECT/CT and H, H, 19 F, F, P and 13 31P and 1 H, H, C MRS compounds compounds C MRS 13 C, C, 19 F, F, 23 - sys . The Na, and and Na, ------67 Nuclear Physics for Medicine – Chapter II – Medical Imaging 68 Nuclear Physics for Medicine – Chapter II – Medical Imaging when this effect is much smaller than for humans, for than humans, is much effect smaller when this attenuation the to obtain as well as body the within CT-energy attenuation coefficient(μCT, linear X) CT, SPECT/CT, PET/MR SPECT/MR, and and information from CT can be used to obtain a finer afiner to obtain be used can from CT information implemented PET/MR. of today as in non-negligible. For PET attenuation in the example, diameter mouse. In the CT case, the attenuation the case, CT the In mouse. diameter ment, this technique has been recently has transferred technique ment, this obtained without CT (bottom) and with CT cor (bottom) CT CT without obtained with and the magnitude of this correction in small animals is is animals small correction in of this magnitude the morphological the fact, In scanners. to small-animal only is type latter this combined modality, truly the rections and image fusion (top). fusion image rections and a linear formula and for and PET formula to 511a linear keV by a bilin 1.6 is 1.3and rat, and for for a 5 a cm3 cm diameter ation study. ofobject by radiation the under Even by a errorquantitative affected the due attenu to correction scatter ation PET of and the images. has to be scaled to the 140.5 to the to bescaled has keV for value SPECT by emission images. In fact, the emission images are images emission the fact, In images. emission Figure 6 Figure interpolation. ear spectrum, ranging from 10 to ranging 70 keV.spectrum, Hence the distribution radiotracer of the localisation spatial combined environ PET/CT clinical the in scanners coefficients are measured with a continuous with coefficients are measured X-ray man, correction cm diameter factor 4.5 is for a40 studyattenucoefficient for under themap object of In the shadow of the successful application shadow of the of successful In the CT images are mostly used to improve used mostly are images the CT shows typical images images shows typical - - - - - Early diagnosis and therapy and connectedare to diagnosis Early PET/MR it is worth noting: dynamic studies, MR/ studies, PET/MR dynamic noting: it worth is PET cross correlation, MR-guided motion cor motion MR-guided correlation, cross PET sensi and functionality complementary offer PET attenuation correctionPET an must information inser the SiPMsallowed has and MPPCs PS-APDs, is becoming increasingly necessary. In fact, the the fact, necessary.In increasingly becoming is in the same system, either as a PET insert or as a or as a PET either as insert system, same the in molecular imaging, the multimodality approach multimodality the imaging, molecular for As genetic information. and imaging molecular of its parts. A schematic scheme of the structure of Aschematic scheme structure of the of its parts. to have that known It quantitative well is MR. of an that has a significantly greater impact than the sum thesum than greater impact asignificantly has that on the capitalises acquisition tivity. Simultaneous sequences special and (i.e. UTE) atlas, brain tation, field magnetic high the oftion aPET within system been going on to find the best way ondo to tobeen find segmen going it: attenuation correction,based alot of research has the a CT. was bestwith made be performed, This reason PET/CT for introducing clini the in systems received great development. attention and The Figure 7 combined Figure depicted is system in a typical and PET in the preclinical scenario are now are scenario mostly preclinical the PETand in advent of state APDs, new detectors solid as such 2.2.5.2 2.2.5.2 have been proposed in combined modalities. MRI have MRI been proposed combined in modalities. strengths of each, providing a hybrid technology a hybrid ofproviding technology each, strengths combined structure from the beginning. MRI and and MRI beginning. from the combined structure MR theAs for field. preclinical, the in also and cal, combined PET/MR systems SPECT/MR and have Among the many applications with acombined applications many with the Among PET/MR Pisa, 2013). Pisa, P, IFC-CNR, Salvadori and D Panetta of (courtesy only image PET bottom: scanner; PET/CT IRIS the with obtained Top: PET/CT image IVISCAN). raytest- (IRIS, examples preclinical recent most the of one on performance imaging Typical 6. Figure . - - - - - Preclinical PET/MRI scanners based on APDs or PET/MRI on based APDs scanners Preclinical Cross section of the combined PET-MR system proposed for the TRIMAGE PET-MR-EEG project (courtesy of A. Del Guerra, 2013). Guerra, Del A. of (courtesy project PET-MR-EEG TRIMAGE the for proposed system PET-MR combined the of section 7. Cross Figure Several detector prototypes based on based detectorSiPMSeveral prototypes are magnetically shielded PMTs shielded market. on are the magnetically being developed. being rection of PET reconstruction. PET and image frame of ENIAC CSI. ENIAC of frame Applied Technologies in the Microelectronics and Philips ST (Hungary), Debrecen of University MTAby Atomki, molecular imaging developed for scanner animal small based aSiPM MiniPET-3, PET-MR combined the in obtained heart rat injected FDG- an of Image 8. Figure 69 Nuclear Physics for Medicine – Chapter II – Medical Imaging 70 Nuclear Physics for Medicine – Chapter II – Medical Imaging The benefits The benefits are to dose the reduce radiation by MR scanners. The rotating gantries used in usedPET gantries The rotating scanners. MR (so scans be MR blood flows, forexample, can that to show used the is both imaging Multi-modality l l l CT scanner. PET/CT scanner. CT introduced 15 was years ago Clearly simultaneous imaging is preferable, for preferable, is imaging simultaneous Clearly for anatomical location with PET SPECT. and location with for anatomical ibility. Some preclinical prototypes used light guides guides light used prototypes Some preclinical ibility. be detected can for atumour example, so that, ing now coming on the marketBiograph on (e.g. the now Philips coming Conversely, netic field. the detectors PET not must done sequentially rather than simultaneously. rather than done sequentially moredetected). diffi However, technically is this mMR). TechnologymMR). from nuclear physics detector noise. electrical introducing field or the perturbing of modern fields magnetic intense the patible with SPECT/CT means multi-modality or PET/CT. now are Commercially, which on sale. machines and body the place in processes taking molecular the magnetic field, however field, the magnetic morethe route popular from photomultipliers to be locatedto allow further aPET/ in CT located and using PET imaging using happen are they which location in anatomical the New challenges use functional MRI as well as simple anatomical simple as anatomical well as MRI functional use been in use for a few years it was, until very recently, very for until afew use years it was, been in and multi-modality is standard for PET SPECT and standard is multi-modality and and the first simultaneous PET/MR aresimultaneous first the scanners and theoperation sensitivescanner eitherMR by affect and SPECT can also be affected by the MR mag the by beaffected also SPECT can and example to avoid motion artefacts between scans, example to avoid scans, between motion artefacts eliminating the CT scan, and the possibility to possibility the and scan, CT the eliminating seems tosensors of be to use semiconductor light to overcome used is systems incompat magnetic the incom are that photomultipliers with scintillators 3. 3. cult because typical SPECT and PET scanners use use PET SPECT and scanners typical because cult The new challenge is to combine MR imaging imaging is to MR combine The challenge new Although PET/MR multi-modal imaging has has PET/MR imaging multi-modal Although - - - - - TOF modules can be made using nuclear physics nuclear using bemade TOF can modules (sequential TOF PET/MR exists). MR-compatible MR-compatible TOFPET/MR exists). (sequential or SiPMs)(APDs to replace photomultipliers the or will also allow non-standard use of PET non-standard use technol allow also will Despite the excellent performance reached performance Despite excellent the by PET 3.1 3.1 ing, as well as the strategic choices in the design design choices the strategic the in as well as ing, systems. imaging detectors, there room is for improvements that eitherby put detectors to replace scintillators the SiPMs) with building as detectors (fast scintillators mercial market are to integrate SPECT with MR mercial market MR areto integrate SPECT with measurement, time resolution, MR compactness, time measurement, adifference making physics currently are systems semiconductor use research systems market while ogy, such as in-beam measurements during particle particle measurements in-beam during ogy, as such aCompton using by collimation electronic or else to replace scintillators by semiconductorto detectors. replace scintillators the overall performance of a PET scanner: detection of detection performance a PET overall the scanner: contribute that relevantto to improvethe aspects all sessions. therapy SPECT collimators the detectors CZT behind ting blocks for TOF PET/MR. SPECT/MR from far is an MR environment for simultaneous operation environment MR for an simultaneous to detectors integrateand fast for TOF PET in and enabling the development of new multimodal development the of enabling newand multimodal where from nuclear techniques challenges, the are efficiency, spatial resolution, depth of efficiency,interaction of resolution, depth spatial compatibility, speed and power consumption. and speed compatibility, camera of made semiconductor detectors. The next challenges the yet to be solved comin challenges The next These last two last These (SPECT/MRand TOF PET/MR) All the PET the components follow reviewed the in All Research is being carried out worldwide order carried in being is Research Detector design Detector - - - - • • • The figure of merit that summarises the suitability suitability the summarises that of merit figure The To photon converter a primary as for be used aPET (fixed photonenergy) andSPECT a photon(wide with ε, N, τ related to the crystal density, light yield yield density, light τ relatedN, ε, crystal to the with PE: photopeak efficiency photopeak PE: S69–S85.] 36 (2009): Imaging Mol Med JNucl Eur R. Lecomte from [Adapted SPECT and PET in scintillator used most the of 1. Properties Table form crystals at alow (acceptable)form crystals cost. is a set of inorganic crystals, whose properties are crystals, of aset is inorganic not stopped recent in and years some new candi dates havedates emerged. photons. When these conditions are met, a high ahigh conditionsmet, are these photons. When reached single being when counting limit mance photon counting statistics, it requires the capability it capability requires the statistics, photon counting has scanner moretime performance efficient and measurement. However, for search new the materi requirements: following the meet of providing the most accurate input information input most accurate information the of providing subject are to continuous systems, of global the of a crystal is usually defined as: defined usually is of acrystal to the 3D or 4D reconstruction algorithm. reconstruction 3Dto or the 4D to trigger at very low threshold, with the perfor the with low at very threshold, to trigger 3.1.1 research and development, with the ultimate goal goal research development, ultimate and the with als that would better meetrequirements the better would for that a als respectively. decayand time, energy range) detector, a scintillating crystal must must crystal range)energy detector, ascintillating light yield and a short rise-time of the scintillating scintillating of the rise-time ashort and yield light summarised in Table in LYSOsummarised and 1. best the LSO are choice for scanners that also aim at the time of flight of flight attime the aim choice also that for scanners 10 Light yield (mm) 1/μ@511keV Effective Z decay time Primary PE (%)@511keV 662 keV ΔE/E (%)at (g/cm Density resolution); high light yield (related yield time and light energy to the high conversion (i.e. high density efficiency);high short rise time to optimise the time resolution. time the to optimise time rise short The state of the art for art thePET/SPECTstateThe of scanners As an optimal timing resolution related is to the timing optimal an As η ~ε In addition, the technology must provide must uni technology the addition, In 3 ph/MeV Scintillators 3 ) 2 √ N/τ √ eff NaI 50 3.67 38 25.9 250 18 6 BGO 73 7.13 9 11.2 300 44 10 GSO 58 6.71 8 15.0 60 26 8 LSO 65 7.35 30 12.3 40 34 10 - - - - worsens the image quality due to a low ability to due to alow ability quality worsens image the for the photoelectric effect in organic scintillators scintillators organic in effect photoelectric the for forward. interaction of the registered gamma quantum. In In quantum. registeredinteraction of the gamma at detector and plastic of the thickness increasing ing process, and by taking advantage of the excellent excellent of advantage the by process, taking and ing new PET devices under construction, the decrease the construction, new PET under devices few yearsallow novel last developed the in methods distinguish between quanta reaching the detec the reaching quanta between distinguish deposited in the scintillator corresponds to the scintillator the deposited in marginal improvement step a significant marginal rather than PET for scintillators known to alternative possible promising preliminary results, the technology is technology the results, preliminary promising at the collection light the pattern, photonic crystal of a patient. This drawbackis compensatedofthe apatient. This by be compensatedwill by detectorof efficiency the tor directly and quanta re-scattered quanta and body the in tor directly the increase of the acceptance. The small efficiency efficiency The small acceptance. of increase the the of the of depth the determination time same the resolution apossible but time suitable, are suggest to approach a possibility theoretical the with time, the effective usage of the usage of TOF effective technique. the for allowing response scintillators, of organic timing Compton transferredthe toelectron the via scatter range close to the maximum of energy which can be be can which of energy maximum close to the range addition, thanks to the large solid angle covered angle solid large by to the thanks addition, photonHowever, optical yield. insufficient and and yield density, the SPECT light scanners: and limit value of value about 100 ps. limit light allow the best measurement best interaction of the the allow light short decay time, suffer from lowstopping suffer power decayshort time, still in an early stage. early an in still be improved. would surface However, despite some events energy these the for ofselection only which LYSO 64 7.19 32 12.6 41 33 10 Plastic scintillators, which would provide would which avery scintillators, Plastic GAGG crystals have a GAGG as been recently crystals studied Should the scintillators be engineered with a be engineered with scintillators the Should LGSO 59 6.5 16 14.3 65 28 9 LuAP 65 8.34 12 11.0 18 32 15 YAP 33 5.5 17 21.3 30 4.4 4.4 , n° Suppl. 1 , n° Suppl. LaBr 46 5.08 60 22.3 16 14 3 3 - - 71 Nuclear Physics for Medicine – Chapter II – Medical Imaging 72 Nuclear Physics for Medicine – Chapter II – Medical Imaging TDC that provide the energy and time information, information, time provide and that energy the TDC TOF-PET. were commercial PET/MR forfirst used the scan Once the primary photon conversionOnce primary the and efficiency The most important parameters of (secondary) photon detectors. photon (secondary) of parameters important most The 2. Table in in SiPM the sensitive area of basic integration within presentadvantages: insensitivity, interesting avery order requiredis in to exploit raw the information nents should be compatible with a time resolutionnents be compatible atime should with ner; however, long rise and (low drawbacks gain their directly providing digital output. digital providing directly didates for TOF-PET.didates the and rise-time short The processing electronics and eliminate the need the for eliminate and electronics processing ments: field compatibility. compactness magnetic and ous performances of these devices are summarised are summarised devices of performances ous these time resolutions as low as 150 ps (FWHM). The The resolutionsvari low 150time as as ps (FWHM). to segmented SiPM matrices. couples adetector that to crystals continuous design approach could that of 100 lower the In ps. limit high for hybrid while APDs PET/MRthan imaging, performance fortime) high unsuitable them make require donot important meet two gain, high the rate collection and yield photon light secondary the 3.1.2 3.1.2 based onbased photomultipliers (PMTs), despite which, respectively. coupled reach dSiPM to LYSO crystals requirements field of magnetic compactness and addition, the high gain could allow single photon single allow could gain high the addition, at best. photon performance detector ahigh optimised, are high level of homogeneity compohigh of SiPM matrix external processing. Each micro-cell of the array is is array of the micro-cell Each processing. external low even bias voltage them makes more attractive control with active cooling, would make it make possible would active cooling, control with count rate dark kept is the if under which, counting, connected to an integrated counter and an integrated integrated an and counter integrated toan connected gain and short rise time make them the best can best the them make time rise short and gain Magnetic fieldsensitivity Temperature sensitivity (%/K) Bias (V) Quantum Efficiency (QE)@420nm(%) Rise Time(ns) Gain Detector Table 2 Table APDs, that are insensitive to magnetic fields, fields, to insensitive are magnetic that APDs, In recentIn research years, projects have on focused Clinical PET and SPECT scanners are typically aretypically PET SPECT scanners and Clinical SiPMs, on the other hand, besides meeting the the besides meeting hand, other on the SiPMs, dSiPMs, developed by Philips, are based on the arebased on developed the dSiPMs, by Philips, Photon Photon detectors . Yes < 1 > 1000 ~ 25 ~ 1 10^5 PMT - - - - - first secondary photons emitted in the crystal de- the crystal in photons secondary emitted first CdZnTe are solid-state devices that allow the direct CdZnTe direct the allow that solid-state are devices in small modules that couple that semiconductor modules the small in nominal expected values. The construction and The construction values. expected nominal netic fields. density readout or sub-pixel positioning electronics electronics positioning sub-pixel or readout density it not is as limited good, beextremely detectors can promising technology forimprovement the technology promising of spa protocols. achieve devices best the While uniformity. material micrometers (200–400µm). optimised design, typical resolution by values stand typical design, optimised time resolution. Should this limitation be over limitation resolution. this Should time tion is not limited by charge generation by charge not is statistics but tion limited for a140 charges keV 30000 typically devices: tion orderthe ofpossible 100 Their performance ps. resolution keeping atime of resolution, while tial tion is of the order of 2.5 mm, but the use of high of order of high is buttion use the the of 2.5 mm, by other phenomena, such as electrical noiseby or other phenomena, electrical as such by the readout circuitry. A typical device resolu device A typical readout circuitry. by the but photon rather and spreading statistics, by light 2% resolution at than 140 better keV to an thanks and intrinsic insensitivity to temperature mag and insensitivity intrinsic and respect resolution related to the the time with and allow for an intrinsic resolution of of intrinsic few for hundreds an allow close are to 5% atard systems 140 keV, that a value hybrid PET systems, thanks to their compactness to their hybrid thanks PET systems, excitation process, which are key to an excellent excellent excitation key are to an process, which energy release. As a consequence, the energy resolu aconsequence, release. energy As the energy limit, however, (5–15), low gain their limit, in is which special attention to the capability of detecting the the of detecting attention capability tospecial the conversion respect to scintilla with large is yield conversion The rays charges. to electrical of gamma for candidate excellent be an would come, UFSD require will prototypes first of the characterisation can helpdevelopment the can of dual-isotope imaging could deteriorate both the signal to noise ratio signal deteriorate the could both crystals and the readout the same and on the electronics crystals No ~ 3 300-1000 ~ 70 ~ 5 50-1000 APD The spatial resolutionThe thesespatial semiconductorof Ultra Fast Silicon Detectors (UFSD) Fast anew are Silicon Ultra CdTe- or CdZnTe-based detectors integrated are Semiconductor detectors on based CdTe or No 1-8 30-80 ~ 25-75(PDE) ~ 1 ~ 10^6 (d)SiPM No Negligible 100 ~ 75 ~ 0.1 5-15 UFSD ------view of the system performance, since it allows it since allows performance, system of the view Front-end a key ena becoming electronicsis PMTs, APDs or SiPMs, whose signals are processed are PMTs, whose or signals SiPMs, APDs SPECT tomographs that exploit the modularity to SPECT tomographs exploit modularity that the State-of-the-art on based are segmented scanners ing, digitisation, signal processing), making them them processing), making signal digitisation, ing, level high the and of number channels increasing dimensions. Ageneral trend to is integrate moredimensions. delivered to patients. possible improvements that key parameters of the lower with doses images provide quality better improve measurements that more timing accurate requires of number channels pled increasing to the cou localisation This reliability. and performance improving both and connections the minimising on a single channel, which are then detectedby then are which channel, on asingle cost and reductions in allows of that integration the patient. the the noise and background reduction therefore noise background and the and operating with powertogether reduction higher and of increase performance this allows technologies bling technology (KET) for detectors due (KET) to the technology bling 3.1.3 3.1.3 3.1.4 by dedicated ASICs and FPGAs. and by ASICs dedicated also tend to movealso closer or even onto detectors, the filter (amplification, ASICs in moreand functions avoidalso motion camera the of head the around enhance sensitivity and resolution of and a by sensitivity focusing enhance exposure, while maintaining high quality resolution. quality high maintaining while exposure, low-power and performance the so that designs, speeds, an important feature for feature apatient’s reducing important an speeds, ASICs (SoC). on achip systems These multi-channel substrate. System have designers profitedfromthe crystals that collect most of the secondary photons most secondary of the collect that crystals The evolutionmicroelectronics systems. of cooling notcompactness are obtained by spoiled large innovative tocompactness build of modules such given region systems ofthese interest. Additionally, Any change in the detector design is related is to detector design the in change Any Such a design is also useful from the pointof from the useful also is adesign Such Module layout Module Front-end electronics - - - via the light sharing and/or the time difference read and/or difference time the sharing light the via 3D spatial resolution, time resolution, resolution,compat3D MR time spatial while the axial position along the crystal is obtained obtained is crystal the position along axial the while severallong (upwith to 10 layers: cm)such thin and field and acceptably field priced. SiPM matrices, with high gain and the possibility to possibility the and gain high with SiPM matrices, ibility, compactness, speedcompactness, poweribility, and consumption. describe the overall system performance: efficiency, performance: system overall the describe detector of choice for almost every ongoing research ongoing detector of every choice for almost help would improve which TOFdistribution, the photons, prompted single detect some projects based posed. The segmented crystal could be placed axially, axially, be placed could The segmentedposed. crystal vol respect annihilation to the with placed radially ps range. If the scintillator rise-time and the pho the and rise-time scintillator the If ps range. TOF the measurement, on optimising focus mostly reso spatial high very photoncapabilities, counting single gain, high very project:with efficient, are they approach depends measurement. Suchan strictly - clus a allow would The crystal continuous matrices. of merit already discussed, is usually segmented and segmented and usually is discussed, of merit already only be achieved with a cooling system that allows allows that system acooling be achieved with only to control countSiPM the capability dark on the photon time secondary of the of amulti-sampling blocks read by segmented on continuous scintillator oppositeon the sides. ume. ume. using the cluster size for DOI measurement size the cluster and the using double the of advantage with ter reconstruction, resolution among the different cell contributions to to contributions cell different the among resolution rate to distinguish and trigger the torate, limit so as a temperature stability within about 1˚C. within a temperature stability a design provides DOI excellent a measurement,design an a matrix element closequite to 100a matrix ps). also are They lution and excellent timing resolution (with intrinsic resolution (with intrinsic timing excellent lution and so as to reach an overall resolution 100–150 to overall the reachso as an in compact, compatible with operations in a magnetic compact, compatible operations amagnetic in with can result This counts. by dark triggered channels from reconstruction cluster the to contributions The scintillator, selected according to the figure figure the to selected according scintillator, The The availability of high performance segmented performance high of The availability Recently, two alternative designs haveRecently, alternative designs two been pro Custom front-end electronics developments developments front-end electronics Custom SiPMs (analogue or digital) are the photon the are SiPMs (analogue or digital) out a SiPM matrix. aSiPM out front-end electronics to read- Figure 9. Example of compact compact of Example - - - - - 73 Nuclear Physics for Medicine – Chapter II – Medical Imaging 74 Nuclear Physics for Medicine – Chapter II – Medical Imaging vention on small internal structures and lesions. and structures internal vention on small when developing endoscopic adetector for an first photon(s)first de-excitation and to fromthe crystal Several new approaches to the detection of primary newSeveral approaches of detection to primary the keep the system performance constant. performance keep system the itself; this simplifies the construction of the of overthe construction simplifies this itself; in large-scale high energy physics experiments, and and physics energy experiments, high large-scale in provided also are choice by the of solid-state ibility segmentedis key to optimise the or continuous, network, which providesnetwork, which and processing real-time of the analysis the asegmented crystal, With nals. distinguish them from the spurious dark count sig dark spurious from them the distinguish dling could come could concept from the of “deferred dling photons originating in the e the in originating photons photon SiPMs. detectors as such on the market),on the front-end the contribu electronics tial resolution of microns), tial (hundreds work in well more sensitive, allow more precise, lower will tion, the to identify resolution capability time the is the crystal the resolution. Whether time system to the contributes source that become main can the tion enough short are formationton time detector signal uniformity is also being addressed by designing by designing addressed being also is uniformity 3.1.5 been below. proposed,described are and radiation doses and less invasive imaging and inter and less invasive and doses radiation imaging of a case the in while clue, shape the is signal rising active cooling systems that are very important to important very are that systems active cooling arrays. detector to larger its scaling allows and system all true be must able to distinguish algorithm analysis response time is the in detector uniformity the and as well as the secondary photon aPET detectors secondary in the as well as used widely particles charged for detectors plate allel types. cancer asymptomatic approach, which, combined with timing resolu timing approach, combined with which, earlier detection and patient-tailored and detection earlier treatment of low as required to detect single photons, low cluster required the as to single detect large area detectorslarge (~2–3 metres) square be can strong magnetic fields and are inexpensive, so that inexpensive,areand so fields strong magnetic events. count background from dark signals system. continuous crystal, where the threshold must be as where beas must threshold the continuous crystal, coincidence determination within the network network the within determination coincidence coincidence”. berouted events can to Single aring could in principle replace the crystal scintillators, scintillators, principle in replacecould crystal the good (as it forlatest SiPM is available the matrices The The need for precise temperature controland An important innovation han to data real-time important An Ultimately, all of these features point towards features of these all Ultimately, Resistive plate chambers (RPC) are gaseous par gaseous plateare Resistive (RPC) chambers RPCs provide (20–30 time excellent ps)RPCs spa and System compactness is particularly important important System compactness particularly is compat design System MR compactness and New detector concepts detector New + e - annihilations have ------(<30%) amuch it amajor is as implies drawback, were available. were shown to have significant influence on the rise rise the wereinfluence on shown to have significant Brunner et al., the intrinsic time resolution be time could intrinsic the al., et Brunner PET measurement ongoing. is PET devices. Contrary to planar imaging, which includes scin includes which imaging, to planar Contrary 3.2 isotope distribution (PET,isotope distribution SPECT or Compton not directly obtained from the measurements, but measurements, from the obtained not directly didate for PET/MRI hybrid imaging and in-beam in-beam and for PET/MRIdidate hybrid imaging detectors. According to simulations performed by to simulations According detectors. mance in positron-annihilation detection. A spatial Aspatial detection. positron-annihilation in mance light detection of photo-detector. The simultaneous might be an attenuating medium (CT) medium or aradio attenuating be an might Cherenkov investigated. photons, being photons is tion issue. issue. tion dose minimisa the when addressing unsatisfactory tric) conversion above still avalue probability 47%, light produced The photoelectric effect. the through increase. dose deliveredthe patient to the will respect to standard with acceptance geometrical the tigraphy, or radiography, tomographic images are are images tomographic radiography, or tigraphy, leadtopic to improved might resolution time of PET measurement extensive research and time on this –akey-feature for scintillators the of inorganic time responsetaneous to incident 511 keV annihilation jection ionisation chamber, ionisation jection supplemented by a tion of the Cherenkov effect, which bypasses the Cherenkov oftion the bypasses which effect, by a relativistic electron is detected in atime-pro detectedin electron is by arelativistic effi bismuth innovative that (TMBi) an is liquid increasing and view field of alarge providing built, resolution of 1mm are foreseen, with a single interaction (photoelec interaction asingle foreseen,are with a photon resolution energy of about 10% FWHM perfor promising to avery leads signals charge and TriMethyl PET alternative systems. to standard an an “object” froman its“projections”, where object the tomographic so-called of result the are the appropriate if ps, low 30 as as front-end electronics a process based on mathematical algorithms that that a process algorithms based on mathematical reconstruction larger number of annihilations to provide statistics of number annihilations larger scintillation process and provides almost instan process provides and almost scintillation ciently convertsciently 1 MeV photons less than of energy comparable therefore PET and to systems standard cameras). Tomographic image reconstruction is is reconstruction Tomographiccameras). image graphic reconstruction is to obtain the image of image the to is obtain graphic reconstruction The lowefficiency detection for 511 keV photons To improve resolution, exploita time the the Liquid calorimeters are also being considered being as also are calorimeters Liquid Still, investigation of RPC-based PET acan as of investigation RPC-based Still, Simulation and reconstruction and Simulation process. Classically, the goal of tomo goal the process. Classically, 3 , a sub-nanosecond timing, and and , asub-nanosecond timing, or or image ------Traditionally, a tomographic corresponds to image a & Gullberg 2006). & Gullberg vide 3D images (fully 3D reconstruction) 4D (fully and 3Dvide images (FBP) are still used for quantitative image analysis analysis for used quantitative image (FBP) still are Figure 8).Figure Therefore, iterative meth reconstruction in spite limitations. in of their is to find an image estimate successiveby In estimate image steps. an tois find thethewhen case meas is particularly This images. to better leads usually turn, in process, which ing image 4D account; into taken also is time if images power computing enabledincreasing has devel the main advantage of iterative methods is their ability ability of advantage iterative their is main methods pro directly can techniques reconstruction modern (2D section plane image) of inspec object the under present state-of-the-art most research recent the and formation pro image phenomena the underlie that ods arepreferredods tomography, emission in although reconstruction image opment more of sophisticated of computers modern Computers areality. CT made tion of the injected tracer over injectedtracer oftion the time. tomography, concentra the to is study whose goal emission dynamic in it motion, and essential is tory Avolume (3Dtion. by image) constructed thus is we section, will this oftions In tomographic systems. to some (such reviews excellent by Defrise that as of algorithms variety a wide few decades, last the urements device arenoisy, or whenimaging the amoreto include description imag of accurate the are methods analytical on which assumptions the are methods reconstruction Analytic methods. tion iterative and reconstruc categories:two analytic into bedivided broadly can which algorithms, tion 3.2.1 3.2.1 based usually do not do tomography. emission hold in usually based are solution, and mathematical onbased adirect reconstruction is particularly useful in cardiac PET cardiac in useful particularly is reconstruction proposedin first was reconstruction 1917,the advent analytical methods, such as filtered backprojection as such methods, analytical SPECT,and regionsby or to affected image respira Nowadays, sections. several reconstructed aligning simulations. and reconstruction image advances in simula accurate and more and detailed algorithms, complex the to physical simulate essential also are amath implementedare computers. in Although have been presented. We refer interested the reader ematical solution for the problem of tomographic problemtomographic of the for solution ematical still widely used for CT reconstruction. However, for reconstruction. used CT widely still Continuously subsequent etc. emission, radiation radioisotope the decay and materials, scintillation cannot provide uniform or complete sampling (see or provide completecannot uniform sampling photons behaviour of the optical as such within cess, The goal of The goal iterative techniques reconstruction At At present, reconstruc there severalare image Compared to analytical reconstruction, the reconstruction, Compared to analytical Image reconstruction ------voxels. The that moreare contem effects physical Monte-Carlo simulations haveMonte-Carlo simulations proved to beavery within the so-called system response- system or model sys so-called the within One of the main strengths of iterative algorithms of iterative strengths algorithms One of main the SPECT) should be modeled. The system model The bemodeled. SPECT) should for a certain device can be very challenging given challenging bevery can device for acertain image elements, respectively.image For aconventional its components for PET SPECT. and Approaches naturally leads to the Maximum-Likelihood (ML) Maximum-Likelihood to the leads naturally model onniques based are aPoisson this model; of decay radioactive nature detection, or radiation design of the cost function, as will be described in in be described will as cost of function, the design objective an function, system, imaging the and data dle the SRM. Factorisation of the SRM in several in Factorisation of SRM the SRM. the dle model. Most commonly used reconstruction tech reconstruction used commonly Most model. choicephenomena the into account in be taken can models usually allow for but faster less accurate allow usually models for Point the models Spread Analytical Function. becomes. Several SRM the less sparse the plated, arethat mod morecorrectly principle, the effects physics of the image formation and degradation physics formation degradation and image of the mate of the true object. mate true of the of the geometry and arrangement of the detector of the arrangement and geometry of the the underlying physics, which include the statistical statistical the physics, include which underlying the paragraphs. following the the for image, the models ‘ingredients’: same the useful tool to compute the whole SRM or tool severalof to compute whole the SRM useful reconstruction. the it during to handle and SRM, the havetechniques been proposed to compute han and of be composed might of several millions image the and of number data the M being Nand to NxM, corresponds which matrix, of the dimensions the In scatter,inter-crystal etc. cross-talk, effects, tion from rays originating of gamma probability tion correspond detec elementsto the the SRM of the PET or In SPECT, (SRM). tem response matrix 3.2.1.1 3.2.1.1 based on measurements can provide very realistic providebased on measurements can realistic very reconstructed image. However, image. reconstructed SRM the computing a certain location. In the first place, the effects place, first the In location. a certain and the interaction of radiation in matter. interaction of in The the radiation and the in as well as descriptionand of models, the underlying The algorithm. optimisation an and eled and included within the SRM, the better the the better the SRM, the within included eled and in (andelements detection on the collimator the lies in their ability to include accurate models of models accurate to include ability their in lies statistical nature is contemplated within the data data the contemplated is nature within statistical criterion to determine which image is the best esti best the is image which criterion to determine components makes it easier to calculate and storecomponents and it makes easier to calculate 10 than PET be larger scanner, N can clinical can also include a description of crystal penetra adescription of include crystal also can in emission tomograhy The behaviour of the imaging device is described described is device imaging theThe behaviour of Most iterative share techniques reconstruction Physics and iterative image reconstruction reconstruction image iterative and Physics 8 , and and , ------75 Nuclear Physics for Medicine – Chapter II – Medical Imaging 76 Nuclear Physics for Medicine – Chapter II – Medical Imaging (TOF) to PET, algorithms requires dedicated which fly. This approach is usually the one chosen when fly.This approachusually is SRM, for example using Monte-Carlo simulations; Monte-Carlo simulations; for example using SRM, in the comparison step. the in improved. to lesion be and (in detectability) ofity terms SNR photons. This annihilation of two the arrival the in at doneis usually preservedis This exploited. and For PET, estimate. image contribution the of acci iterative algorithm. In this step, the measured data data measured step, the this In iterative algorithm. dedicated algorithms, TOF PET allows image qual image TOF PET allows algorithms, dedicated data”, “list-mode data measured the with i.e. dealing into account betaken also coincidences can dental measured for an object being described by the last described by last object the measured for being an of the SRM is to calculate the system model on-the- model system the to is calculate SRM of the and models accurate between balance the optimise subsequent the and need ofof channels detection Some attempts SRM. the within built are ments, measure or additional from CT,obtained MRI recon the within included or scatter, bealso can contribution the of allows matrix system of the the various physical phenomena various the to be calculated translated into clinical PET. combination with In clinical into translated technology, proposed 1980s, been recently the has in provided difference time by the tron annihilation thelatter since system models, cost ofthe simplified data the in whole contained the information that List-modetime. it makes possible reconstruction Much SRM. of the computationthe handling and avery currently is accuracy tation model cost and components various the system of the to calculate based on analytical approaches, have been proposed onbased analytical factorisation the since be prohibitive. case, any In proposed, but computational the been also cost can response model. Finding a balance between compu between abalance Finding response model. are compared to the ideal data that would have would are compared that data ideal been to the active field of research. comprehensive have models alternatives; analytical are calculated on the fly; however, fly; on the calculated butare fast accurate notare compressed (such sino intoas histograms have been made to include object scatter within the the have been toobjectmade include within scatter however, most the common approach the to is use exploit the location constraint for the positron-elec the for constraint location the exploit the few tolast years in expended been has effort lately. system models for list-mode reconstruction, usually usually reconstruction, list-mode for models system in elements several poses challenges image smaller comparison step the of the within estimate scatter process. previously factors, Attenuation struction separately, approaches different be combined can computational efficiency. A way to avoid the storage grams), but arestored accorded registration to the As mentionedAs number above, increasing the Time information is the key in time-of-flight key in the is Time information Patient-dependentas attenuation such effects, ------‘core’ of a reconstruction algorithm. Most widely Most widely ‘core’ algorithm. of areconstruction A completely approach different implementis to the ML estimation problem is ill-conditioned, which which problem estimation ill-conditioned, is ML (before convergence), post-reconstruction smooth convergence),(before post-reconstruction ones. However, most(OSEM) popular the being the its accelerated and version(MLEM) Ordered- (TV) regularisation are earning much interest in earning are regularisation (TV) The penalty MAP). (Maximum-a-Priori algorithm, which can be achieved through early stopping early be achieved through can which Likelihood-Expectation-Maximisation algorithm algorithm Likelihood-Expectation-Maximisation One of the main drawbacks of iterative drawbacks One main image of the Some proposed of the approaches rely on parallel Subsets-Expectation-Maximisation algorithm algorithm Subsets-Expectation-Maximisation function. The latter approach can also be derived be also if latter The approach can function. function (orfunction some prior) include ana also might image noise, but usually at the expense of higher of higher expense at the noise, but usually image ing, or by adding a penalty function in the objective the in function apenalty or by adding ing, noisy images. Noise regularisation is thus needed, needed, thus is Noise regularisation images. noisy data, such as those arising from detec gaps between arising those as such data, metries of the imaging device to be exploited, or to beexploited, device imaging of the metries process, which remains an active field of an research. remains process, which response of system the matrix calculation the might the problemthe aBayesian framework in formulated is aforementionedthe criterion, Maximum- the ML of optimisation on based the are techniques used grids. on based irregular those tures; the use of graphical processor units (GPUs) processor of graphical use units the tures; configurations. PET ring tors or partial for CT. priors especially offer community, TV the from patient of the obtained information tomical 3.2.1.2 be computer expensive, but also the image reconbe computer image the expensive, but also renewed attention given their ability to reducerenewed ability attention given their reconstruction within a field gate programmable within reconstruction its computational is Notreconstruction cost. only results in unavoidable noise in the data causing unavoidable causing in data the results noise in alternatives are polar pixels, which allow the sym the allow which pixels, polar are alternatives array (FPGA). array alternativea promising to compensate for missing Compressed (CS) sensing recon or MRI. a CT has earned much attention in recent much earned attention in has acost- years as been devotedhas to accelerate reconstruction the els are the preferred option. In the last few years, few preferredyears, the are last the els option. In effective alternative, especially useful for TOF PET.useful alternative, especially effective struction process Therefore, such. as struction effort much spherical based functions (“blobs”) havespherical deserved based functions struction approaches and CS-based total variation variation approaches total struction CS-based and computational cost. Other potentially interesting interesting potentially Other cost. computational computing using clusters, or multicore architec clusters, using computing reconstruction The cost function and its optimisation are theare and optimisation its function The cost Concerning the image model, rectangular vox rectangular model, image the Concerning Accelerating iterative image image iterative Accelerating ------Tomographic be employed can images for different visual inspection, lesion detection, quantification lesion quantification detection, inspection, visual Compton scattering in the detectors, partial volume detectors,partial the Compton in scattering compensation of degradation phenomena in ET image formation unavoid processesimage thus are and in the single frame, the frames are reconstructed frames the frame, single the in motion detection external on based an frames in meth non-gating and categories:into two gating al et Rahmim in possible”. be“as goodas should image other On the novel able to compensate methods for attenuation novel TOF-PET as such technologies or PET/MR, diagnostics and therapy follow-up in clinical rou therapy and follow-up clinical in diagnostics deal with motion have with beendeal proposed (see reviews patient and organ motion. In particular, cardiac cardiac particular, motion. In patient organ and properties or characteristics that a “good image” a“good image” that properties or characteristics purposes. PET and SPECT are commonly used for used PET SPECT commonly are and purposes. medical research, or pharmacology. It obvious is medical ods. In gating methods, the acquired data are split are split data acquired the methods, gating In ods. of-view. PET, In also coincidences accidental might relation a linear quantitative information, obtain end, the In etc. physiological parameters, of certain tion content of the images. Several strategies to strategies content Several tion images. of the tion algorithms of choice beable should to provide. algorithms tion main the are which determine will purpose this of the for quality ofapplications, the any these that, tomography emission time, of same rodentsthe and At radiotherapy planning. in delineation tumour Moretine. recently, for used arealso PET images tion and the attenuation have the and tion been proposed. also artefacts or geometries, ring to limited-angle brain studies might strongly distort the informa the distort strongly might studies brain 3.2.1.3 by simultaneously estimating the activity distribu activity the estimating by simultaneously be a source due of Truncation inaccuracy. artefacts and respiratory motion (in thorax or abdominal abdominal or (in thorax motion respiratory and activity concentration. For this purpose, several concentration. purpose, Foractivity this attenuation and Compton scattering in the patient, patient, the Comptonin attenuation and scattering becompensatedable, butthe can of case for.is This purpose: final on the depends image a reconstructed bio for pigs acommon is tool cardiology) and in hinder quantification. Motivatedthe advance by quantification. of hinder from of to information be extracted kind the hand, examinations), and involuntary head motion in involuntary examinations), and effects are related to the underlying physicsandare underlying therelated effects to need effects to be accounted for; somethese of effects, variable spatial resolution thespatial acrossvariable field- effects, for example To traceruptake. image, fromest an larger animals (such monkeys for as neurosciences animals larger system. Assuming that there is little or no motion there little is that Assuming system. voxel image required is ship and between values reconstruc the turn, in which, and exhibit should consists of extracting certain parameters ofparameters inter certain ofconsists extracting Quantitative image analysis (quantification) analysis image Quantitative One main source of image degradation is degradation source of image One main Image quality, quantification and and quantification quality, Image ., 2007), which can be grouped can which 2007), ., ------Among these approaches, these there that Among strategies are To solve group the dose burden of4D-CT, the the Monte-Carlo (MC) have simulations been always (i.e. worsening the signal-to-noise(i.e. the ratio). worsening To over For these cases, dedicated simulation software, spe software, simulation dedicated For cases, these Geant4, EGS, MCNP, FLUKA, and Penelope. and These MCNP, EGS, FLUKA, Geant4, increase of dose not justifiable for all the patients. all for ofincrease dosenot justifiable some cases, respiratory In same conditions. the in 9. Figure signal-to-noise shown in ratio, the as ing exter The algorithm. astandard with individually interaction of particles in matter, usually at the matter, in usually ofinteraction particles components. or their Simulations systems imaging image and the motion estimation of the 4D-PET. of the motion the estimation and image nal signal could be arespiratory could belt for respiratory signal nal distribution (image). motion of cor the distribution Regardless mentioned former Monte-Carlo the section, in as adetector, Additionally, etc. position within methods that jointly estimate motion and activity motion activity and estimate jointly that methods signal not do rely which onexternal any methods, to image the on motion effects the allows method simple This gating”). motion (or named “dual both, cardiac a for electrocardiography an or motion prohibitive in the case of complex imaging devices. devices. prohibitive of complex case the imaging in of the provide can packages simulations accurate employed currently in being are tracking particle physical phenomenon parameter, since or acertain of Dimitris Visvikis proposed to a method gener Visvikis of Dimitris optimise new techniques for data correction, image correction, forimage data new techniques optimise of tomography emission [Harrison 2012]. MC simu this is done by acquiring a 4D-CT that entails an an entails that a4D-CT done is by acquiring this acquired are PET mapthe images and CT the that later The approachimprov time. to same leads the non-gating sophisticated of development the to the effects of the underlying physical phenomenaunderlying the of effects the complex very is physics the experiments and real in 3.2.2 be reduced, but cost at of the increased noise levels rection method, accurate quantification requires quantification accurate rection method, response reconstruction. for model image interaction of the reconstruction reconstruction, ate dynamic CT images combining areference combining CT images CT ate dynamic other and motion separately image, and assess at data acquired the of all use make general, in and, are especially useful to examine the effect of a single of a effect single the to examine useful especially are have for advancement becomeand the essential also physics, particle nuclearand tool in a fundamental emission tomography. Especially relevant ones are are ones relevant tomography. Especially emission expense of large computing times, that might be might that times, computing of large expense lations are often used to optimise the design theof design novel used lations areoften to optimise simulations are also used to calculate the system system the to used calculate also are simulations come these limitations, much research dedicated is come limitations, these cannot be easily isolated. isolated. beeasily cannot Several multi-purpose packages for packages photon multi-purpose Several and Simulated data are also cardinal to test and cardinal also are data Simulated Simulations ------77 Nuclear Physics for Medicine – Chapter II – Medical Imaging 78 Nuclear Physics for Medicine – Chapter II – Medical Imaging EGS, PeneloPET,EGS, PET-SORTEO, or EIDOLON), whereas SiMIND was originally developed for originally was whereas SiMIND GAMOS being based on a GEANT4 framework. on based aGEANT4 being GAMOS Simulating unconventional imaging devices might might devices unconventional imaging Simulating SPECT. These dedicated packages are usually SPECT. usually are packages dedicated These Some packages arePET specific PET-(PETSIM, faster but less flexible than general-purpose than ones. butfaster less flexible ing the source code;however, the ing devices, for standard tomography, preferred. packages Several usually is they provide such features they of anumber interesting be difficult or impossible even withoutmodify be difficult as GATE, SimSET, GATE and GRAY, GATE, as or GAMOS, have been developed PET for SPECT, both and such cially conceived for photon-tracking in emission emission in photon-tracking conceived for cially - field field of research. ing time. When speed is the main issue, analytical analytical issue, main speed the is When time. ing native is the use of GPUs, which remains an active an ofnative GPUs, use remains the is which dependent phenomena. the desired performance. On the other hand, effort effort other hand, On the desired performance. the and comput trade-offaccuracy between a to find and phantom description, or modeling of time- phantomand or description, modeling complex source detectoras electronicsmodelling, has been put in to accelerating simulations by paral simulations beento put accelerating has in lelising the software or adapting it for distributed it for or adapting software the lelising simulation packages, such as ASIM, might provide might ASIM, as such packages, simulation computing environments. A very promising alter promising Avery environments. computing As for image reconstruction, one main issue is is issue one main reconstruction, for image As different gates of very low statistics. low very of gates different to correspond rows two The image. and motion of reconstruction through simultaneous performed is compensation Motion Right: applied. is correction gate-based A Middle: applied. correction no column: Left correction. its and motion of effect The 12. Figure reconstruction algorithms. (right) iterative and (left) analytical using reconstructed were data The scanner. aclinical from images 11. Reconstructed Figure the object. the of modifications via function cost this minimise to called is function optimisation an and built is criteria, regularisation as well as data and estimates between differences combine may which function, acost and data actual the to compared is estimate This object. the of parameterisation a given from scanner the in measured be should that data the estimate to employed is measurement, the of process, plus a statistical model physical the on information The reconstructions. iterative statistical- of Sketch 10. Figure - - - “charge integration” used cameras CCD CMOS and Thus, thecurrent advent Thus, of X-ray photon counting ventional “charge integration” CCD CMOS and (CT). novel This approach several advantages, brings Hybrid detectors pixel [Wermes 2005] form a Hybrid applied arrays pixel to X-ray might detection field in molecular imaging. in molecular field CERN and other nuclearphysics other and experiments. CERN Technical specification of some hybrid pixel detector circuits. detector pixel hybrid some of specification Technical 3. Table 3.3 3.3 in a photon counting mode that can replace can con that mode aphotonin counting in X-rayin computerised tomography (CT). Applied new generation of digital X-raynew generation of digital working cameras novel intrinsic anatomical and functional imaging imaging functional and novel anatomical intrinsic modality that will hopefully open a new door in the open the a new door in hopefully will that modality provide informa can physics spectral experiments, provide X-ray anew generation of digital photon tion on the X-rays transmitted through an object. object. an X-rays ontion the through transmitted developed for the originally was which through, of break detection toX-rays, the technological this through bump bonds ( bump bonds through 3.3.1 but it can also be from different materials of higher higher of materials be from different but also it can range and photon energy discrimination. discrimination. energy photon and range requirements quite successfully at the LHC at the requirements successfully quite hundreds nanometers thick with p with nanometers thick hundreds elised sensors and readout sensors and connectedelised electronics effective atomic numbers such as cadmium telluride telluride as cadmium effective atomic such numbers sor consists of n-type high resistivity silicon of afew silicon resistivity high sor of consists n-type dynamic absence noise, ahigh the of dark as such spectral CT spectral cameras used in X-ray in used cameras computerised tomography energy high of detectors vertex in used construction replace could conventional that cameras counting cameras enables developmentcameras the CT: of spectral a Pilatus II PIXIRAD XPAD3 Medipix3 (SPM) Medipix2 Eiger Hybrid comprise of association pix pixels the these Hybrid detectors pixel have fulfilled Photon counting with hybrid pixels hybrid with counting Photon Photon counting: towardsPhoton counting: of pixels Number (60 ×97) 5’820 (512 ×476) 243’712 (80 ×120) 9’600 (256 ×256) 65’536 (256 ×256) 65’536 (256 ×256) 65’536 Figure 13 Figure ). Usually, the sen the ). Usually, [µm Pixel size 172 × hexagonal 60 130 × 55 × 55 × 75 × + pixel implants, 2 ] [counts/pixel/s] Count rate 2 ×10 10 10 10 10 16 ×10 6 6 6 6 - - - - - 6 6 (CdTe), (CZT) or gallium telluride cadmium-zinc Figure 14 (see Figure e.g. ( with hybrid have detector pixel circuits with been built In X-rayIn CT, of X-ray amount the absorption that Schematic view of a hybrid pixel detector. pixel ahybrid of view Schematic 13. Figure for the detection offor detection X-rays the hybrid pixels using ing as acounter. as ing induces a useful contrast for imaging depends on depends contrast for imaging a useful induces in the pixel sensor are collected on the ASIC via via ASIC on the collected sensor are pixel the in oped, most of which so far have so far most one ofoped, which threshold, only threshold(s) act memory stored arethen a local in bond bump convertedan the connectionand after efficienciestion at X-ray energies up120 keV. to The 3.3.2 readout (ASIC), chip electronics pixelised is which able detection thresholds. Signals overcoming the Signals able thresholds. detection in currenteither a or a voltage stage amplification sensor, pitch the same at using as the designed is (GaAs),arsenide to provide photon better interac signal that is compared with one compared is or that several adjust with signal CMOS processes. standard spectral X-rayspectral imaging. sensors bonded bump of pixelised several modules Table 3 Table The charges generatedcharges The by photoninteraction X-ray of assembly one of an or consisting cameras Several ASIC designs have been devel designs ASIC already Several Spectral X-ray imaging X-ray Spectral ). [keV] Energy range 1 –100 5 –60 6 –30 5 –30 4 –30 3 –30 ) and have) and to pioneer been used [e persion (r.m.s.) Threshold dis- – 57 55 360 20 50 – ] 50 130 72 140 180 125 [e (r.m.s.) Noise – ] - - - - 79 Nuclear Physics for Medicine – Chapter II – Medical Imaging 80 Nuclear Physics for Medicine – Chapter II – Medical Imaging The increase The of contrast-to-noise ratio givenfor a E pixels of 130 of pixels to form a detector of 11 of adetector form to vertically tiled are chips seven of modules Eight modules. horizontal form to sensors silicon thick 500 µm to bonded bump ASIC, XPAD3-S of composed camera XPAD3 the of Picture 14. Figure K-edge imaging can be obtained by changing the the by changing beobtained can K-edge imaging atoms compose of the that energy K-shell binding (25.5 keV), (33 iodine keV), (50 keV) gadolinium with energy. Subtractive analysis of X-ray energy. Subtractivewith analysis absorp image weighting, either at the projection eitherat the or at the weighting, image nomenon referred is K-edge. the to as It then is detector pixels with only one energy threshold, one threshold, energy only with detector pixels pixel threshold around the K-shell binding energy energy K-shell the around binding threshold pixel possible atomic to sense the composition of mat of X-raysprobability phe sharply. increases This and/or appropriate bins energy by performing mal opti the by choosing be maximised can material several authorspast, have pointed out benefits the or gold (80 keV)these of identification the permit of X-ray computed in information tomog spectral tion abovetion below K-edge and the of values selected absorption sudden changes these ter by analysing traversedthe matter, photoelectric absorption the X-raythe element. of energy, specific each is which attenuation ofcoefficient the dependency on to the X-rays of the atomic energy and the density the and reconstruction image level. image reconstruction raphy. or more two detectors, with resolving Energy energy bins, permit material decomposition thanks decomposition material permit bins, thanks energy composition the penetrate. In they of matter the contrast agents in a CT image. aCT contrast in agents (17 yttrium contrast as such agents keV), silver K of the selected contrast agent. In the case of case the selected ofcontrast In agent. the Moreover, of X-rays energy when the reaches the Indeed, after energy calibration of the pixel, of calibration energy after Indeed, × 130 µm 2 . × 8 cm 2 composed of more than 500,000 500,000 than more of composed - - - - - X-ray photons or within above threshold, energy an 16 Figure example, an As 50 kV, 600 µA X-ray50 kV, generated was by a spectrum 600 µA 360 projections were the of360 5 s reconstructed with with with while it reveals clearly the mouse kidneys and ureters. and mouse kidneys it the reveals clearly while In a photon counting camera, every pixel can select select can pixel every a photon camera, In counting FDK algorithm. K-edge imaging of the mouse ofsup the K-edge imaging algorithm. FDK Principle of K-edge imaging of iodine ( iodine of imaging K-edge of Figure 15. Principle CMOS detectors, because it necessitates settling CMOS detectors, because it necessitates settling images are acquired with three different thresh different three with acquired are images pressed bone structures that do not uptake iodine, do not that uptakepressed iodine, bone structures filtered by tube anode copper;molybdenum 100 µm olds: olds: quite a large amount of functions in a small surface surface asmall in of functions amount a large quite without photon count every and individually olds, the of chips) with as hybrid well as detectors, pixel to the increase in absorption associated to in increase its K-shellto the that has to be smaller or equal to the pixel sensor pixel to the or equal to be has smaller that (MIP)tions K-edge and absorption CT of standard silver,with copper pipes rubber filled twisted three 3.3.3 3.3.3 be quantified, more energy bins must be taken into taken be more must bins energy be quantified, ( energy binding reconstructed within energy windows ( windows energy within reconstructed and iodine solutions. iodine and and ( and achieved using conventionalachieved using ‘charge integration’ be cannot feature this noise. Indeed, dark adding of aphantom silver of made K-edgeand imaging energy windows when pixels have when pixels windows severalenergy thresh larger size XPAD3 camera ( XPAD3 size larger surface. This makes a makes ASIChybriddetector This pixel surface. Iomeron®. 200 µL of with amouseinjected A scans of detector amouse without translation. scanning or a chip pair a single using built (typically size small consideration. contrast agent. If more than two materials have materials to two morecontrast If agent. than K-edge imaging has been demonstrated using been demonstrated has using K-edge imaging Figure 17 Figure DE E Prospects E 1 1 = ( – 1 and DE and E E 2 ) permit discrimination of the selected of the discrimination ) permit K presents maximum intensity projec intensity presents maximum –DE Figure 15 Figure 3 equivalent to afew keV. Thanks 1 ), ), E 2 = shows the result of iodine showsof result iodine the ), subtraction of images of), subtraction images E Figure 14 K and E and 3 E ) that permits permits ) that = ( K = 33 keV). E K E + 2 –E DE 3 3 ) ) - - - - various applications. various K-edges using X-rayK-edges using detectors to photon counting which makes it makes possible forwhich CT to develop spectral within the energy range of soft range energy the X-rays ( within I (33 keV) are shown in (c) and (d), respectively. (d), (c) and in shown are I (33 keV) and (25.5 keV) Ag of values K-edge the below and above absorption X-ray of analysis subtractive after obtained data of rendering volume 3D algorithm. FDK the using reconstructed and 25.5 keV of athreshold with acquired are (b) and (a) in presented Data solutions. I and Cu Ag, with filled pipes rubber twisted three of made phantom a of (b) rendering volume 3D and (a) slice Transverse 16. Figure CT, or gold nano-particles, which all have K-edges all CT, which or gold nano-particles, iodine is thus possible by thus subtractive is processing iodine inflammation would would representinvaluablean tool inflammation dinally both the tumour vascularisation and the the and vascularisation tumour the both dinally longitu able to image vivo. Being in dynamically possible whose relative therapeutic targets contri modelled, and understood correctly performance ment. Vascularisation and inflammation are twoare inflammation and ment. Vascularisation of tumour vascularisation and inflammation can be be can inflammation and vascularisation of tumour several mil acomplexquite with integrated circuit of gold nano-particles can be used to study arte to study beused can of gold nano-particles the technology of hybrid pixel detectors with sili of hybrid detectors pixel with technology the tively). K-edge imaging of gadolinium, gold and tively). of gadolinium, K-edge imaging and (MRI) resonance forused imaging magnetic Markers growth. tumour on effects their to assess butions to tumour growth have growth to becharacterised butions to tumour rial inflammation and theprovide information on inflammation rial analysis of X-rayanalysis absorption above below and their respec gold, and 80 keVand gadolinium for iodine, no treat currently with tumours aggressive brain example, it has been demonstrated that imaging itexample, been demonstrated has imaging that labelled with gadolinium and iodine contrast agents contrast agents iodine and gadolinium with labelled difficulty, elements. Despite of this transistor lions select detected X-raysselect another As energies. by their are CT, which spectral consider let us glioblastomas, composition of atherosclerotic plaque. atherosclerotic of composition con sensors now is mastered their and rather well As an example of a prospective an As application of E K = 33, 50 ------MIP of K-edge images. K-edge of MIP (bottom) images. CT absorption 17. standard of MIP (top) Figure 35 keV of a few percent, only is whereas silicon in Furthermore, CdTeFurthermore, and brittle wafers quite are CdTe hybrid of is utmost cameras pixel or GaAs iodine K-edgeiodine ( above K-edge the to address imaging importance not directly transferable to human clinics. transferable to human not directly different dilatation coefficients the of dilatation different sensor CdTe do not permit hybridisation of large modules. do not modules. of hybridisation permit large more than 80% of X-rays 80% tel more than cadmium interact in the methodology developed on preclinical models, models, developed methodology on the preclinical of CdTe diameters waferstively small or GaAs and the Si integrated circuit. However, Si integrated the circuit. and given the even using small size detectors, would be easily if if be easily would detectors, size small even using new technology, by targeted this is that range energy luride above this energy. Thus thedevelopment energy. above Thus luride this of can barely sustain mechanical stress, e.g. due to e.g. stress, mechanical sustain barely can Nevertheless, X-rayNevertheless, above absorption efficiency E K = 33 keV). present, At rela the - - 81 Nuclear Physics for Medicine – Chapter II – Medical Imaging 82 Nuclear Physics for Medicine – Chapter II – Medical Imaging X-ray, contribute formation to the more of the it will detected of the X-ray energy the higher the cameras, To PET of isotopes potential awhole class has date, which will be nano-particles labelled with metallic metallic with labelled be nano-particles will which of and/or identification discrimination permit will CT. rejection the of lowX-rays Furthermore, energy 3.4 increase of fromincrease Compton background scattering dose extra The nucleus. resulting daughter the in 2011]. al., et vivo [Jorgensen in information of functional amount alarge providing thus image, from predominantly results which contrast, image or grey-scale white” CT and positivelyimpact “black delivered to the patient, as well as the expected the as delivered well patient,to as the multiple contrast agents simultaneously, some contrastsimultaneously, multiple agents of integration charge with than CT photon counting or even pair creation,or even prevented has pair of iso use the those where, in addition to the two back-to-back two to the addition where,those in aparadigm bring detectedX-raysthe will that to improve signal-to-noise ratio. image photon of Poissonthe to Hence, the count. statistics photon whereas with counting detected signal, the integration’ ‘charge with Indeed, ratios. to-noise the detection of detection soft the with X-rays, to be better tends been excluded from medical application. These are application. These been excluded from medical by detectors photon suppresses counting X-rays that are scattered with large angles and thus also tends tends also thus and angles large scatteredare with signal- contrast by and improving image accuracy and locate those within the anatomic grey-scale CT grey-scale anatomic the CT locate within and those higher-energy higher-energy emitted 511emitted keV elements identified from by their K-edge signature, from elementstheir identified by signature, K-edge shift from “black and white” to CT.“black “colour” from This shift cameras, every detected photon detected every contributes evenly cameras, counting detectors to get spectral information on information detectors to get spectral counting β + coincidences: γ γ coincidences: More importantly, it is the ability of photonMore ability it the is importantly, In summary, photon counting will potentially potentially will photon counting summary, In Nuclear medical imaging using using imaging medical Nuclear g ray excited from an emitted is state b + annihilation photons, a third third a photons, annihilation -PET - (LXe), acting simultaneously as scatter, as absorption simultaneously (LXe), acting with a ring of PET detectors (similar to the con of to PET the detectors aring (similar with of responsethe line (LOR) the by defined as with with a Compton camera based on a cryogenic time aCompton time with on camera based acryogenic However, of custom provided there availability is Figure 19 Figure Determining the intersection of this Compton intersection of the cone this Determining kinematics of an incident of photon an detec a suitable kinematics in imaging properties of aCompton where camera, the imaging apparent disadvantage this cameras, ised gamma detectors serve as a Compton scattering unit, while while unit, aComptondetectors as serve scattering photon. A small LXe-TPC yielded has photon. prototype Asmall materials like BGO or LSO, or from or novel BGO LSO, like scintil materials [Oger results promising al et asensitive reconstruc allows positron annihilation on on projection chamber (TPC) filled with liquid xenon with projection (TPC) filled chamber the realisation of a medical imaging system based based system imaging of amedical realisation the topes as such utilises solid-state detectors to Comptonset up the utilises decay oftion the position PET of the isotope. of acone surface (seeto the 18 Figures 19 and one event source restrictedthe position, within of a photon scattering with (i.e.tion system inelastic registration of the Compton scatter and absorption absorption and scatter Compton the of registration examinations. PET in distribution radioactivity realising ‘3 a higher sensitivity for the reconstruction of the reconstruction for the sensitivity a higher approach laboratories several European pursued in 3 foradditional the medium scintillation and a (quasi-free) electron) exploited is to reconstruct energy absorber. be combinedenergy could modules Such lators like LaBr like lators several Compton (as camera modules shown in (either from well-established crystals scintillation could be turned into a promising benefit, offering benefit, offering into a promising be turned could Figure 18 Figure in cept illustrated Here, double-sidedcamera system. strip silicon A second, more conventional, experimental experimental more conventional, second, A In 2004, a project was started in France, aimed at France, in aimed a project started was 2004, In Presently two approachesPresently two pursuedtowards are b + - g coincidences. Both of ondraw the them coincidences. Both ) could be arranged to detect either the to either the detect be arranged ) could g imaging’ by combining a PET scanner aPET scanner by combining imaging’ 44(m) 3 Figure 19 , see Figure Sc, Sc, 86 Y, Y, 94 Tc, Tc, et al et [Oger (from xenon liquid with filled chamber time-projection acryogenic by formed camera aCompton in additional photon is detected the approach this In nucleus. daughter isotope PET excited the from emitted photon third aprompt and photons two positron annihilation from (LOR) line-of-response a of detection the on based ‘3 the of Schematic drawing 18. Figure ); of aset alternatively ., 2012]. ., 94m ) act as the photon the as ) act Tc, Tc, imaging’ principle principle γ imaging’ 52 Mn, or Mn, ., 2012]). 34m Cl. Cl. rd ). ). - - - - -

Europe, the topic the Europe, PET of ‘unconventional’ isotopes 14,15 where already afew tensofwhere intersec reconstructed already LORs would be needed to be reconstructed. Beyond beneeded would to bereconstructed. LORs b b in coincidence. in in the treatment the delayedin of emission photons from however, US; the for example in studied, is so far ity contained in a voxel size of 2x2x2 mm avoxel in contained ofity size 2x2x2 no dedicated project to develop a ‘ during hadrontherapy treatment promptduring photons may open up the possibility to exploit awhole class may open possibility up the et al et opportunity for building a ‘hybrid detector’, a‘hybrid where for building opportunity sensitive highly a of new PET isotopes,offering the 3 the towards direction the LOR and the between tions be illustrated by the setup shown in shown in setup by the be illustrated and highly resolving localisation of the photon of the localisation resolving highly and apeutic proton or ion beam with the tissue, while while apeutic proton tissue, the or ion with beam system has been reported. has system of g sensitivity high source position. The could be detected fromcould nuclear reactions ther of the conventional PET-based a few thousand analysis, + + annihilation photons or the additional g additional the or photons annihilation (+ The concept of b O) bedetected. could Finally, this technique would also provide also the would technique this Finally, ., 2014]. ., g rd ) decay of online produced) decayb of online photon are sufficient to localise activ the photonlocalise to sufficient are

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g the same with a with same the + -PET’ detection -PET’ detection emitters ( emitters Figure 19 Figure -PET can can -PET photon photon g 3 [Lang [Lang -PET’) -PET’) 10,11 C, C, - - - , LOR from b from LOR the define to modules camera Compton three of Figure 19. of the 3 the of coincidence with the detection scintillator as absorber. a scatterer and aLaBr and a scatterer (DSSSD) detector strip silicon consists of a double-sided rd photon. Each module module Each photon. Arrangement Arrangement + annihilation in 3

83 Nuclear Physics for Medicine – Chapter II – Medical Imaging 84 Nuclear Physics for Medicine – Chapter II – Medical Imaging The main physical advantage charged of hadrons The main 4.1 4.1 l l l (i.e. protons ions) or therapy light radiation is in Hadrontherapy) placed at agiven depending depth Uncertainty in range [Paganetti 2012]. [Paganetti range in Uncertainty 4. Table 4. 4. in the path of the beam. However, in clinical prac However, beam. of the path the clinical in in Interfaces position of the beam range is not known with the the with not is range known position beam of the on the energy at the entrance and the interactions interactions the entranceand at the energy on the tice significant uncertainties remain and the exact theexact and remain uncertainties significant tice based on their finite range in tissue, with no or only with no or only tissue, in range finite based on their range uncertainties in the order the in of several milli uncertainties range to contributing factors Main precision. required a minor exit dose after a Bragg peak peak Bragg a Chapter(see dose after exit a minor 1, Total Total (excluding*) inhomogeneities* Range degradation;locallateral inhomogeneities Range degradation;complex in tissue Mean excitationenergies (I-values) CT gridsize I-values) CT conversiontotissue(excluding CT imagingandcalibration Biology (alwayspositive) Dose calculation: Patient setup Beam reproducibility Compensator design for commissioning Measurement uncertaintyinwater Independent ofdosecalculation: patient the in Source of range uncertainty Quality control in hadrontherapy control Quality 4.6% +1.2mm 2.7% +1.2mm ± 2.5% - 0.7% ± 1.5% ± 0.3% ± 0.5% ± 0.5% + 0.8% ± 0.7mm ± 0.2mm ± 0.2mm ± 0.3mm uncertainty Range

- - verification during or shortly after irradiation, and irradiation, after shortly or during verification representwould vivo verification an methods opti Positron tomography emission (PET) currently is in operation ( operation in different in be classified can uncertainties range ing investigation. Another promising imaging tool in tool in imaging promising Another investigation. therapy benefit its potential has fortumour ion tissue in of order particles range in the to measure framework the of European adedicated within ing includ investigated, ion therapy being beam are during or in between fractions. 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While pre-treatment dosi pre-treatment While ). Table 4 Table , in addition to addition , in ------tis theelectrons of with positrons annihilate These 4.1.1 with an energy of 511 energy an with keV emission an and each Particles impinging on tissue induce, among oth among induce, on tissue impinging Particles Table 5. different physical processes. different distribution has to be performed has of basis on the distribution measured events results in a3D b in eventsmeasured results of a PET scanner, these annihilation photons can of aPET annihilation scanner,these their respective half-life, and positrons are released. positrons and released. are respective half-life, their positron These tissue. atoms irradiated the of the bution. of the coincidence. Reconstruction be detected in of Therefore,butions. nuclear extensive modeling angle of approximately 180°angle ( necessary. is interactions electromagnetic and emitters undergo radioactive decay according to decay radioactive according undergo emitters positroners, due to nuclearreactions emitters with since ß since photons annihilation of emission two sue under compared directly to the applied dose distribution, applied to the dose distribution, compared directly in particle therapy particle in methods of Family Anatomy Anatomy Physical Virtual The measured activity distribution cannot be cannot distribution activity The measured Thus, a simulation of the β expected of a simulation Thus, Positron emission tomography tomography emission Positron Methods for beam range verification. range beam for Methods + -activity and dose originate from completely doseoriginate and -activity Name treatment treatment Imaging post target the after detector Implanted tumour or path in detector Implanted CT” ion “3D and radiography” probe”, “2D “1D range verification vivo in offline Online- verification vivo in Online upstream treatment, during or Pre line off treatment Pre- Calculation Method imaging resonance Magnetic energy higher with or distal range the on signal Measure detector implanted an from pattern Measure time energy or residual range Measure detection PET imaging secondary Prompt verifier range electronic Integrated Dosimetry calculations Cross Figure 20 Figure + -activity distri -activity Short description Short tissue ofVisualisation variations in images of irradiated irradiation short a for energy ahigher use or off, fall the at dose alow measure mold), adental in balloon, rectum (e.g.a in target the after just adetector Implant range residual the to calculate used be can modulator the with synchronised a detector of signal time the beams, passive modulated For ranges finite with calculations perform/validate ration power stopping of images to reconstruct and/or power stopping integrated the to validate body the traversing after range residual of Measure to it close or room treatment the in imaging PET using beam the of interactions (C, O,…) by nuclear activation tissue of Detection treatment during emitted neutrons?) particles, charged gamma, (prompt secondaries prompt of Detection yet) existing (not detector “transparent” // depths equivalent water different at arranged beam, the of border the around Measurement dosimetric systems with characterisation Dosimetric different analytical) vs Carlo (e.g. Monte models and CT) energy (e.g. dual data image different of Use ). By means ). By means + -activity -activity - - e photons with an energy of 511 of emitted. are energy keV an each with photons nuclei may e.g. lose a neutron, resulting in the positron emitters emitters positron the in resulting aneutron, lose e.g. may nuclei a for therapy particle in imaging PET of Principle 20. Figure and and (projectile) colliding with an an with colliding (projectile) netic slowing down and the nuclear interactions ofnuclear interactions the and down netic slowing model all physical processes electromag from the all model the impinging ions and further secondary parti secondary ions further and impinging the to has The simulation distribution. measured the time course of the irradiation and imaging. This This imaging. and irradiation of course the time consideration under treatmentthe of plan, the cles with the atoms of the tissue, the induction of induction the atoms the of tissue, the cles with calculated + , which annihilates with an electron e electron an with annihilates , which 15 O, respectively. They disintegrate under emission of a positron apositron of emission under disintegrate They O, respectively. b + -activity can be then compared be then can with -activity 16 O atom of the irradiated tissue. Both Both tissue. irradiated the of O atom [mm] accur 2- 3 1 2 1 1-3 ? 2 1 2 -4 - of the tissue. Annihilation Comm post treatment post additional dose or area critical in implant need implantneed calculations to feedback interactions nuclear vivo, in interactions nuclear vivo, in border beam in measurements upstream media homogeneous in measurement uncertainty of estimation 12 C ion C ion 11 C - - 85 Nuclear Physics for Medicine – Chapter II – Medical Imaging 86 Nuclear Physics for Medicine – Chapter II – Medical Imaging Tatsuno, Japan. An example of clinical application Tatsuno, example of clinical An Japan. PET scanner is located in the treatment the located is roomPET in scanner and operated was use from 1997 clinical in PET scanner PET scanner directly integrated into the treat integrated intothe directly PET scanner corresponding PET MC prediction (middle). The arrow marks an example of good range agreement (adapted from [Bauer 2013] with permission). permission). 2013] with [Bauer from (adapted agreement range good of example an marks arrow The (middle). the to prediction MC PET HIT, at comparison in (left) corresponding dose treatment ion carbon planned the of delivery after measured (right) activation 21. PET Figure Chiba, Japan. Chiba, Shakirin 2011. in-beamfirst is PET, Shakirin The which Figure 21 Figure shownis in investigated, which are described in detail in detail in described are which investigated, imaging of the β of the imaging in-beam first treatmentintegrated intothe site. The requires PET a dedicated and scanner irradiation diagnostic devices, typically combined with CT CT combined with typically devices, diagnostic butconventional required, is PET scanner dedicated ple, at HIT, Germany, Heidelberg, HIBMC, and for at example, HIMAC, installed; are purposes for PET research of in-beam scanners prototypes Japan, Kashiwa, located is atment NCCHE, gantry reaction processes, for example double differential β the emitters, positron offline implementation is in clinical use, for exam use, for clinical implementation in is offline of β of utes, depending on the location of the scanner. This location This on scanner. of the the depending utes, measurement tothe aPET and system transported Germany. Another Darmstadt, at GSI, to 2008 processes these require All detection. until tissue of positrons oftion thermalisation positrons, the tigated at MGH,tigated USA. Boston, allows the measurement the of β allows attenuation of the annihilation photons the in annihilation attenuation of the and transport the electrons, with annihilation and after irradiation. An in-roominvesAn is - scanner PET irradiation. after small Furthermore, available. commercially is and extensive knowledge of electromagnetic and nuclear nuclear and ofextensive electromagnetic knowledge scanners, can be used. After treatmentthe patient is After beused. can scanners, cross sections. The third modality is off-line PET, where modality third The no in-roomis PET.The second modality theHere Although already implemented in clinics, PET implemented clinics, already in Although For PET imaging three implementations three For are PET imaging + activity starts with time delays of delays several min time with starts activity + -distribution takes place shortly place shortly takes -distribution . + disintegration and forma and disintegration + -activity during during -activity - - - - variety of prompt gamma emission occurs. These These of prompt occurs. emission variety gamma 4.1.2 (TOF) information for PET monitoring in order to to order in PET monitoring for (TOF) information During tumour irradiation with particles a large alarge particles with irradiation tumour During from other secondary particles, e.g. neutrons, light neutrons, light e.g. particles, from othersecondary ing targets, application of PET targets, for other various ing are investigations improve Further quality. image detector developments future a research and field in therapy requires more particle technological in is a Compton camera, which uses two or more two aComptonis uses which camera, independent treatment from entirely the device ing requires synchro 3D information systems, imaging multi with acollimator camera with amulti-slit is front ahole in of or a aslit with acollimator i.e. of afew MeV. range energy an in However, besides photon energy therapy. unconventionalin high evaluation therapy, for automatic interesting ions no mechanical collimator is necessary. is collimator no mechanical device beam-positioning upstream an with nisation dealing with improvements with of knowledge on the dealing ple slits in front of in detector. of ple the slits For kinds those position-sensitive detector. Amore advanced system ( photons prompt rays excited from the gamma addi nuclei, in prompt from rays nuclearde-excitation arise gamma of several groups is the use of ultra-fast time of flight ofof flight several groupsof time ultra-fast use the is of PET measurements, as well as application as of of PET PET well as measurements, ties are being investigated to shield the background background investigated the to shield being are ties of arises background amount asubstantial tion reaction cross sections, feasibility of PET forreaction mov cross feasibility sections, and methodological developments. Amajor methodological issue and and selectively acquire information from information prompt selectively acquire and energy- and energy-position-sensitive and thus, detectors and, such as ahodoscope. as such charged fragments as well as Compton as scattered well as fragments charged gamma emission. gamma Another possibility of prompt ray possibility imag gamma Another camera, gamma approachA first is a collimated Prompt gamma ray imaging ray gamma Prompt Figure 22 Figure ). Thus, several imaging modali imaging several ). Thus, ------4.1.4 4.1.3 Ion measurement radiography of enables direct the During irradiation with primary ions heavier than primary with irradiation During prompt gamma radiation. of emission under de-excites and excited is nucleus target The collision of a of collision the for shown imaging vertex interaction of Principle 23. Figure an with colliding ion aprojectile of example the using imaging gamma prompt of Principle 22. Figure proton, which leaves the irradiated tissue and is used for imaging. for used is and tissue irradiated the leaves which proton, fragments have to leavefragments energy enough patient the irradiated tissue ( tissue irradiated nuclei of incident the ions of with the collisions in respect. this in performed. ments on homogeneous have targets been recently produced are fragments projectile protons, lighter tion between photons between tion becomes hadrons and possible It supposed is investigation. discrimina that under the residual range of high-energy low-intensity ions of high-energy range residual the study simulation afeasibility imaging, vertex tion ions can of impinging range the distributions, tex pointof of ion–the a Bymeans nucleus interaction. ion gives path impinging the with intersection the and particles charged emerging of the trajectory be critical can of beam the microstructure time the be verified. For this method, also known as interacas known also method, this Forbe verified. although information, of flight time the by using rejection by means of a TOF gamma camera is also rejection ofcameraalso by is aTOF means gamma and can be easily detected. A reconstruction of the of the Areconstruction detected. beeasily can and has been reported and the first promising measure promising first been reported the has and comparison between simulated and measured ver measured and simulated comparison between Improving detection efficiency and background and background efficiency detection Improving Ion radiography and tomography and radiography Ion Charged particle imaging particle Charged 12 C ion with a target nucleus. The projectile ion loses a loses ion projectile The nucleus. atarget with C ion Figure 23 Figure 16 O atom of the irradiated tissue. tissue. irradiated the of O atom ). Some of these light ). Some light of these - - - - X-ray resolution Spatial method of the images. CT 4.2 Mass spectrometry is a technique that was devel was that atechnique is spectrometry Mass New prototypes are currently under development under New arecurrently prototypes where analytical aspects dominate, there alot are of dominate, aspects where analytical CT, which currently introduces the larger source of larger the introduces CT, currently which for heavier ions. However, anticipated is to 1mm is limited by multiple Coulomb scattering in the the in by scattering multiple Coulomb limited is range the eliminating again treatment planning, in ofpatient the place atimages of the treatment. In introduce the reader to modern mass spectrometric readerspectrometric the mass tointroduce modern to section of this applications.goal situ It the is in and science biology,space geology, chemistry, ing development nuclear in further and use its wide toit a keyexplore method was suba atomic and ning range calibration curve deduced X-ray from the curve calibration range ning now called nuclear and particle physics. At that time physics. time that At particle and nuclear now called discovered and analysed in great detail, and besides and great detail, in discovered analysed and to what foundation is the laid which discoveries, patient, which is more pronounced for protons than than protons for more pronounced is which patient, ener at higher obtained power images ratio, these measurement of adirect providing images, metric many others[Mün13].many sciences, natural these Besides its application found as spectrometry physics, mass of isotopes was made: that the chemical elements of chemical isotopes the made: that was oped It years ago. hundred led more to epochal than on health and medicine, with some emphasis with on medicine, and on health uncertainties connected to the usage of calibrated of calibrated connected usage to the uncertainties dependence weak energy to of stopping the the ionthe stopping power ratio relative to water. Due ofterms pre-treatment the can method verification, traversing patient. It the may replace X-ray radiog tissue imaging. tissue sample preparation presenttechniques, and mass include tative quantitative requirements. and These blocks of were matter more many building time that 1913 in and discovery tomic particles, seminal the both for protonsboth ion carbon beams. and protons. evenbe achievable, more for the scattering vivo treatment the in plan to validate used be also range uncertainties due to different duephysical to different pro uncertainties range raphy resolution to density produce low high dose, applications, where mass spectrometry fulfills quali fulfills whereapplications, spectrometry mass includscience,of fields many tool in analytical an have number. mass Since of different constituents environment, climate research, health, nutrition, research, health, environment, climate enable volu can of imaging extension radiographic spectrometry applications for medical analyses and and analyses medical for applications spectrometry security and many others. Here, others. many and we concentratesecurity cesses ofcesses ion photon and Tomographic interaction. gies than for therapy can be used as a patient as formodel beused therapy can than gies Mass spectrometry spectrometry Mass ------87 Nuclear Physics for Medicine – Chapter II – Medical Imaging 88 Nuclear Physics for Medicine – Chapter II – Medical Imaging Mass spectrometry (MS) separates and analyses the the (MS) spectrometry analyses separates and Mass (which is the ability to measure the true mass value value mass true to the measure (which ability the is field magnets, quadrupole mass spectrometers, mass ion quadrupole field magnets, magnetic fields; this ensures that the spatial or time-wise separation of different species depends only on their mass-to-charge ratio. mass-to-charge their on only depends species different of separation time-wise or spatial the that and/or ensures this electric of fields; forces the by magnetic governed is and molecules or atoms gas with collisions from suffer not does vacuum motion The ion detector. the and that ensures analyser system mass source, ion spectrometer: mass every in present components the of view Schematic 24. Figure few 10,000 [which is typical for fragments of for com fragments few 10,000[which typical is its original form or to ionised molecules atoms, its original important ones being ones being important The time. separationin separationand ions: spatial [hydrogen is the lightest chemical element] chemical [hydrogen lightest the is to a plex biomolecules like proteins]),plex biomolecules like resolving mass ratio) mass-to-charge data detectors (including and to their according or spatially ionsperses the timely spectrometers, mass elements, common to all main of a certain species; inaccuracies should not should species; exceed inaccuracies of acertain operation from ~1,000 accuracy to and 1,000,000), according sorted sample, of constituents the of the the the of sample material), amounts to investigate small ppmthe level). properties other these, Besides for ranges routine and be high number should this may heaviest to that beana the mass lightest the (TOF) time-of-flight traps and systems. ratio. Today mass-to-charge increasing to an there mass yield systems).tative all devices Such analysis building blocks and the chemical composition chemical of the blocks and building ratio. Two the to disperse concepts principal exist and a large variety of combinations of these exist, of combinations exist, of these variety alarge and of ion-source analyser, mass and types many are quanti and display graphical storage, acquisition, depictedare in ( to its mass-to-charge according a substance all specialised for certain applications. The most for certain specialised all power like the sensitivity the like from one unit ranges mass this typically lysed, sample under investigation is transformed from transformed is investigation sample under spectra, which represent the intensity distribution represent which distribution spectra, intensity the clusters), (the dis element, analyser which central commonly used mass analysers comprise sector analysers mass used commonly characterised by several parameters. The The most by several parameters. characterised Mass Mass spectrometry The performance of a mass spectrometer of amass performance isThe dynamic range (the ability to distinguish adjacent masses; to distinguish (the ability Figure 24 of an instrument (the ability (the ability instrument of an (the ability to measure very to very measure (the ability mass range mass : ion source (where the (the from range m/z ) - - - -

Most specific for a certain areapplication sample Most for specific a certain certain MS/MS sequencing, With technique. MS (e.g. laser light, which is used in laser ablation ion laser in used is which (e.g. light, laser works reliably for previously unknown analytes, analytes, works for reliably previously unknown former samples the mass range stepwise with the the with stepwise former range mass samples the its surface (atoms,its surface ions molecules), and can which necessity of multiple scans to cover ofnecessity scans multiple whole the mass niques exist, tailored for the specific physical and physical forspecific the tailored niques exist, preparation, ionisation and inlet techniques. Here, techniques. preparation, inlet ionisation and this information; structural obtain position and com deduce one the ofcan fragment, each masses in step, while afirst beselected in can molecules or by (e.g. desorption by microscopic of droplets a is these techniques all of The goal analysis. of the or or tions. Measurement duration as well as repetition as well Measurement as tions. duration to dissolve the sample by the impact of sample impact photons by the the to dissolve bility of tandem-based analyses, the so-called MS/ so-called the of tandem-based analyses, bility be analysed by the mass spectrometer. mass by such the When be analysed by this two-step analysis. two-step by this rare and very abundant species simultaneously) abundant very rare and rate are further critical properties for some critical appli rate further are covers latter the range mass entire the while range, a focused ionising source is rastered in small steps source rastered is small ionising in a focused at once) determine the potential for certain applica at once) for certain potential the determine are used in secondary ion spectrometry, mass SIMS) secondary in are used of conceptsand tech variety infinite almost an the and fragmented a second is molecule step the especially when they are large and/or large are when they complex. The especially laterally across a sample and for every pixel a mass across amass forpixel asample and every laterally spectrum is recorded, an “image” can berecorded can recorded, “image” is an spectrum solvent) it that releases such microscopic from debris sources)which ions, (e.g. or energetic swift particles of complex bederived biomolecules can structure applications cations. chemical properties of the sample and the purpose purpose properties the sample of and the chemical component the pieces by assembling detected; Present techniques for medical and imaging imaging and medical for techniques Present scanning or non-scanning operation non-scanning or scanning Some modern instruments provide capa the Some instruments modern (the (the - - - - - vessel; they are connected by an atmospheric connected are by an vessel; pres they - (enrichment) before analysis. (for comparison: the typical diameter of amam diameter (for typical comparison: the DESI generates ions by a thin jet of electrostatically jet of generates electrostatically DESI ions by athin ionisation (MALDI, left) and desorption electrospray ionisation (DESI, right). For details see text. see details For right). (DESI, ionisation electrospray desorption and left) (MALDI, ionisation Figure 25. ionisation of the substance from the surface, while while surface, from the substance ionisation of the of advantage takes MALDI (DESI). ionisation electrospray desorption and (MALDI) ionisation that mechanisms transport introduced by various described here. They all have specific strengths and havestrengths all here. described specific They depending on the sample, environment on the pur and depending pose. Common to all is the generation the is of charged Common to all pose. matrix/ acidic on an impinging light laser pulsed desorption matrix-assisted laser spectrometry: mass Figure 25 information. prevented original to obtain be must or contamination degradation migration, of how the constituents are distributed and struc and of how distributed are constituents the original spatial composition and the integrity of composition spatial integrity the and original the sample needs to be preserved, and analyte sample analyte the needsto be preserved, and the necessity for necessity pre-concentrationthe of samples to remove of but interest, material also towards the spectrometer operates mass the a itself vacuum in substances Biological obtained. is information tural tissue. tissue. spectrometer by its mass towards collected the and analyser. analyser. techniques Both atmospheric system. pressure inlet to improve used selectivity simultaneously are the are often processed ambientwhile pressure, atair eral resolutioneral order of the of 10 to 50 micrometres sample fragments that can be analysed by the mass mass by the beanalysed can that sample fragments field acceleratedsample are debris electric by an desorbed charged the and cases, both In surface. and desorption extraction, for solvent combination imaging in used shows concepts widely are two that are (API) sample interface fragments the sure and characteristic applicability to individual problems, to individual applicability characteristic or animal human any beapplied tocan basically obliquelysample on the solvent,charged impinging Many other methods exist, which cannot be cannot which exist, methods other Many In imaging mass spectrometry (IMS), the spectrometry mass imaging In Present commercial IMS instruments reach a lat Present instruments commercial IMS Desorption and ionisation techniques that are widely used in analytical mass spectrometry: matrix-assisted laser desorption desorption laser matrix-assisted spectrometry: mass analytical in used widely are that techniques ionisation and Desorption - - - -

The overall area that can be sampled is in principle besampled is thatarea can The overall 3D-IMS. A stack of IMS images from the analysis of analysis from the images Astackof IMS 3D-IMS. MS range from new diagnostics, understanding of understanding from new range diagnostics, MS Examples are given in the following. the given are Examples in while research laboratories havewhile reported sub-cel with three-dimensional imaging mass spectrometry, mass imaging three-dimensional with Imaging mass spectrometry, where high spatial spatial spectrometry, where mass high Imaging Since the measurements performed are the Since on biological for each pixel, e.g. on proteins, peptides, lipids, etc. etc. lipids, on peptides, proteins, e.g. for pixel, each illness and its genesis and to therapeutic developments. illness wideof applications range emerges due infinitely biopsies. tumour small including dle the complex mass spectra. Medical benefits of Medical complex the spectra. mass dle malian cell is of the order of is the of 5to cell 20 micrometres), malian matrices, they require sensitive, high resolving mass mass resolving require sensitive, high they matrices, substances. biological other many and metabolites neuropeptides drug and drugs, lipids, peptides, of tissues, provides foranalysis features the unique label-freeis and The method ments ionised. and to microscopic frag be“dissolved” can material overall available measurement time, so that typical typical so that measurement available overall time, to record the of instrument and spectra the mass unlimited, but in practice depends on the speed on practice the but depends in unlimited, information characteristic yield spectra mass the source rasters across sample and ionising the the to the fact that basically every organic or inorganic or inorganic organic every basically that fact to the almost An sections. tissue in oftribution analytes provide can objects of three-dimensional slices thin resolution spectrometric mass combined is with analysis of the sample material, is a versatile and and aversatile is sample of material, the analysis areas of the order of a few square-millimetres or oforderareas the of a few square-millimetres - dis spatial the to analyse method universal almost comprehensive and organ, of an e.g. a detailed ‘view’ especially when combined with classical histological histological classical when combined with especially lular resolutions to down ~1 micrometre.lular Typically, spectrometers with high dynamic range able range to han dynamic high spectrometers with It providesinformation on proteins, specific stains. and imaging centimetres can be analysed. Large potential arises arises potential Large beanalysed. can centimetres Medical applications of mass spectrometry spectrometry mass of applications Medical - - - 89 Nuclear Physics for Medicine – Chapter II – Medical Imaging 90 Nuclear Physics for Medicine – Chapter II – Medical Imaging • Tissue recognition • Tissue Very appealing is the potential of mass spectrom of mass potential the is Very appealing Here, precise and fast identification ofby means arrow points to the imatinib distribution, which is concentrated in the outer stripe outer medulla (figures reprinted from ref. [Röm13]). ref. from reprinted (figures medulla outer stripe outer the in concentrated is which green The kidney. mouse distribution, the in imatinib the to points substances arrow different of distribution the yields spectrometry mass imaging Right: characteristic is that (m/z=494.2660). peak imatinib mass for the indicates label green The square-millimetre. 1/1000 about of area an outer has the of pixel each spectrum medulla; mass outer stripe single-pixel Left: imatinib. drug anti-cancer the with treatment after kidney amouse of 27. spectra IMS Figure RSC). Chemistry, Faraday from Discuss patterns (reproduced characteristic human (bottom) different show healthy a and (top) tissue bladder cancerous of a spectra mass Right: London). College Imperial credit: (figure device the surgery left: during Bottom Society). operation in Chemical 2010 American Copyright 7343. 82, Chem. Anal. from of permission with analysis (reprinted tissue spectrometric mass for vaporised system inlet Venturi-pump an with combination in electro-scalpel an of principle Top left: 26. Figure faster (~30 minutes)faster but less reliable techniques. it into the mass spectrometerit mass an performs into the and instant mass spectrometric analysis. The obtained The obtained spectrometric analysis. mass instant ponent analysis. Characteristic patterns indicate indicate patterns Characteristic ponent analysis. lipidwhich different profiles, exhibit spectra mass spectrometer: mass heat into the ported to used is - trans and electro-scalpel released is by an material mation. The “knife” collects some smoke, collects sucks “knife” The mation. mass spectrometry can be a solution. The tissue beasolution. The can spectrometry mass are analysed by multi-dimensional principal com principal by multi-dimensional analysed are infor of biological smoke in amounts rich is that etry for histology. Typical histological analyses take for take histology. Typicaletry analyses histological several hours. Forseveral hours. intra-operative there exist cases cut through the patient’s the produces and tiny tissue through cut - - - The above sections illustrate that IMS is a highly highly is a IMS that The aboveillustrate sections • Multi-modal imaging • Multi-modal valuable method for studying biological samples. biological for method valuable studying whether the cut tissue is cancerous or not. It also cancerous or is not. It also tissue cut the whether However, samples such complex invariably are and its metastases by different mass patterns. Figure 26 patterns. mass by different its metastases different types of molecules, enhances the infor the enhances of molecules, types different use of several different methods, each optimised for each optimised ofmethods, severaluse different operation the tion in room examples of and tumour from cancer original the to distinguish and types and lipids, to peptides and proteins. Therefore, to peptidesand the lipids, and of variety alarge contains section tissue a single tissue. normal and cancer of various identification of metastases allows shows the principle of the electro-scalpel, itsapplica shows principle the electro-scalpel, of the chemical species ranging from salts, amino acids acids amino from salts, species ranging chemical . 149 , 247 by permission of The Royal Society of of Society Royal The of , 247 permission by - -

The growing number of applications and the analyti the and of growing number applications The vant neuro-transmitters are either peptides or small either are peptides or small vant neuro-transmitters 200,000). Envisaged applications in environment applications in Envisaged 200,000). method spectrometry. Each mass imaging MALDI with ultra-high mass resolving power resolving (in mass excess of ultra-high with of amouse slice tissue out same on carried the was field deployment and use in many daily circum daily in many deployment field use and Chem Anal. from permission with reprinted Figure staining). (H&E stain eosin and hematoxylin using images histological classical Bottom: ratios. mass-to-charge characteristic various to refer values m/z the respectively; source, aMALDI with imaged proteins different of and source aDESI with imaged species lipid different of distributions intensity show row central and top The methods. different from obtained brain, a mouse on information Complementary 28. Figure including miniaturised and portable apparatus for apparatus portable and miniaturised including pressure interface for universal in situ analyses analyses situ in pressure for interface universal physics astrophysical precision is and experiments, developed for nuclear spectrometer,mass originally providesmethod complementary perspec a unique, H&E conventional combining imaging modal molecules. rele of many the since analyses, spectrometry mass Agood example tissue is by IMS. mation gained the developmentthe techniques, of different many technique. each with analysis tive by allowing brain. The combinationfrominformation of brain. each and life-sciences are, e.g., life-sciences are, and developmentand Figure 29 shown in is stances. A novel laboratory instrument for Anovel research stances. laboratory instrument staining, DESI imaging mass spectrometry and and spectrometry mass imaging DESI staining, for suited ideally are which samples brain, of the with ultra-high mass resolving power power resolving mass ultra-high with compact, mobile, and itcompact, and atmospheric combines mobile, an stimulated has spectrometry of mass potential cal New developments for in situ applications applications situ in for developments New . 83 , 8366. Copyright 2011 American Chemical Society. Chemical 2011 American Copyright , 8366. Figure 28 showsexample of multi- an : this TOF : this - - - - • • • The hitherto unrivalled combination of ultra-high ultra-high combination of unrivalled hitherto The IMS and in situ capabilities provides new analytical provides capabilities situ new analytical in and IMS medicine. power for in situ applications in environment, life-sciencesand resolving mass ultra-high with spectrometer mass TOF performance Figure 29. devised fordevised nuclear physicscontinue experiments, medicine and neighbouring fields. neighbouring and medicine broad-band, non-scanning resolution,mass MS/MS, opportunities that will stimulate new field applica stimulate will that opportunities to stimulate and cross-fertilise new applications in cross-fertilise and to stimulate example developments These of tions. living are a how mass spectrometry methods and instruments, instruments, and methods how spectrometry mass wildlife and humans, humans, and wildlife careproducts personal and pharmaceuticals with wastewater monitoring: wastewater detection and identification of food contaminants: food of identification and detection identified and quantified, and quantified, and identified security: tions or food-packaging migrants, that need that to be migrants, ortions food-packaging adultera food additives, drugs, veterinary toxins, num increasing there steadily numerous are and bers of contaminants, e.g. pesticides, natural natural pesticides, e.g. bers of contaminants, are of increasing concern represent ofare and increasing to a threat essary. are andnec countermeasures detection effective cal weapons by terrorists is an existing threat and and threat weapons existing cal by an terrorists is A modern example of a newly developed high- developed anewly of example Amodern the possibility of deployment of possibility biologi the contamination of water water of contamination - - - - -

91 Nuclear Physics for Medicine – Chapter II – Medical Imaging 92 Nuclear Physics for Medicine – Chapter II – Medical Imaging The maturity of the nuclear imaging sector can be be sector can imaging the of nuclear The maturity vious year have year new onesvious and in are been discarded Medical imaging in general, and nuclear medicine in in medicine nuclear and general, in imaging Medical l l l Conference, and witnessing howof pre trends the Conference, witnessing and Outlook introduced, tested and dismissed at high speed. One speed. at high dismissed tested and introduced, nowadays pursued by new being are technologies dynamising the activity of nuclear physics groups, activity the dynamising detector field, employed technologies medical the in particular, for which detection of radiation emitted emitted of detection radiation for which particular, of development physicsNuclear different. very is of technological evolution neverof has technological been so fast tion sector, such as the IEEE Medical Imaging Imaging Medical sector,tion IEEE the as such the spotlight. spotlight. the are not only fields two these in activities our that where rate the industry, medical demanding the nuclear physics base, knowledge experimental the that their work in radiation detection, simulations, simulations, work detection, radiation their in that by the atomicby involved, nucleus is the experienced has research and clinical use within the year. the within use research clinical and and continues to exhibit evolution continues to and exhibit at exponential arena, though, trends and technologies are being being are technologies and trends though, arena, into biomedical translated are new techniques and experiments may take several years to design, fund, fund, may several years to take design, experiments appli find might processing, data and electronics, it and nuclearphysics battleground, experimental the fromefiteddeveloped in and technologies tested set up, run and analyse data. In the nuclear imaging nuclear imaging the In data. analyse and set up, run were borrowed PMT scintillators, as and fromsuch most past nuclear the in while that seenfact by the future. the increase in only trend will this seems that evolution ben largely has this past, the In speeds. conferences in the nuclear imaging instrumenta conferences nuclearimaging the in leading the year every by attending this assess can pace but their that synergetic, complementary and But today we realise medicine. nuclear cation in 5. 5. The urgedetectors to Theevolve is imaging nuclear Nuclear physics groups have been aware always - - - - Just to address the hardware side, novel scintillators, hardware the side, novelJust to address scintillators, while, on the other hand, mid-term stability in the the in mid-term stability hand, other on the while, PET/MRI systems. In the preclinical field field com preclinical the In PET/MRI systems. CT, PET/MRI scanners, devices for quality controlCT, for PET/MRIdevices quality scanners, few years. years. few in the medical imaging industry. industry. imaging medical the in ing the cross-fertilisation between the fundamental fundamental the between cross-fertilisation the ing of technologies tomorrow.imaging X-ray spectral imaging has taken a big step forward in the last last the a big step in taken forward has imaging nuclear physicsnuclear application in groups their and nuclear physics research been involved has the in detection. There are Thereexamples many of detection. research duction and widespread and duction acceptance of PET/CT introdriventhe been by mostly has This decade. physics experiments, makes it possible to train and and it makes possiblephysics to train experiments, molecular imaging. molecular photodetectors DAQ and have systems received a today. available technologies imaging molecular sophisticated ment develop most and highly the more recently deployment by the of simultaneous a practice in most clinical up-to-date the place in of hadrontherapy, becommon to afew, name will they can find the resources and knowledgeimplethe andto resources find can they where academia in active groupsthe typically are oncology, in and especially practice, clinical in units bined modalities are diffused and necessary, since diffused are bined modalities research in detector and technology carried out in out in carried technology detector and research in research, who have careers later successful pursued and in general experts in technology for nuclear technology in general experts in and advance of medical imaging and, more interestingly, and, imaging advance of medical how our current efforts are paving the waytheare for paving how efforts current our ers trained in nuclear physics in groups basicers trained doing shape the best technicians, doctors, researchers doctors, shape technicians, best the needed toface goals scientific multi-national nuclear great boost from these activities, thus demonstrat thus great activities, from boost these We have seen that multimodality in nuclear in We have multimodality seen that This chapter of provided how has This aglimpse ------These models should should onrely a These profoundknowledgemodels feel more than ever that it is our duty to help everfeel and duty more it our that is than interconnection. Increasing computing power computing and Increasing interconnection. models accurate purpose, For this quality. image nuclear physics laboratories basic nuclearsci and detector, pro in and new technologies electronics nuclear physics research devel community, and development coexist, at times even within the same same the even within development at times coexist, promote of developments translation the from our fromphysics world real arefar application, activities ments. of novelperformance provide and devices increased opment activities in medical imaging detector imaging medical opment in activities of highly specialised experts, very often trained trained often very experts, specialised of highly involvement the requiring reconstruction, of image physical phenomena of underlying their the and processes formation degradation and image of the through participation in nuclear physics nuclear in experi participation through to interface with the medical imaging industry. We industry. imaging medical the with to interface continue fact to provide in they fieldbest to the test be accompanied should imaging tation for medical by corresponding advances in image reconstruction reconstruction image by advances corresponding in research group.developments These provethat, and preclinical environments. preclinical and fea make computer should advances in technology exploitimproved the order in to fully modeling, and ence experiments into practical tools for the clinical forclinical tools the intopractical ence experiments even outside from the it if basic appears nuclear that sible the implementation of these models as a part sible apart implementation as the models of these be developedshould or prototype. for scanner each cessing. Moreover, cessing. mass critical help to obtain they This chapter reflects the fact that inside theinside that chapter fact the This reflects We haveinstrumen noticed advances in that also ------[5] [4] [2] [9] [7] [6] [3] [1] [10] [8] [Mün13] Spec.349- Mass J. Int. Münzenberg, G. [Röm13] Römpp al et A. References Applications of Radiation Detectors of Radiation Applications Tomography 139 (2013) 759–783: spectrometry “Mass T.; Combs, S. E.; Debus, J. & Parodi, K. K. &Parodi, J. Debus, T.; E.; S. Combs, Imaging Systems: Emission and Transmission and Emission Systems: Imaging treatment. carbon ion verification scanned of Instr. Meth Instr. 350 (2013) 9-18: “Development of mass Radiother. Oncol., Radiother. Molecular imaging in living subjects: seeing subjects: seeing living in imaging Molecular R154. (2011). X-ray spectral “Biomedical imaging; (2013). clinical Implementation initial and H.B. Barber, H. Roehrig and D.J. Wagenaar, and H. Roehrig H.B. Barber, Instrum. Meth. A541:150-165,2005 Meth. Instrum. Simulation of Medical (Ed.),Buvat, Simulation I. Proc. of SPIE, vol. 8143 ofProc. SPIE, et al et Lang C. S.M. Jorgensen, D.R. Eaker and E.L. Ritman. E.L. Ritman. and D.R. Eaker S.M. Jorgensen, T. G. Image (2006). &Gullberg, M. Defrise, Rahmim, A., Rousset, O., & Zaidi, H. (2007). H. O.,&Zaidi, Rousset, A., Rahmim, T. al Oger et (2003). T.F.,Massoud, S.S. Gambhir, Harrison, R. (2012). R. & Harrison, C. Grupen, In: Bauer, D.; Sommerer, Unholtz, J.; F.; Kurz, N. Wermes, “Pixel detectors for tracking and and N. Wermes, detectors for tracking “Pixel (2012). in H. Paganetti uncertainties Range C.; Haberer, Welzel, C.; K.; T.; Herfarth, Strategies for motion tracking and correction correction and tracking motion for Strategies fundamental biological processes in anew processes biological in fundamental in PET.in PET Clinics imaging with high resolution in mass and and resolution mass in high with imaging nuclear medical imaging with high high with imaging nuclear medical doi:10.1088/1748-0221/9/01/P01008. promises and challenges,” in Medical in challenges,” promises and using using proton role therapy the and of Monte Carlo present” their spin-off in imaging applications,” Nucl. imaging in spin-off their Nucl. Compton telescope, Nucl. imaging a medical reconstruction. experience of offline PET/CT-based ofexperience offline sensitivity in positron tomography in emission sensitivity light. light. simulations. simulations. spectrometersAstonand fromto Thomson space” Genes Dev. Genes b + g coincidences, JINST 9 P01008. coincidences, JINST 9 P01008. . A695 , Springer Berlin Heidelberg. Berlin , Springer . (2012). xenon for Aliquid TPC . (2014).. Sub-millimeter Phys. Med. Biol. Med. Phys. , Phys Med Biol Med Phys

17

107 : 125. : ., Histochem. Cell Biol. Biol. Cell Histochem. ., :545. , 2 (2):218–26. (2), 251–266. (2), , 814302. ,

57

51 :R99–R117 : R139– : , edited by by edited , 93 Nuclear Physics for Medicine – Chapter II – Medical Imaging 94 Nuclear Physics for Medicine – Chapter II – Medical Imaging • • • • • • • • • • • • • • • • • • • • • List of Contributors (ChapterList of Contributors II) Jose ManuelUdias,Spain Josep F. Oliver, Spain Alex Murphy, UnitedKingdom Alberto DelGuerra,Italy Christoph Scheidenberger, Germany Christian Morel, France Guillaume Montemont,France Christophe deLaTaille, France Wolfgang Enghardt, Germany Irene Torres-Espallardo, Spain Ian Lazarus,UnitedKingdom Peter G.Thirolf, Germany Paola Solevi,Spain Magdalena Rafecas,Spain Marlen Priegnitz,Germany Katia Parodi, Germany Fine Fiedler, Germany Peter Dendooven,Netherlands Piergiorgio Cerello, Italy David Brasse,France Faiçal Azaiez,France 3. 3. 2. 1. Introduction Chapter III Chapter Conveners: Ulli Köster Conveners: Radioisotope Production Radioisotope medicine nuclear for radioisotopes of Properties topics specific and Examples facilities and methods Production 3.3 3.2 3.1 2.2 2.1 3.4 1.2 1.1

Theranostics

evolution and trends Europe: in use radionuclide of Statistics (non-nuclear) treatments applications versus conventional medicine nuclear of success of Examples Production facilities Nuclear reactions accelerator vs 99 therapy for Radioisotopes imaging for Radioisotopes Mo/ 99m

Tc supply issues: reactor reactor issues: Tc supply

(ILL) –Marie-Claire (ILL) Cantone

103 135 129 128 131 117 111 99 (Milano) 2.3 3.5 3.8 3.7 3.6 1.3

Targetry for radionuclide production laboratories physics nuclear from spinoffs of Examples radioisotope production and research for accelerators and reactors research of exploitation Joint nuclear physics and medicine nuclear of Synergies and radiochemistry 177 and pharmaceutical R&D and pharmaceutical for biokinetics Radiotracers Lu, a showcase for nuclear physics physics nuclear for ashowcase Lu,

136 139 128 137 124 141 110 111 98 97 95 Nuclear Physics for Medicine

The field of nuclear medicine covers all medical The fieldall ofmedical nuclear medicine covers (brachytherapy) is formally part of the field field of the “radi (brachytherapy) part formally is with improved applications. with properties for certain how today and and were produced historically l l l Introduction for choice thera the as of treatment well options,as natural decay chains but have decay chains to be producednatural by dedicated “medical cyclotrons” coexists with com with cyclotrons” coexists “medical dedicated or stage procedures localise to detect, diagnostic plementary productionplementary research at multi-purpose therefore becovered. also will and medicine molecules. procedurespeutic where capable radionuclides of procedures performed are include worldwide. These or therapy. of diagnostics purpose outlook is givenoutlook is “novel” radioisotopes for promising nuclear common but with much has in ology” the progression of an illness, decisive parameters progressionthe illness, of an ionising of openuses sources radioactive emitting tions the required radionuclides are not are present required radionuclides the tions in radioisotope productionfrom keepstight profiting accelerators. and reactors patient introducedare into the that forradiation the are needed for what type of applications, how neededare for they what type Todayat nuclearphysics facilities. production at produced were radionuclides initially medical all drivendeliv transmutation, by projectiles artificial few excep applications. With nuclearmedicine all ered by accelerators or nuclear reactors. Historically Historically reactors. nuclear or accelerators ered by form elemental to or appropriate bound either in synergies with other nuclear physics activities. An An nuclearphysics other activities. with synergies sites treated the to the used, are targeting selectively This chapter will illustrate which radioisotopes radioisotopes which illustrate will chapter This The application closedof sources radioactive Radionuclides are the essential fuel that drives drives that fuel essential the are Radionuclides Every year over 30 million nuclear medicine nuclearmedicine Every over year million 30 - - - - - 97 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 98 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 1. 1. l l l ficult to produce, ficult but severaldozen have properties for nuclear medicine Over the last decades more than 3000 radioactive radioactive 3000 more decades last than Over the facilities. Many are very short-lived very are Many dif or extremely facilities. ii) i) isotopes have been discovered at nuclearphysics medicine? that make them potentially useful for nuclearmedi useful potentially them make that Properties of radioisotopes Properties allow a radioisotope to find an application in nuclear an in application aradioisotopenuclear to find allow cine. What are the crucial selection criteria that could could criteria selection that crucial the are What cine. 

Half-life: Half-life: Radioactive isotopes may Radioactive properties: decay Nuclear for the hospital. the for ingly. In general, longer range, more penetrating more longer general, range, In penetrating ingly. decay losses during transport between production production between transport decay lossesduring not and much of decay it should ear destination prevent isolation patients. of the to the patient, e.g. after an imaging procedure has imaging an after patient, e.g. to the to and radiopharmaceuticals of the handling the ther hand other On the dose for patients. the the been completed. Even for radioisotopes are that patient’sbe detectedoutside shorter the while body rapidly excreted shorter half-lives may be prefer to reachradioisotope live long enough its should requirements in shielding toradiation minimise 1.1 region, (see Figure to deposit therapeutically used is radiation range itsince can purposes for used is radiation imaging able to prevent long-term waste-handling issues issues able prevent to long-term waste-handling it not hand other should On the be too use. and not hard intense gamma should emit activities, at high are administered apeutic isotopes, which a defined within of energy amount a maximum accord differ will nuclearapplications medicine in half-life should be long enough to avoid belong enough should half-life excessive emit different types of ionising radiation and the the and radiation of ionising types different emit long-lived eitherto avoid burden radiation useless generators notlier. If available from the so-called should not emit short range radiation, to minimise to minimise radiation, not range short should emit Upon introduction in the patient, the the patient, the Upon in introduction ). Ideally imaging isotopes imaging ). Ideally ------from nanometres to decimetres in the human body. human the in decimetres to nanometres from varying ranges with radiation, ionising of alphabet 1.1. The Figure iii) iv)

valent, etc.)valent, coupled appropriate to an molecule Noble gases are well suited to be inhaled and and to suited beinhaled Noble well are gases find a wide range of applications. Free, unlabelled wideof applications. range aunlabelled Free,find Chemical properties: Chemical Ease of large scale production: There may be production: scale of large Ease isotopes that fulfill perfectly the first three con first the perfectly isotopes fulfill that not form stable to are bonds biomolecules that ditions but that are difficult to be producedat but difficult are that ditions may suffer in vivo a infrom i.e. dehalogenation, may suffer quantities for laboratory experiments, e.g. to to e.g. experiments, laboratory for quantities tions require very different chemical properties. properties. chemical different require very tions understand and optimise the mechanism of new mechanism the optimise and understand Under these scale. large in required quality the bone seekers. bone (group 7, Radiometals bonds. of the tri breaking required for many other applications. Halogens required for applications. other Halogens many radioisotope applied is clinically. amore conventional while radiopharmaceuticals, alkaline earth metals and rare earth metals act as as act metals rare earth and metals earth alkaline exhaled for lung ventilation studies but they can but they studies ventilation for lung exhaled can relatively easily form such bonds, but they but form they relatively bonds, such can easily circumstances they may still be used in smaller smaller in be used may still they circumstances Different medical applica medical Different - - - - 1.1 100 and 200 keV are ideal for gamma cameras and keV and cameras 100 200 and for gamma ideal are This imposes a high energy limit for the usedthe phofor limit energy high imposes a This 1.1.1 variety of applications: the isomer isomer the applications: of variety (T computedtomography) photonemission (single It happens that there is one isotope that fulfils well well It happens there one is that isotope fulfils that but also emit gamma rays that allow monitoring of the in vivo distribution. vivo in the of monitoring allow that rays gamma emit also but minus decay. I decay. minus Table 1.1. Table Gamma cameras for the 2D imaging method scin method imaging for 2D cameras the Gamma SPECT. Table 1.1 showsoverview radioiso of the an SPECT. to transition It decays internal by an from from it suitable even for more complex chemical labelling it suitable even for more complex labelling chemical detection efficiencyrespectively. detection dem 1.2 Figure detect gamma rays or X-rays gamma detect sufficiently are that procedures. Most importantly, it is easily available available procedures. it Most easily importantly, is detectors and cameras SPECT Gamma may suffice. onstrates in simplified form that formphotons simplified between onstrates in the optimisation criteria discussed above for criteria alarge discussed optimisation the topes most frequently used for imaging with gamma gamma with topes for most frequently used imaging become would less collimators the or else tons, 3D SPECT method corresponding the tigraphy and beta radiation is emitted. The 6 hour half-life makes makes The6 hour half-life emitted. is radiation beta rely on collimation to achieve position resolution.rely on collimation animals that is often used for often is that (radio-)pharmaceuti animals small in for imaging while for are suited humans, efficient or too thick,efficientresolution reducing or ortoo overall energetic to leave patient’s the exces without - body 99m sive photon Thus attenuation. energies above 70 keV can be regarded as stable for practical purposes. No beregarded purposes. stable for as can practical or SPECT.cameras developmentcal lower energies (down keV) to 30 gamma rays of 141gamma keV, for energy ideal close to the Xe-133 I-123 In-111 I-131 Tc-99m Kr-81m Lu-177 Tl-201 nuclide Radio- Ga-67 1/2 Tc Radioisotopes for imaging Radioisotopes Scintigraphy and SPECT and Scintigraphy =0.2 million years) so long-lived is that it that million =0.2 99 Mo/ Isotopes typically used for SPECT imaging. IT stands for internal transition from an isomer, EC for electron capture and β and capture electron for EC isomer, an from transition internal for stands IT imaging. SPECT for used typically Isotopes γ gives the number of emitted gamma rays or X rays relative to the total number of decays. decays. of number total the to relative Xrays or rays gamma emitted of number the gives 99m Tc generators (see below). 126 13 67 192 6 0.004 161 73 (h) Half-life 78 99m Tc. It emits 81 159 245 171 364 141 167 190 208 113 70 (keV) Eγ 185 93 99g

Tc Tc - - - - - • • in a 1 cm thick NaI crystal as function of photon energy. photon of function as crystal NaI thick a1 cm in efficiency photopeak and encapsulation) (detector aluminium cm 0.2 and tissue 10 soft cm through transmission of Product 1.2. Figure developed for a large variety of nuclear medicine of medicine nuclear developed variety for alarge time a multitude of technetium compounds has been been has compounds of technetium amultitude time applications: 99m 99m will enrich close to bone metastases and make and close to bone enrich metastases will For observation of small lesionsFor SPECT tech the observation of small infarcts and coronary artery disease. artery coronary and infarcts imaging, mainly to detect bone metastases from bone to detect metastases mainly imaging, in their surroundings. Consequently surroundings. their in Figure 1.3 nique provides resolution, better see Figure phosphate. Consequently bone building cells show cells phosphate. Consequently bone building prostate or of consists breast cancer. Bone mineral methylene diphosphonate) for used are bone test and at rest, allowing diagnosis of myocardial of myocardial diagnosis at allowing rest, test and stress a blood flow during myocardial to measure cameras. gamma with scans visible bythem planar high uptake of phosphates high bone and metastases lead usually to a strong enhancement of the uptake uptake toof enhancement astrong the lead usually carbonated hydroxyapatite, i.e. mainly calcium and and calcium carbonated hydroxyapatite, mainly i.e. Given favourable these properties of Tc-phosphates and diphosphonates (e.g. MDP: MDP: (e.g. Tc-phosphates diphosphonates and Tc-sestamibi and 38 83 94 91 82 89 10 64 10 6 59 I 21 42 (%) γ

131 99m I and I and Tc-tetrofosmin used are 177 Lu are therapeutic isotopes isotopes therapeutic are Lu β EC EC β IT IT β EC EC type Decay - - - 99m 99m Tc-MDP Tc-MDP - for beta- Tc, over over Tc, . - 99 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 100 Nuclear Physics for Medicine – Chapter III – Radioisotope Production • • • • • • Today second-most the SPECT isotope is universal (tumours) and inflammation sites. Thus gallium gallium sites.(tumours) Thus inflammation and 123 123 Parkinson’s disease. Parkinson’s disease. major dose due to radiation relative rapid exhalation. of neuroblastoma and adrenal gland tumours. gland of neuroblastoma adrenal and quality images, and due to the longer half-life the the longer due to half-life the and images, quality the beta-minus emission of emission beta-minus the Heretives to Technegas studies. ventilation for lung of for diagnosis imaging brain in used transporter to alternative an as urements for and thyroid imaging body and are bound in areas of rapid cell division of rapid areas division in bound are cell and body renal function measurement and renal imaging and and measurement imaging renal and function renal rections are higher (seerections higher are 2), to lower Figure leading radiation dose is higher too. higher dose is radiation analogue with high affinity to the dopamine dopamine to the affinity high with analogue alternative to to alternative 99m 99m 99m Various Various Additional Additional Technegas consistsof MAG3) function. assessment of kidney allow is used for thyroid imaging tothyroid detect can for used thyroidis imaging thyroid and the in enrich it will i.e. anions, iodide detect sites of infection or inflammation, e.g. in e.g. sitesdetect or inflammation, of infection embolism. pulmonary detect under developmentunder of applications. for avariety aggregates used for lung perfusion studies to studies perfusion for used lung aggregates aerosols. These can be inhaled and exhaled and andexhaled inhaled be aerosols. These can serve for lung ventilation studies. studies. ventilation forserve lung cer or thyroid other malfunctions. cases of fever of unknown origin. of fevercases of unknown I-MIBG (m-iodobenzylguanidine)I-MIBG for detection I: As iodide it is ideal for it thyroid ideal is iodide uptake meas As I: 99m 133 Free gallium ions behave iron-like in the human ions behave human the Free iron-like in gallium 201 Tc is also used for labelling of leukocytes to of leukocytes Tc for used labelling also is TcO Tc-MAA (macro are albumin) aggregated Xe and generator-produced and Xe Tl can be used for myocardial imaging as an an as imaging for beused myocardial can Tl Tc-pertechnetate. 4 – 99m (pertechnetate) to behaves similarly 99m Tc DTPA (DMSA, compounds or 99m Tc compounds are in clinical use or use Tc clinical are in compounds Tc-MIBI but attenuation cor the 123 I-iodohippurate serves for for serves I-iodohippurate 123 99m I-ioflupane is a cocaine Tc attached to carbon 133 Xe does not does Xe cause 81m Kr are alterna are Kr - - - - 1.1.2 1.1.2 vivo compoundbehaviour of a given or as chemical (BR 18 It is the extreme sensitivity of tech nuclear detection sensitivity extreme It the is Desirable properties of positron for emitters PET for applications. theR&D Often prime selection cri for peptide receptor [Mae11]. detection isotopes such as isotopes as such in water of only 0.6 mm. Fluoride can be rapidly Fluoride watercan 0.6 ofin mm. only question (Tablein Table 1.2 and 1.3). isotope. nuclear techniques in larger concentrations. larger in nuclear techniques variety of alarge such use safe assures niques that positron energy to assure stopping and annihilation annihilation stopping and positron to assure energy of substances and many could not be used with non- not could with be many used and of substances orders many of i.e. magnitude of few nanograms, corresponds to quantities just trace this of MBq, used isotopesused some SPECT isotopes other used are tions converge for many applications of one isotope: isotope: one of applications converge many for tions macroscopic to betoxic in elements known are these since glance at first appear surprising might thallium in the property, to study chemical e.g. terion their is by gamma cameras. In addition to these clinically clinically to these addition In cameras. by gamma below appear. would levels toxicity where chemical a suitable peptide (e.g. octreotide) to Labelled sites. inflammation to localise used are are high branching ratio for positron emission branching high are of to tens range hundreds the in are used activities However, the amounts. while that one to realise has half-life and chemical properties for application the chemical and half-life labelled to reinjected) removed then labelled leukocytes, scans (with scans same chemical element as a promising therapeutic element apromising as chemical same close to the point of emission, as well as suitable as well close point to of as the emission, to the isotope belonging complementary imaging F. It BR has The in vivo distribution therapeuticdistribution vivoof somein The The administration of elements like gallium or gallium like elementsof The administration Similarly to Similarly b Positron emitters for PET for emitters Positron + ), no or low emission of gamma rays, limited ), no rays, orlimited low of emission gamma 67 b + Ga) or indium scans (where scans Ga) or indium = 99.8% with a short average ashort = 99.8% with range 99m 131 Tc for SPECT, here condi these I or 177 Lu can also be monitored also Lu can 18 99m of injection after observed Figure 1.3. (middle) compared to a to compared (middle) image aSPECT and (left) Figure 1. al Eet Even-Sapir from SNMMI of permission by Reprinted F-fluoride PET image (right). (right). image PET F-fluoride 2006; 47 2006; Med JNucl ., Tc-MDP on a planar scan scan aplanar on Tc-MDP 111 Bone metastases In also serves serves also In 111 : 287. In is is In - - - FDG scan. In addition FDG may detect infection may infection detect FDG addition In scan. FDG PET alternative to Table 1.2. the total number of decays. of number total the for the detection of Alzheimer’s disease. offor detection Alzheimer’s the ies in the brain. the ies in show enhanced an malignancies Many imaging. dine as one of the nucleosides. PET scans with FLT one as nucleosides. of the with PETdine scans to more delivery permitting thus transport, during diseases. pared to 1.8 hhalf-life). processing more challenging but it can be labelled but be labelled it can processing more challenging in proliferation.It accumulated is marker for cell oncology as alternatives to FDG for imaging of for alternatives imaging to as FDG oncology oped development. orin under are areused They trapped in the cell sufficiently long to enable sufficiently PET cell trapped the in (fluorodeoxyglucose). FDG is use is a It modified to a variety of organic molecules. Various molecules. of organic to avariety Several progresstreatment. therapeutic of cancer therapies or to therapy adapt the accordingly. therefore generate thymi new includes DNA that thema making arebone-seeking, anions fluoridethe below). of producing ease the hand other On the rylation but cannot be metabolised. Thus Thus staysit bemetabolised. but cannot rylation receptors in a variety of neurological and psychiatric psychiatric receptors ofand neurological a variety in remote com locations time, (many hourstransport and stably linked to many organic compounds, compounds, organic to many stablylinked and e.g. by replacing OH e.g. larger quantities of quantities larger specific cancers or for apoptosis imaging cancers to specific or follow for apoptosisimaging stud for metabolism beused glucose sites can and compounds are available for brain imaging of neuro imaging availablefor are compounds brain for beta-amyloid plaque allow compounds imaging of response to validation early for serve very can which and rapidly are proliferating that cells cancer of decay amount losses compensation for acertain compact accelerators production situ for (see in glucose metabolism and are therefore are and a metabolism glucose detected in phospho after cells up in taken is that glucose use of sufficient are gies for enabling production, Rb-82 Ga-68 F-18 O-15 N-13 nuclide Radio- C-11 Many more Many 18 11 Injected as simple(NaF) as fluoride solution,Injected salt By far the dominant dominant the By far C is short-livedC is (T F-labelled fluorothymidine (FLT) fluorothymidine F-labelled as serves Common short-lived PET isotopes and their average positron range in water. I in range positron average their and isotopes PET short-lived Common

18 F compounds haveF compounds been devel 99m 18 F at medical cyclotrons allows cyclotrons allows F at medical Tc-bone (see scans Figure 1.3 - groups. ener projectile Low 1/2 0.02 1.13 1.83 0.03 0.17 (h) Half-life 0.34 =20 min) which makes its its makes =20 min) which 18 F compound in clinical F compoundclinical in

95.4 89.1 96.7 99.9 99.8 BR 99.8 (%) β 11 +

C ). ------This is often associated with more aggressive types types aggressive moreassociated with is often This Thus this isotope is extremely promising, but at pre isotope promising, extremely is this Thus very short-livedvery simple as compounds used are and ( with PET,with alternative corresponding to the an as PET while PET while Consequently longer-lived PET isotopes required are SPECT tracers. for peptide receptor imaging. Fixedfor aero to carbon peptide receptor imaging. from a long-lived its short half-life, radiation exposure to the patient. to the exposure radiation its half-life, short comparedimprovedand accuracy to specificity i.e. show lower oxygen concentrations than usual. showi.e. lower usual. concentrations oxygen than been uptake reached. has once optimum the imaging isotopes to for becoupled immuno- to antibodies diac imaging. In heart perfusion studies it showed studies perfusion heart In imaging. diac PET as alternatives to studies perfusion dial difference between hypoxic - tis between versus norm-oxichypoxic difference obtained from a obtained or or of cancer and with a higher resistance of cancer ahigher with of and cancer the PET scanner. PET the to follow the uptake dynamically or to perform uptaketo the follow dynamically predicted is to become and “ used the the usual SPECT isotopes and minimises, due to SPECT isotopes minimises, and usual the as simpleas Rb and II) with a transition potential very close to the close to the very potential atransition II) with and antibodies or antibody fragments show fragments relatively or antibody antibodies labelled to many biomolecules by using macrocyclic macrocyclic biomolecules to by many using labelled ion bestably trivalent it can lent for PET”. asmall As sent outpaces demand sue regions. Certain tumours may become hypoxic, tumours sue regions. Certain peptides. as such slow order of the biokinetics of to hours days. many studies ventilation lung it allows “Galligas” as sols short-lived biomolecules as such isotopes. Larger chelators. At present it is the main PETchelators. present At isotope used main it the is 15 O-water or 201 At presentAt Not all applications can becovered applications can Not with all 15 Copper is special since it has two redox it two Copper since has special is states (I 68 Still shorter-lived Still O O (T Ga (T Ga Tl. Production has to Productionbelocated closeto has very Tl. 1/2 β 1.48 0.83 0.25 0.74 0.49 0.39 E (MeV) 44 + 1/2 mean gives the number of emitted positrons relative to to relative positrons emitted of number the gives Sc is well suited for mid-sized molecules for suited molecules mid-sized well is Sc = 2 min) and = 2 min) and + 13 cation, is another alternative for car another is cation, = 68 min), obtained conveniently min), obtained =68 64 N-ammonia respectively) for myocar for respectively) N-ammonia

Cu, Cu, 82 68 Sr/ 89 Ge generator, is increasingly increasingly generator, is Ge Zr and and Zr 82 82 82 Rb generatorRb injected and Sr production capacities. Rb (T Rb 13 N N (T 124 5.4 2.8 0.6 2.4 1.5 1.1 (mm) Range 1/2 I are the preferred the I are 1/2 =75 seconds), = 10 min) are 99m Tc equiva Tc 99m Tc Tc - - - - - 101 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 102 Nuclear Physics for Medicine – Chapter III – Radioisotope Production ATSM (diacetyl-bis(N4)-methylthiosemicarba vivo generators where alonger-lived decays nuclide (T Hadrontherapy, Chapter 7.2]. For treat optimum Hence, most positron have emitters either long Table 1.3. Overview of longer-lived 1.3. Table PET isotopes. four diagnostic PET emitters with different half- different PET with emitters diagnostic four zone) hypoxicregions may reaching be reduced probability (BR probability it therefore to is identify necessary ment planning to Cu-I it upon leaves which compound and the unfavourable T relation between renal perfusion. renal half-life and the branching ratio for- positron emis branching the and half-life concentrationhigher respective of the Cu positron half-lives (T emitter makes hypoxic regions hypoxic Copper makes visible. has emitter lived ones are also useful to measure myocardial and and myocardial to measure useful lived ones also are lives: stays internalised in the cell. Consequently the cell. the in stays internalised sion electrondecay. capture versus competing compound the Cu-II in bound areas. hypoxic such called oxygen enhancement effect is enhancement effect reduced oxygen called [see so- treatment the since by radiation against cells I-124 Zr-89 Y-86 Br-76 Cu-64 Sc-44 nuclide Radio- 1/2 The =9.7 min) and 60 Cu (T Cu Q

-value for b for -value 1/2 1/2 b ) =24 min),=24 + or ) but not both. A way around the ) but Away the not around both. 64 abundant positron emission emission positron abundant Cu (T Cu + decay affects inverselythe decay affects 100 78.4 14.7 16.2 12.7 3.97 (h) Half-life 1/2 61 Cu (T Cu =12.7 h).shorter- The

1/2 and BR and 1/2 =3.3 h), b + 22.8 22.7 31.9 55 17.6 94.3 BR (%) are in in are 62 β Cu Cu + - - Abundant emission of energetic gammas is usually usually is of emission energetic gammas Abundant 94%), 94%), 140 with the high positron branching ratio daugh of the positron branching high the with induce background in the imaging. Mainly due to Mainly imaging. the in background induce 90 of the beta-minus decay beta-minus therapeuticof of isotope the the the decay of the mother nucleus in the targeting targeting the decay motherthe ofnucleus in the ter, after nucleus remains provided daughter the that combine favourable the mother ofthus the half-life emission: tron the radiation burden to the patient, the shielding shielding the patient, burden to the radiation the 1.4 (~GBq)ties (see Figure e internal via tially to ashorter-lived strongposi positron with emitter to the emission of emission 3×10to the rich isotope can bedetectedby isotoperich PET! can fraction Atiny requirements for transport and handling and may and handling and requirements for transport a drawback since this “useless” radiation increases increases radiation “useless” this a drawbacksince enough for PET imaging of therapeutic for PETenough imaging sion accompanied is by prompt ray emission. gamma compound region, targeted respectively. or the Y proceeds via an excitedY proceeds an 0 via Nd (T Nd It is interesting to note evenIt interesting that is one neutron- Table 1.4 some isotopesIn (see Table 134 Ce (T Ce 1/2 0.82 0.40 0.66 1.18 0.28 0.63 E (MeV) =3.4 d) → mean 1/2

44m = 3.2 d) =3.2 → Sc (T Sc – e +

pair creation, thus leading leading creation, thus pair 140 1/2 -5 -5 Pr (BR Pr = 2.4 d) =2.4 → positrons ).

treatment, the middle image image middle the treatment, Licence). Creative Commons Attribution Open Access Licence, Research al et Carlier Th. 7 of Figure from taken were images and the right right the and shows shows tumours. The image left radioembolisation of hepatic 90 with treated were that bottom) on B top, on (A patients two of example the at techniques imaging Different 1.4. Figure 134 + Y-Bremsstrahlung-SPECT state, that decays par decays that state, La (BR La 90 2.9 1.1 2.1 4.7 0.7 2.0 (mm) Range b Y microspheres for for Y microspheres + 99m = 2013; 3 Tc-MAA prior to to prior Tc-MAA ) positron emis positron )

per decay, just 51%). One can b

90

+ 44 Y-TOF-PET. The = Sc (BR Sc : 11 (Springer : 11 (Springer

90 64%) and and 64%) ., EJNMMI., Y activi b + = - - - - -

1.2 1.2.1 1.2.1 3-photon-cameras in clinics will be determine the the be determine will 3-photon-cameras clinics in 3.4.) that will be capable of detecting the gamma gamma the becapable of detecting 3.4.) will that It should be stressed that most isotopes ofIt bestressed that these should Table 1.4. BR 1.4. Table Gamma emitters may be used for external beam beam may for emitters be used external Gamma Correspondingly imaging becomes possible with imaging Correspondingly for this purpose. Today this technique is mainly Today purpose. mainly is technique for this this elements of (tech these for radiopharmaceuticals information of the localisation, i.e. many fewer many i.e. of localisation, information the netium, iodine, trivalent metals) trivalent several of and iodine, netium, development section (see Chapter Imaging, 2, much lower activities, effectively reducing thedose much effectively lowerreducing activities, these isotopes could serve as imaging isotopes in imaging isotopes as serve these could to intersecting “lines of response” in usual PET. of response” usual in “lines to intersecting at present.used none isotopes of drawbacks, much these is these to the body,to the for example for close to a tumour, of patient. Prospects forto the routine availability below): radiation therapyradiation (EBRT). collimated Intense ray in coincidence with the two 511 keV two the ray coincidence in with annihi are of high interest for clinical applications since interest for clinical ofare high applied in emerging countries where alternative countries the emerging applied in approacha “matched theranostics of the (see pair” electron accelerators providing Bremsstrahlung are are electron accelerators Bremsstrahlung providing exist methods labelling and synthesis established 3D mapping compared events required are for full lation gammas. Every provide event then can 3D gammas. lation less widespread. less long-term PET fate promising isotopes. of these gamma ray sources of gamma Tb-152 I-124 Tc-94m Tc-94 Y-86 Mn-52 Sc-44 Cl-34m Radio-nuclide 3-photon-cameras γ-PET) under (alsoare called Sealed radioactive sources can be used in or close in beused sources radioactive can Sealed Radioisotopes for therapy Radioisotopes Gamma emitters 44 Sc, Sc, β + γ gives the number of positrons emitted together with gamma rays relative to the total number of decays. of number total the to relative rays gamma with together emitted positrons of number the gives 86 Y, Y, 124 17.5 100 0.87 4.9 14.7 134 3.97 0.53 Half-life (h) I, I, 152 60 Tb. Co, 137 Cs orCs 12 12 70.2 10.5 31.9 29.6 94.3 54.3 BR β + γ 192 (%) Ir are used used are Ir 1.08 0.82 1.07 0.36 0.66 0.24 0.63 0.84 E mean - - (MeV) “loco-regional” treatment dubbed “brachytherapy”. “loco-regional” A certain dose can be applied either dose by can brief expo A certain (repeated of arteries). clogging (for example 370 of GBq while normal liver cells are mainly supplied by the mainly are liver cells normal while Longer-lived isotopes as such SIR-Spheres respectively) gamma beta- or and the for are frequently used treatmentSeeds of prostate Short-range (X-rays, radiation low-energy gamma in a short time (minutes) time ashort in source intense by avery internal radioembolisation therapy”. radioembolisation Liver- internal metas for “selective stands SIRT importance. clinical ing disks or wires containing containing or wires disks days or weeks or even permanently in the body. the ordays weeks orin even permanently ply line of the cancer by radioembolisation. Here by ofcancer radioembolisation. the ply line the sup venous Thus oneblock can blood. portal or “stents” (tubes) shaped applicators. or specially unnecessary doseoutside treatment of the area. unnecessary the high energy beta emitter emitter beta energy high the hepatic supplied the via artery mainly are tases by SIRT, of brachytherapy, avariant rapidly gain is emitter beta rate). rays and beta particles) is preferred to minimise rays particles) beta preferred and is to minimise a catheter (“afterloader”), then pulled back into theinto back (“afterloader”),a catheter then pulled applicator, source rapidly introduced is the from a are required for this application. requiredare for this emitter emitter either spheres radioactive containing either small long exposure to weaker sources (LDR, low to weaker doselong sources exposure (LDR, sure to intense sources (HDR, high dose rate) high to sourcessure intense (HDR, or storage position. Very compact sources (e.g. metal storageshielded position selected position to the via cancer; radioactivestentscancer; may prevent restenosis Treatment of primary and metastatic liver cancer cancer liver metastatic and Treatment primary of In HDR brachytherapy required HDR given the dose is In In LDR brachytherapy the source remains for brachytherapy source LDR remains the In 3.5 2.1 3.7 1.0 2.1 0.6 2.0 2.8 Range (mm) Range 166 Ho or colloids (lipiodol) containing oneHo (lipiodol) or colloids containing 32 P are fixed in form of “seeds” fixed P are (needles) 344 603 871 871 850 703 1153 1077 628 936 744 1434 1157 2127 Eγ (keV) 192

60

Ir). After positioning an an positioning Ir). After Co, 103 90 153 Pd, Pd, Y (TheraSphere or Gd, Gd, 125 65 61 I, I, 94 100 96 100 31 83 33 100 95 91 100 43 I 169 γ (%) 131

Yb or Yb

Cs or the orCs the 192 Ir) Ir) - - - 103 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 104 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 1.2.2 131 In HDR brachytherapy the high energy beta emit beta energy brachytherapy high HDR the In loco-regional in the fingers. the in in certain forms of “benign” thyroid diseases such such thyroid diseases forms of “benign” certain in be distributed from where it will intraarterially, or intravenously injected or orally administered is non-melanoma skin cancer. skin non-melanoma metastases elsewhere. Thus high high Thus elsewhere. metastases of colloids injection intra-articular of the use makes to preventplaced into arteries restenosis. Lower it selectively. irradiate will and cancer perfused of the beta emitters emitters beta of the used to treat even metastatic thyroid cancer. Also to treatused thyroid even cancer. metastatic Also as even when growing toiodine, affinity their tain bytargeted to knee, the beta Pure joints. offlexible (e.g.tions the arthritis) ter 1.5). (Figure cancer the microscopic The radiation throughout the body (i.e. body whole the to the “system”)throughout ray emitters. ray emitters. activities of activities activity concentration to inflate balloon catheters concentration balloon toactivity inflate supplying is that hepatica catheter into the artery acterised by an enhanced iodine uptake and can be be can uptake and iodine enhanced byacterised an mechanisms. by enriched various locally and higher beta energies for large joints like the hip or hip the energies like beta joints for large higher energy is adapted to the size of the joint: of adapted is the size to the energy ray (or emission gamma without emitters weak with metabolic targeting metabolic simply injected into the right place, we comesimply right injected into the now delivered well- preferentially to the sources then are sized joints like the elbow and elbow and the like joints sized containing radioisotopes to treat severe inflamma containing gamma ray emission)gamma employed are where beta the Antimatter is nowadays familiar to people many nowadays is familiar Antimatter matter is actually used daily in the bodies of bodies the in daily used actually is matter other illnesses via PET imaging. In this regard, regard, this In PET via imaging. illnesses other thanks to its central role as powerful weapon role toin its central powerful as thanks the “demon” that is cancer. is “demon”that the thousands of and patients cancer to display thousands thought of as the “angel” that helps that to defeat “angel” the of as thought antimatter-emitting radionuclides might be might radionuclides antimatter-emitting anti that fact the Demons”. is and known Less science fiction films and as novels such films “Angels science fiction Daily use of antimatter antimatter of use Daily I for therapy. Often thyroid cancer cells main I for therapy.thyroid cells cancer Often systemic therapiessystemic The first targeting mechanism exploited was mechanism targeting first The While the therapies discussed so far are so-called so-called are so far therapies the discussed While Radiosynoviorthesis (or radiation synovectomy) synovectomy) (or radiation Radiosynoviorthesis 188 Beta emitters Beta Re is used alternatively to low energy gamma to alternatively lowgamma used is energy Re 186 123 Re with medium beta energies beta for mid- medium with Re , i.e. the radioisotope the or compound, i.e. is 188 188 I or Re are applied are “cream”Re as to treat Re is applied in liquid form at high form at high liquid applied is Re in 124 of thyroid cells. These arechar These of thyroid cells. 188 , where a radiopharmaceutical , where aradiopharmaceutical I for diagnostic purposes or by purposes I for diagnostic Re, 131 I or 169 90 Er for small joints joints for small Er Y are injected via injectedY are via 131 I activities are I activities 90 Y with Y with - - - - - Table 1.5 < keV/ (<1 (radioimmunotherapy) isotopes the today mainly RIT or therapy) radionuclide receptor (peptide ( new therapies past (surgery the or EBRT). such In 131 which first line therapies had failed. Consequently therapies line hadfailed. first which On the other hand, shorter-range hand, other On less the cause betas isotopes. Chemical homologues of calcium, such as as such homologues of calcium, isotopes. Chemical 89 nates carrying nates carrying disease), metals ( metals be can phosphates. and This of calcium metabolism Compared slowly growing to normal, metastases. pancreatic neuroendocrine tumours (GEP-NET) tumours neuroendocrine pancreatic 90 or combined with other therapy modalities. therapy other with combined or on the average size and perfusion of metastases beta beta average ofon the metastases perfusion and size of the patients during treatment. Therefore patientsof during the for uation. These isotopes differ in beta range in beta (seediffer isotopes These uation. targeting of neuroblastoma. Good therapeutic of Good neuroblastoma. targeting uptake in the bone metastases and are used for used are pal and bone the metastases uptake in the patientsshowed often the - dis advanced of stages vectors. the to bone, the bone metastases often show an enhanced show often enhanced an bonebone, the metastases better targeted by targeted non-nuclear better methods medicine preferred. are both, Very clearly are metastases large targeted directly neighbouring in emission beta required to induce apoptosis of a cancer cell. In In required to apoptosis induce of cell. a cancer response has been observed as a first line therapy line response been observed a has first as results in therapy of lymphoma, while gastro-entero- therapy of in lymphoma, while results preferred are be labelled radiometals can when these requiring more shielding and often an isolationan often and more shielding requiring are successfully treated with PRRT using the using PRRT treated with successfully are as thyrotoxicosisas goitre and (Graves’ Plummer’s and as RIT had to make their first demonstration first of had to their make RIT as today treatments thyroid than other applications harmaceuticals. Hence, “cross-fire the from effect” harmaceuticals. exploited to target them with bone-seeking radio bone-seeking exploited with them to target bone etc.) painful frequently alater develop stage in ease with larger metastases. Still, RIT with Zevalin Zevalin with RIT Still, metastases. larger with ease of lower energy, with oremitters higher or mixtures effectiveness in clinical trials with patients for with trials clinical effectiveness in liative therapy [Lew05]. therapy liative larger metastases with uneven perfusion not every uneven perfusion with metastases larger shows abundant emission of hard gamma rays of emission shows hard gamma abundant cross-fire to adjacent healthy cells. Thus, depending depending Thus, cross-fire to adjacent cells. healthy helps to achieve dose. a morecells distributed evenly reached radiop injected by the bedirectly can cell 90 Sr or Y, Y, I-rituximab and and I-rituximab Y-ibritumomab), ( Bexxar Many cancers (prostate cancers cancer,Many breast cancer, 131 For targeted therapy of tumours such as PRRT PRRT For as such therapy targeted of tumours Beta particles have low linear energy transfer transfer have energy particles lowBeta linear 131 I-MIBG is a molecule used for used metabolic amolecule is I-MIBG I and I and 223 117m ) and their (bio-)chemical their ) and properties. 131 m Ra, as well as phosphates as well or bisphospho as Ra, m), therefore usually many “hits” are “hits” m), many therefore usually Sn, Sn, I is used for used ablationI is of excess tissue. 177 153 32 Lu are used; others are under eval others under are used; Lu are P or stable complexes of radioactive Sm, Sm, 177 Lu-rituximab showed excellent Lu-rituximab 186 Re, 188 Re) show enhanced an 131 I-tositumomab), 131 I - - - - - ( DOTA-TOC and Typical beta-emitting isotopes used for therapeutic applications with mean and maximum beta energies and ranges in water. given. in are ranges and (>5% abundance) rays gamma energies beta Major maximum and mean with applications therapeutic for used isotopes beta-emitting Typical 1.5. Table individual cancer cells that might be released during be released during might that cells cancer individual ( indications present trend towards low-energy emitters beta ognised as the optimum form of therapy optimum the for as several ognised today radionuclide therapies are increasingly rec therapiestoday radionuclide increasingly are below radiolabelled somatostatin-analogues somatostatin-analogues radiolabelled and RIT can now to can patients beextended at earlier RIT and lactic treatmentlactic preventing proliferation the of short-range radiation is preferred. This explains the short-rangeexplains preferred. is radiation This removal For of a tumour. surgical applications such or even prophy as metastases smaller with stages 177 Re-188 Re-186 Er-169 Lu-177 Ho-166 Sm-153 I-131 Y-90 Sr-89 nuclide Radio- P-32 Lu) or even shorter-range ( emitters alpha ).

Figure 1.5 0.7 3.7 9.4 6.7 1.1 1.9 8.0 2.7 50.6 (d) Half-life 14.3 90 Y-/ 177 ). Correspondingly PRRT ). Correspondingly

Lu-DOTA-TATE. Thus, Thus, Lu-DOTA-TATE. 0.76 0.35 0.10 0.13 0.67 0.22 0.18 0.93 0.59 E (MeV) 0.7 mean

90 Y-/ 177 2.12 1.07 0.35 0.50 1.85 0.81 0.81 2.28 1.5 E (MeV) 1.71 see see Lu- max - -

16000 thyroid cancer cases and 25000 other can other 25000 and cases thyroid cancer 16000 I dominates the short-term the I dominates isotopeThe 131 80 years from the accident years from80 the On the [Car06]. 131 from ≈800 000 treatments with treatments with 000 from ≈800 other hand the very same isotope same very extremely is the other hand useful in treating thyroid cancer and hyperthy thyroid and cancer treating in useful reactor accident Chernobyl increaseof in an the ofradiotoxicity fission products. Following roidism. Patients with thyroid problems Patientsroidism. with profit every year [UNSCEAR2008]. [UNSCEAR2008]. year every cers is expected in Europe until 2065, i.e. within within i.e. 2065, Europeuntil in cers expected is I, the useful devil devil useful the I, 10 4.6 1.0 1.7 9 3.3 3.3 11 7 (mm) max Range 8 155 137 208 113 81 103 364 284 637 E (keV) γ

patients are marked in bold. in marked are patients of thousands or hundreds many for used already were Radiopharmaceuticals that parentheses). in III or II I, (phase trials clinical or use clinical in radiopharmaceuticals Figure 1.5. 131 Therapeutic I worldwide worldwide I 16 9 - 10 6 7 29 7 82 6 - - - I (%) γ

- - 105 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 106 Nuclear Physics for Medicine – Chapter III – Radioisotope Production Those cells that have survived and retained the that and have retained survived Those cells in markedis contrast to low-LETThis radiation has therapeuticalpha The particles of potential 1.2.3 various therapeuticvarious approaches this consistent with (electrons and photons) for which the dose required required dose the photons)(electrons and which for fact, in most cases no more than a few alpha par afew alpha no most more cases in than fact, for the inactivation of hypoxic cells may be larger may belarger of cells hypoxic inactivation for the inactivate well oxygenated ones. Unlike low-LET oxygenated ones. Unlike well inactivate limited is tissue biological in range their that implies direct methods in use is clonogenic is use assay. in methods A mon direct effectiveness biological the of addition, delivery. In poorly perfused in found damage). cells, Hypoxic (asdependent state cell oxygenation of on the the dependent on the dose rate, the effect of alpha dependentof effect doserate, on the the particle irradiation on cancer cells (as on as well cells on cancer irradiation particle nearly independent is rate of the of doseparticles radia LET high all Like it. inactivate permanently malignancies. is LET responsiblevalue for high per This micron. treatment the of and in cancer modality ment this olayer of cells seeded and grown on an appropriate grown seeded on an olayer and of cells free radical role mediating plays in oxygen acrucial energies (4–9of particle alpha MeV) linear the ( diseases other producedalpha emitting or artificially occurring ticles passing through the nucleus are enough to nucleus the areenough through passing ticles tions the biological effect of alpha particles does does not alpha particles of effect biological the tions we section the describe this 0.1mm. In to less than produces radiation alpha that in damage intense the by afactor of 2–3 compared required to to that However, cells. it also malignant and healthy both radiation whose biological effectiveness is highly highly whose effectivenessis radiation biological sensitive nearly as are to tumours, solid regions in is it not Thus, of action freerequire radicals. the attempts to as overcome well as it limitation range attempts to imple facilitates greatly radionuclides alpha radiation as cells with normal oxygen levels. levels. oxygen normal with cells as radiation alpha concentration of high double the is particles alpha to considerablyand scope of the increase treatable and seeded again in a highly diluted concentration. diluted ahighly in seeded again and available DNAmechanisms. repair less amenableis to the caused byage particles alpha of that than cycle, cell mitotic the in cell ofage the dependent less the on significantly is particles alpha energy transfer (LET) is of the order of is (LET) the of transfer 100energy keV experimentation. One simplest of mostexperimentation. the and long been recognised. The availability of naturally of naturally The long beenavailability recognised. living cells in general) in perforce is done vitro cells by in living of DNA dam type low-LET the Finally, radiation. substrate is subjected to a known flux of alpha parti of flux subjectedsubstrate is to aknown In DNA breaks induced to the cell. ofstrand the cles. Following the irradiation the cells are removed cells the irradiation the Following cles. The main mechanism of cell inactivation by of cell mechanism main The Quantitative investigation of the effects of alpha of ofeffects investigation the Quantitative Alpha emitters Alpha Figure 1.5 Figure ). For relevant the range ------varying numbers of hits, including a fraction of afraction including numbers of hits, varying 3.8 day half-life radon ( 3.8 gas dayhalf-life well defined number of alpha particles. This can This alpha particles. of number defined well warnings by medical and regulatory bodies of the of the bodies regulatory and by medical warnings Hadrontherapy, section 3.3). section Hadrontherapy, D SF and the applied dose D is found to be well rep applied the to found dosebewell Dis and SF ity. The relationship between the surviving fraction fraction thesurviving ity. The between relationship ies containing about 30–150 of radonies containing per cubic kBq nucleus leads tonucleus its death. leads number of hits per cell obeys aPoisson obeys distribu per cell ofnumber hits the Since per cell. hits ofnumber particle alpha dependence more is complex, aquadratic involving practised in central Europe rather widely despite Europerather widely central in practised still fact, in treatment. is, It this of effect matory providing a direct measure of the survival probabil of survival measure the a direct providing metre of air. A large number of controlled clinical of number controlledmetre clinical Alarge of air. of the nature by which damage incurred to the cell cell to the incurred damage by nature which of the - treatment the of was ankylos of emitters alpha to as the mean lethal dose and its magnitude is typi is its magnitude dose and lethal mean the to as trials have long-term the established anti-inflam trials (such diseases as Rheumatoid century. twentieth averaging procedure with the tion, combines cells is a consequence This exponential. the term of Din bath with a radon concentration with bath per of 0.3–3 kBq (seebe achieved by facilities microbeam Chapter 1 resented by an exponential function SF =exp(-D/ SF function resented exponential by an ability to unlimited reproduction form colonies (a to unlimited ability arthritis) were patients to treated the arthritis) by exposing of the back dates beginning to the emitters alpha hit by a precise, able on cells effect to observe the either by bathing for about 20 minutes in awater in for aboutminutes 20 either by bathing long term carcinogenic danger involved. danger carcinogenic long term caves in or man-made by galler exposure orlitre, in such as photons and electrons, the corresponding corresponding the electrons, and photons as such cally around 1Gy. around for Note, radiation, that lowcally LET involved. It line referred is cell of the characteristic of 50 cells),at least colonyas consisting defined is cells not hit at all. It therefore to is be interesting not at hit all. cells from naturally occurring minerals, and thus thus and minerals, occurring from naturally example of a an radioisotope and extracted abdominal cancers. abdominal this to use ongoing is trial aclinical and purposes for medical “waste” (France) to extract Limoges in openedAREVA facility adedicated 2013In transmutation. artificial not requiring daughter therapy (via emitting itsalpha 212 treatment cancer to waste From 0 ), where D The mean lethal dose translates to a rather small to a translates rather dose small lethal The mean Another long and extensive long therapeutic and use Another One of the oldest medical applications using applications using One oldest medical of the Pb isotope a promising is for alpha targeted 0 is a phenomenological parameter parameter phenomenological a is 212 212 Pb from of stocks Pb for treatment of intra- 222 Rn). This was done was This Rn). 212 232 Bi) Bi) Th ------The first human clinical studies on CRPC patients on studies clinical human first The Xofigo),treatmentthe for ofboneof metastases various cancers such as castration-resistant as cancers such prosvarious - Germany from 1948 until 2006. Radium, charac Radium, 2006. from 1948Germany until is obtained from the decay from the of obtained is produced is and days 3.66 decay byis the of its par injection. by disease, rheumatic inflammatory (AS), debilitating spondylitis and achronic ing 223 not only confirmed the bone targeting of the ofphar thebone targeting not confirmed only deformation and alleviates the pain which generally generally which pain the deformation alleviates and maceutical but also defined the dose safe range. defined butmaceutical also were side concluded effects It was observed. mild tate cancer (CRPC),tate The cancer cancers. breast or lung treatment for AS. of injection the that to concentrate bones,where the sequence the in of atendency has chemistry, terised by its calcium-like tases. A series of preclinical studies on laboratory studies A series of preclinical tases. bones is the basis fordevelopment basis bones the the is of anew radio-pharmaceutical, radio-pharmaceutical, and efficacy expectations needed for clinical trials. trials. clinical expectations needed for efficacy and providedand input considerations related to safety premise its basic targeting established has animals emitter alpha arecent only In study condition. the accompanies decays process slowsalpha the down of skeletal ent ent life) through its daughter its daughter life) through growth which are quite often often centred quite are around- which metas growth therapy of bone metastases. therapy of bone metastases. 2013. Europe in and It great has prospects for ( Xofigo cal radiopharmaceuti the trials clinical successful away. decay Based on before diffusing most will that demonstrated University at Oslo chemists more short-lived (4 seconds half-life) nuclear and ing from switching When of targeting. selectivity the reducing elsewhere, translocated was decay alpha of chain the part of the bones but due to it that diffusion recognised was 224 Later source for radiation medicine. important long-lived long-lived with discovered. Forwas ampoules decades newwere element the soon as investigated as radioisotopes radium of applications Medical difference the makes diffusion Radium: Ra preferentially targets regions of new targets bone preferentially Ra The tendency of radium to concentratetheThe tendency of radium in 228 Ra was explored was therapy forRa alpha targeted in 223 Th (1.91 half-life). in years use in It had been Ra, the corresponding daughter daughter corresponding the Ra, 220 224 Rn daughter (half-life of 55 (half-life daughter seconds)Rn Ra is an alpha emitter whose half-life whose half-life emitter alpha an is Ra 226 223 223 Ra and its decay chain were its decay an and chain Ra RaCl Ra has a half-life of 11.4 ahalf-life has Ra and days 2 224 ) was approved) was USA the in 223 Ra is an effective and safe effective an is Ra Ra-chloride (Alpharadin/ Ra-chloride 227 224 Th (18.7days half-life). Ra to neighbour Ra 227 Ac (21.8 years half- 224 Ra-chloride Ra-chloride 219 Rn is is Rn - - - - - “targeted alpha therapy” (TAT) alpha “targeted or “alpha radio- This agent can be some variant agent be somechemotherapyof can variant This or Amongst these, alpha emitters are the most potent the are emitters alpha these, Amongst whose selection was subject to strict acceptance cri subject towhose was strict selection patients over CRPC 900 enrolling undertaken, was In addition, some pain relief and survival prolon survival and relief some pain addition, In In 2013 regulatory approval of the drug (brand approval 2013 In regulatory drug of the See TableSee 1.6 overview for of an therapeutic alpha for metabolic targeting of bone metastases, exploit of bone metastases, for targeting metabolic from the primary target cell. Thereforethefate cell. of target primary from the ing their enhanced uptake of calcium and chemical chemical and uptake of calcium enhanced their ing study positive amajor III phase indications initial immunotherapy” (α-RIT) when antibodies are used used are (α-RIT) when antibodies immunotherapy” name Xofigo) was obtained in the US and in Europe. in andthe US in Xofigo)name obtained was nitude and will usually result in a delabelling from a delabelling in result usually will and nitude nificant recoil energy that the daughter daughter thenucleus that energy recoil nificant daughter isotopes will be released and, depending depending bereleased and, isotopes will daughter tri preclinical designed demonstrated specially in diagnostic) agent which acts on the targeted cell. cell. targeted on the acts diagnostic) agent which monoclonal antibodies or peptides which preferen or which peptides monoclonal antibodies on relies Its realisation payload to its destination. pared to 11.3 placebo the group months in [Par13]. of targeting vectors, i.e. cancer-specific vectors, i.e. biomolof targeting on their lifetime, chemical properties and biochemi properties and chemical lifetime, on their isotopes. radioactive with of application tagging is tially seek the malignant cells. These These “cell-seekers” cells. malignant seek the tially the in tancy (referred trial of to this analysis interim An teria. these daughter activities is an issue to issue be considered. an is activities daughter these vector. of Hence,the fraction targeting alarge the to 160 keV Table shown in for cases the 1.6. This tar to the bestablylinked cannot they since useful radiotherapy active or possibly some biologically are tagged with atherapeutic (or, with tagged are for matter, that expec of revealedincrease life an ALSYMPCA) as as terbium, astatine, bismuth, lead, etc. are required. arerequired. etc. bismuth, lead, terbium, astatine, as vectors. targeting as is referred as to either modality specific This als. advantage of the alpha fact, in promising; and homologues. Tohomologues. of amore cancer types other target ecules that will carry an attached radioisotope attached as an carry will that ecules use namely required, is strategy elaborate targeting exceeds chemical binding energies by orders of mag binding chemical exceeds 100 particle: alpha uponexperiences of emission an emitters. emitters over gamma and beta emitters has been has emitters beta over and emitters gamma survival of the treated of the group 14.9 was survival monthscom confirmed by an expanded follow-up: expanded an the by median confirmed cal environment maycal move more away or less far type choice this for The most compound. natural gation amongst patients was noticed. Following Following noticed. was patients amongst gation geting vector. Instead other chemical elements vector. such chemical other geting Instead The radium therapies discussed so far areused far so therapiesdiscussed The radium An important feature of alpha decay is the sig of decay feature the alpha is important An For isotopes applications such are not radium 223 Ra-treated group which was later later was which group Ra-treated ------107 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 108 Nuclear Physics for Medicine – Chapter III – Radioisotope Production ( Bismuth can be labelled with well-known chelating chelating well-known with belabelled can Bismuth Overview of alpha emitters used in nuclear medicine. Isotopes decaying mainly by beta-decay are shown in slanted letters. slanted in shown are beta-decay by mainly decaying Isotopes medicine. nuclear in used emitters alpha of Overview 1.6. Table ical studies have studies been performedical with daughter nuclides by scavengers nuclides daughter or by incorporating theaway.this on application Depending diffuse are reached. Verydaughters short-lived daughters mainly been used in combination with peptides that that peptides combination with in been used mainly of alpha emitters: the first comprises those decaying thosecomprisesdecaying first of the emitters: alpha the primary nuclide into lipids or carbon nanotubes or nanotubes carbon into lipids nuclide primary the unavoidable spread be acceptable or might not (see insignificant stable or radiologically until to 5alphas of 4 one adecay mother i.e. decaychain ters, in result orto to astable radioisotopes only emit daughter that below). release of the to Strategies control limit and but longer-lived (seconds daughters to hours) might tolerated. be give rays. latter The orbeta no gamma radiologically agents (e.g.agents DOTA), butisotopes both ( exploration. under are have half-lives short (T have sufficiently quick uptake and with antibodies antibodies quickhave with and uptake sufficiently lem of daughter activities but are mainly short-lived. but mainly are activities lem of daughter seeking blood cancer cells. More preclinical and clin and More preclinical blood cells. cancer seeking significant dose, i.e. their uncontrolled their can release i.e. dose, significant m U-230 Th-227 Ac-225 Ra-224 Ra-223 At-211 Pb-212 Bi-213 Bi-212 Tb-149 nuclide Radio- s to ms) will decay locally before diffusing very far far very before diffusing decay locally s to ms) will The second class decays to alpha emitting daugh alphadecaysThe second emitting to class The “single alpha”do not emitters haveThe the“single prob In In Table 1.6 Table

one can observe two distinct classes classes distinct observe one two can 20.8 d 20.8 18.7 d 10.0 d 3.66 d 3.66 11.4 d 7.2 h 0.76 h 0.76 1.01 h h 10.6 4.1 h Half-life 1/2 ≤1h). Thereforethey have Po-214 Rn-218 Ra-222 Th-226 Bi-211 Pb-211 Po-215 Rn-219 Ra-223 Po-213 Bi-213 At-217 Fr-221 Bi-212 Pb-212 Po-216 Rn-220 Bi-211 Pb-211 Po-215 Rn-219 Po-211 Po-213 Po-212 Po-212 Bi-212 Daughters 213 212

Bi since it is itBi since is Bi and Bi and 213 0.16 ms ms 35 s 38 0.51 h 130 s h 0.6 ms 1.8 4 s 11.4 d 4 m h 0.76 ms 32 s 294 1.01 h h 10.6 0.15 s s 56 130 s h 0.6 ms 1.8 4 s 0.5 s 0.5 4 m m 0.3 m 0.3 1.01 h Half-life Bi) Bi) s s - - -

s s

vivo delabelling. Efforts are ongoing to improveare to ongoing the Efforts vivo delabelling. with trace quantities supported by quantities trace computational with with For therapeuticto ensure applications it essential is in AML patients [Jur02]. Other promising studies studies promising Other patients [Jur02]. AML in 212 determined by laser spectroscopy with astatine iso astatine spectroscopy by laser determined with ofits applicationresides inmore its (bio-)difficulty properties of an element, was only experimentally experimentally properties element, only of was an atomic one offundamental the of astatine, potential positive ongoing. intraperitoneal is cancers and cancer gastric and ovarian breast, metastatic performed melanoma, for treatment of leukaemia, understanding of astatine chemistry by experiments by experiments chemistry of astatine understanding [Dad09]. diseases even and viral terial be overcome beta-decaying the when using a stable bond to the targeting vector to minimise in in vector to minimise a stable bond targeting to the with vivo generator”.trial “in an Iclinical Aphase halogen iodine, but it is also close to the metalloids. metalloids. close to the but it also is iodine, halogen even outside oncology, such as serious fungal, bac even outside oncology, seriousfungal, as such shown a significant reduction of leukemic blast cells cells reduction blast of leukemic shown asignificant chemistry. Astatine is aheavier is homologue of Astatine the chemistry. conveniently available from a chemistry [Cha11].chemistry ionisation the Interestingly, Pb-TCMC-Trastuzumab HER-2 patients with in The drawback of the short half-life The of Another “longer-lived” alpha emitter is is emitter alpha “longer-lived” Another with labelled antibody Anti-CD33 213 Bi labelled antibodies and peptides have and been antibodies Bi labelled 5 5 4 4 4 1 1 α Cumulative 0.17 1 1 /decay

6.71 6.45 6.88 6.62 6.59 6.78 8.34 3.97 7.74 7.74 (MeV) E α mean 225

Ac/ 213 Bi generator.Bi >50 >50 >50 >50 >50 55 75 25 65 65 (μm) Range 212 211 213 Bi might Bi might 212 At. The The At.

Bi has has Bi Pb as as Pb - - This in turn leads to a highly heterogeneousdose highly to a leads turn in This validated by clinical trials. to benchmark now experimental can as value serve (CERN) and ISAC and (TRIUMF). (CERN) 177 which exist in solid tumours (such elevated the tumours as solid in exist which It is the only clinically useful alpha emitter below emitter alpha useful clinically only It the is fusing alpha-emitters radiation therapy (DART) (DART) therapy radiation alpha-emitters fusing micrometastases cancer prostate of treatment for for [Zal08]. treatment cancer Phase of Itrials brain interstitial fluid pressure) fluid thatinterstitial theprecludeefficient ISOLDE facilities ISOL available at the only is 227Th nude mice. While several clinical trials inves- trials several clinical While nude mice. nuclear medicine applications. medicine nuclear distribution with numerous “cold with the spots” in distribution [Bey04,Mue12] but so far this interesting isotope interesting [Bey04,Mue12] this but so far partially overcome injection intra-tumoral by direct partially treatment the of malignancies in results promising of the targeting molecules, this option yet has to be this molecules, of targeting the of the radiobiological effectiveness of alpha effectivenessof radiobiological the of ver tigating the safety and efficacy of α-RIT show of α-RIT efficacy and safety the tigating used against acute myeloid leukaemia as well as can as acute myeloid well as leukaemia against used topes produced [Rot13]. (CERN) at ISOLDE This therapy method. The basic idea is to treat tumours treat The basic tumours is to idea therapy method. may some barriers be of these While mass. tumour because of physical barriers largely is This tumours. blood-borne targeting molecules inside the tumour. tumour. the inside molecules blood-borne targeting been proposed long-lived another as emitter. alpha bodies (HuM195 against bodies Lintuzumab) and are under preparation. under are of neuroblastomaand with and it can be conceptually classified as a brachy classified be conceptually itand can has been proposedhas recently [Ara07]; it termed is dif erately enhance the range of action in solid tumours tumours solid of in action range the erately enhance subsequent the and extravasation of dispersion the leukaemia are ongoing; preclinically other types of types other preclinically ongoing; are leukaemia direct comparison serve for can This lanthanide. properties of chemical a well-known the lead with support “in silico” design of astatine compounds for compounds of astatine design silico” support “in sus beta radiation (of radiation beta sus consider the diffusion of daughter isotopes daughter of delib to consider diffusion the solid against fail treatments such generally clusters, or microscopic by cell isolated cells characterised in lines derived cell human and mice in lines cell murine treating experiments comprised preclinical and cancer breast ovarian and against cally with targeted being are cancer intestine. and cers ovary of the Lu). First preclinical studies have studies been reportedLu). preclinical First A particular case is is case A particular A method that makes a virtue of the necessity to necessity of the a virtue makes that A method Most research of over the has decade last the Preclinically Preclinically Clinical trials employing employing trials Clinical 211 -labelled trastuzumab is being studied preclini studied being is trastuzumab -labelled At-labelled antibodies have been used clinically haveAt-labelled clinically antibodies been used 211 At-labelled antibodies haveAt-labelled been antibodies 161 149 Tb or chemically similar similar or chemically Tb Tb (4.1Tb half-life). hours 211 At labelled antibodies antibodies labelled At 225 225 Ac-labelled vectors. vectors. Ac-labelled Ac-labelled anti Ac-labelled 230 U has has U ------– is inserted through a fine-gauge needle into theinto needle afine-gauge through inserted – is α-particles’ lethal energy away energy source. from the lethal α-particles’ continuously extend must destruction α-RIT. Cell destruction. cell to massive tumour leading α-decays, vessels. It contributes two α-particles through its through It contributesvessels. α-particles two words, DART overcomes imposed by limitations the with no chemical interactions, occasionally entering entering occasionally interactions, no chemical with well-localised high radiation dose through their their dose through radiation high well-localised finite number of sources at a typical spacing of a spacing typical of sourcesnumber at a finite Since the α-emitters begin their journey in the intra- the in journey their begin α-emitters the Since from their surface. As these atoms these spread As inside surface. from their few millimetres, similar to brachytherapy. other In similar few millimetres, for production the of is the case, tumours may betreated a by deploying tumours case, the is ing the tumour themselves, but allows considerable but themselves, allows tumour the ing 228 diffusion and vascular convection,deliver theya and vascular diffusion decay of the source from or the following recoiling directly by the determined mediate agents (the diffusing atoms)the that take (the agents mediate diffusing involved,subsequent is their mechanism distribu of magnitude higher than the α-particle range in tis in range α-particle the than higher of magnitude about source (two the ordersover afew millimetres own decay and through that of its exceedingly short- of itsexceedingly that decay through own and the short range of α-radiation by introducing inter of α-radiation range short by introducing the may to be beexpected tumour the throughout tion targeting space no and molecular cellular tumoral interstitial combined byof the effects tumour the the extra- and intra-cellular space source the near intra-cellular and extra- the over and aperiod tumour Once the inside tumour. with beginning α-decay chain one the idea, uses the by intra-tumoral implantation of specially prepared of implantation specially by intra-tumoral by recoil of a daughter atom during the α-decay of the by atom recoil of during adaughter radioactive sourcesradioactive of relatively low which activity, release of their recoiling daughters. To daughters. recoiling release ofimplement their a third α-particle: it to β-decays α-particle: a third point. at same the blood porous the network leaving ofand tumoral the sourcea parent consists of isotope.par Thus, half-life), either α-decays to which half-life) to or β-decays atoms of remaining the half-life) while atoms, ent α-emitting atoms embedded below closely its ent α-emitting less affected by the obstacles that hinder systemic systemic hinder thatthe obstacles by less affected lived daughter lived daughter life), sue) for DART to be therapeutically relevant. If this sue) this relevant. If for DART to betherapeutically stay below its surface. stay below its surface. source by releases, recoil, of activity small prevents that at adepth from them entersurface, continually release short lived α-emitting atoms release lived short α-emitting continually conducting wire (0.3–0.5 mm diameter) carrying a a (0.3–0.5 wire diameter) mm conducting carrying Th (1.91 half-life)as a thatgeneratoryear serves The diffusing atoms areatoms the released from source diffusing The 216 Po (0.15 second half-life) and 216 Po away from the source, giving rise to Po rise away giving source, from the 216 224 Po, which disintegrates essentially essentially disintegrates Po, which 212 Ra embedded in the wire surface surface wire the embedded in Ra 224 Pb enters the tumour either by Pb enters tumour the 220 Ra half-life (3.66 half-life days),Ra the 212 224 Rn, a noble gas, diffuses in in diffuses anoble gas, Rn, Po (0.3 microseconds half- Ra. The source – a thin thin The source – a Ra. 220 Rn (55.6Rn seconds half- 212 Bi (60.6 minutes 208 212 Pb (10.6Pb hours Tl (3Tl minutes 224 Ra Ra - - - - - 109 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 110 Nuclear Physics for Medicine – Chapter III – Radioisotope Production The logical progression of the increase in selectivity progressionThe increasein logical selectivity the of in injectedtumours The response ofsubcutaneously 1.2.4 will specifically internalise into cancer cells is max into cells cancer internalise specifically will 193m Considerable related prolongation expectancy of life from beta to alpha emitters would be Auger elec beAuger would emitters from to alpha beta it may successful, If trial. for its first-in-manclinical imised. Auger emitters such as as such emitters Auger imised. rather are double breaks but they strand inducing provide addi a low-cost transportable easily and tron emitters. Low-energy Auger electrons Low-energyAuger havetron emitters. the selectivity of very targeted delivery agents that that agents delivery targeted of very selectivity the brachytherapy”. mode of “high-LET tional rather now simple, is poised technologically is tion was lungs to the a decrease load in of metastatic the complete to the animal. of the growth cure tumour approach basic premise ofvalidated. the was this attributes low body. concentration the throughout blood. by the out taken tumour of the tially bearing both murine and human derived cell lines lines derived cell human and murine both bearing relatively long half-life ofrelatively long half-life a very short range of nm to of m nm range short a very also routinely observed. DART, observed. routinely also whose implementa of down slowing from ranged the models mice all harmless while outside of non-targeted cells. Thus Thus cells. non-targeted of outside while harmless energy transfer. If they are brought are close to the they transfer. If energy lenging to find suitable internalising agents [Kas11].internalising suitable to find lenging life), α-decays to stable then which significant distances from the source and arefromandthe sourcepar distances significant cell’s nucleus they may be extremely effective in effective may nucleus be extremely they cell’s cleared from the tumour through the blood redis the through cleared fromtumour the Auger electron therapy, a long-term project project along-term therapy, electron Auger In 1927 (briefly after the discovery Auger of 1927the after In (briefly Claudius Regaud and Antoine Lacassagne Lacassagne Antoine and Regaud Claudius to achieve, the attempts so far have been unsuc far so have been the attempts to achieve, not perhaps impossible is this While to destroy. seeks one of cells in protoplasm the fixed tively which dimensions, of molecular radiations ting would consist of heavy elements capable of emit elements of heavy consist would cessful.” selec and to the organism be administered could ter production methods, we arenowter production closer methods, than biotechnology, radiobiology and Auger emit Auger and radiobiology biotechnology, electrons) the radiation therapy pioneers therapy radiation the electrons) ever to finally realising this early dream. early this realising ever to finally concluded: concluded: In a series of preclinical experiments on mice on mice experiments of aseries preclinical In Pt or Pt Auger electron emitter electron Auger 195m After three generations of R&D in Pt are very promising, but it is still chal but it still is promising, very are Pt “The ideal agent for cancer therapy cancer for agent ideal “The 212 Pb itsatoms travel to m and high linear linear high m and 117m 208 Pb. Due to the Pb. to the Due Sn, Sn, 125 I, I, 161 212 Tb, Tb, Pb Pb ------1.3 Radioisotopes are not necessarily used solely used for arenot Radioisotopes necessarily (metabolic activity, etc.) by external counting of (metabolic counting etc.) activity, by external Nobel prize in physiology and medicine in 2001 is in medicine physiology and in Nobel prize SPECT or PET studies with small animals, mole animals, small with SPECT or PET studies key regulators of the cell cycle that was rewarded was that cycle the of cell key regulators the 31 purpose. for this 3 istered in small amounts are sufficient. The The isotopes sufficient. are amounts istered small in admin efficient andactivities consequently very is or therapy, radiotrac as serve may also imaging they used for radiotracer studies in cell colonies or small colonies or small cell in forused studies radiotracer animals. For work ground-breaking example the on animals. ers for quantification of certain in vivoin processes of erscertain for quantification largely based on radioassay techniques employing employing based on techniques radioassay largely and pharmaceutical R&D pharmaceutical and samples (blood, urine, exhaled air). Here exhaled detection urine, samples (blood, cules marked with marked with cules H, H, P. In basic pharmaceutical R&D in addition to addition in R&D pharmaceutical basic In Radiotracers for biokinetics for biokinetics Radiotracers 14 C, C, 32 P, P, 45 Ca, Ca, 51 3 Cr, H, H, 14 57 C or Co, 59 32 Fe, Fe, P are also frequently P are also 75 Se, etc. are used used are etc. Se, - - - A large diversity of nuclear reactions can be used beused of reactions nuclear can diversity A large The specific activity of a radioisotope, usually of aradioisotope, usually activity specific The l l l However, one to con has purposes for practical for radioisotope For production. acomparison of 2.1 isotopes over all (radioactiveisotopes over plus stable) all isotopes. ity than the same amount of longer-lived amount same the than ity isotopes. isotopes with very high specific activity. Else the Else activity. specific high very isotopes with 2. 2. different methods one theto consider has methods notdifferent only producible quantity, but two additional propertiesproducible additional but quantity, two mg, we also give R we also mg, or antigens respectively)or antigens radio to use it crucial is ure of the activity per mass. Agiven of pure amount per mass. activity ofure the applications: for nuclearmedicine essential are that the same element may be interfering but also those those element but same also the may beinterfering “carrier-added” (c.a.).topes called are therapeutic effect. effect. therapeutic Production methods methods Production bolic targeting of thyroid very or bone metastases targeting bolic radioisotopes accompanied by a lot of stable iso to diluted on avoidpurpose an radioisotope often is atypical in vivo behaviour of ultratrace quantities. quantities. vivo behaviourof in ultratrace atypical of stable isotopes (“cold”) same of the admixtures have few selective sites only (peptide receptors high specific activity is not required. Instead theInstead is not required. activity specific high element have that no therapeuticFor effect. meta of GBq/mg units expressed or in Ci/mg,- a meas is a) The specific activity specific The a) seeking agents carrying cold isotopes have that no carrying agents seeking by “diluted” radioisotopes the sider often are that shorter-lived activ isotopes obviously a higher has selective sites tumour- beblocked would with and facilities and In the tables, in addition to the usual unit GBq/ unit usual to the addition in tables, the In Depending on the use, not only stable not isotopes only of use, on the Depending Pure radioisotopes are called “carrier-free” radioisotopesPure arecalled and On the other hand for tumour cell types that that types cell for hand other tumour On the Nuclear reactions Nuclear as the atomic ratio the of as radioactive - - - - - “effective specific activity” the over activity ratio of “effectiveactivity” specific T While specific activity is a measure impuri stableof is a measure activity specific While Neutron capture on stable targets usually leads to leads Neutron usually on capture stable targets where where hospital. the in handling waste S = 60 for transmutation of the target into the product,F into the for target of transmutation the nides) or elements other (e.g. iron) interfere that in duced by neutron is capture minus emission. The only positron of only The emitter emission. minus of chemically similar elements (e.g. lantha other similar of chemically the labelling process. Therefore as onedefines often labelling the the neutron flux density and t density neutron the flux long-lived of very admixtures particular topes. In of radioiso unwanted absencethe of admixtures measures radioisotopic purity ties, or radionuclidic the mass of all interfering elements. interfering of all mass the radioisotopes beavoided should to avoid- unneces a one-step reaction transmutation given is by: 2.1.1 stable target into the wanted intostable radioisotope. the target Only achievable by activity the thenspecific significantly, neutron-rich isotopes decayslightly that by beta- burden on facility patient dose to extra the and sary cross-section are essential to achieve a high spe to achieve ahigh cross-section essential are cific activity by converting a large fraction of thefraction of large a by converting activity cific clinical relevance that could in principle bepro in relevance could that clinical get or product by nuclearreactions) not do interfere b) Radioisotopic purity b) Radioisotopic 1/2 Co, Thus high neutron flux and neutron flux high Thus If other reactions (such as destruction of the tar of reactions other the (suchIf destruction as

the half-life of the product,s of the half-life the Neutron capture Neutron N A 153 a N

. Sm, Sm,

A σ is Avogadro’s is A constant,

. φ 169

. ( Yb and and Yb 1–exp ( – 177 ln(2) Lu can be produced Lu can with T 1/2 64

. irr t Cu. Cu. irr the irradiation time.

)) the cross-section the a high capture the atomic mass, atomic mass, the ------111 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 112 Nuclear Physics for Medicine – Chapter III – Radioisotope Production “carrier-free” no of product stable if the impurities Enrichment is performed via ultracentrifugation of performed ultracentrifugation is via Enrichment for repeated separations of the daughter. After each for each repeated After daughter. of separations the increased after irradiation sepa by physical mass irradiation increased after isotope were present in the target material and other other isotope and were material present target the in isotope. However, neutron cases capture certain in isotopes). meth the to behandled; has material radioactive if isotopes. However, mentioned the enrichment all material. enriched highly ing of obtain difficulty of the indication isotopes an as depleted stable other isotopes in donot that contrib differs chemically from the target and can therefore and can fromthetarget chemically differs but directly radioisotope not does produce final the produced by neutron same to belongs the capture more isotopesthe than efficient physical but ones, over to the contribute can substantially material isotope and target useful the in enriched is material ods take time (decay time take ods losses!) have and overall an ticularly high neutron flux is required to bypass is neutronto required bypass flux high ticularly consecutive by two target neutron Apar captures. short-lived since interesting isotopes can ticularly “non-carrier- so-called to products leads in usually radioisotope final the wanted isotope.to Thus the be even would techniques more to implement costly ionisation or laser ortion dissociation selective laser ute production to the desired of radioisotope. the be extracted again and again, even half-lives many again, and again be extracted indirect production This separated. be chemically ration of the radioisotope from remaining stable ration radioisotope of the from remaining respectively. and Most arecostly of techniques these radioisotopes can only be reached only radioisotopes from can astable able at remote places (see 2.1.6). section precursora radioactive decays that by decay beta cost ofproduced the radioisotopes.tables The all appreciable ( activity specific after the end of irradiation. Hence, generatorstheend irradiation. are of after ate isotope longer-lived is it generator may as serve factode often are which (n.c.a.) quality, added” essential to shorter-lived make essential avail isotopes easily target to the identical chemically is element, i.e. valuable (loss ofunity radio below efficiencywell longer-lived intermedi the desired radioisotope. If single separation is performed after decaythe separation performed is to after single separation new daughter activity will grow in and grow and in will activity separation new daughter isotopic of target show the abundance natural the complex, therefore the cost of highly enriched target target enriched complex, therefore cost of the highly can be separated again. Such generators Such par are beseparated again. can used. chemicals gaseous compounds, electromagnetic mass separa mass electromagnetic compounds, gaseous To optimise specific activity often the target the often To activity specific optimise In certain cases ( cases certain In In principle specific activity could also be also could activity principle specific In If the intermediate isotope intermediate short-lived, the is If a Chemical separation methods are generally generally are separation methods Chemical 166 Dy, Dy, 188 W, W, R > 0.05) in this way. >0.05) this in 195m Ir) the required required the Ir) ------

Thus 30 MeV Thus employed protons to make areusually MeV protons to exploit (p,2p) (p,4n) reactions.Also (see ( Fission of actinide targets efficiently efficiently produces targets neu Fission of actinide Proton (p,n) induced reactions as such (p, and of photo-fission or fission from stable Figure 2.1. flux; therefore particu with positions irradiation flux; from all other products other except isotopes other offrom all isotopes with compactisotopes accelerators. with Additional dominate for lowdominate proton energies ( uct produceduct by double neutron increases capture tens oftens MeV. protons with of 100 MeV Finally or topes as such separated be chemically can and target actinide the from tron-rich ranging atomic masses isotopes with the same element, thus leading to relatively high to relatively high leading element, same thus the reaction channels such as (p,2n), as such (p,3n)reaction channels or (p,4n) roughly in proportion neutron of square in to the the roughly reactions forproduction the of neutron-rich iso and are essential for production of essential are mostand PET are openedare proton at consecutively higher energies. about 85 to 150. neutron Most frequently thermal 2.1.3 2.1.2 efficiently the intermediate shorter-lived isotope isotope shorter-lived intermediate the efficiently ered. The product elements differ chemically from chemically The ered. differ productelements larly high neutron flux are neutron to required producehigh flux high larly specific activity isotopes viadouble neutron activity specific capture. specific activity. activity. specific mainly Today capture ofcapture good use of the (p,2n) excitation functions and 70 and (p,2n) of the good use excitation functions R ≈0.5) and Proton induced reactions induced Proton Fission Figure 2.1 Figure Example of a double neutron capture reaction leading leading reaction capture neutron adouble of Example 186 W to the generator isotope isotope generator the W to 235 133 U is used, but neutron-induced fast used, U is 47 Xe ( Xe ). The specific activity of the of prod activity ). The specific Sc or Sc R ≈0.1) produced are by fission. 67 Sc require protonsSc of several 238 U are also being consid being U arealso 188 W. W. 99 Mo ( Mo ≈ 5–15 MeV) 5–15 MeV) R ≈0.1), ≈0.1), 131 a I ) - - - - - When it comes to practical, economical high yield yield high it economical comesWhen to practical, variety of products which gives the method more gives method of the products which variety ventional production scheme been setup has or for with the ISOL method at ISOLDE (CERN), but (CERN), it at method ISOLDE ISOL the with For certain isotopes that cannot be reached easily bereached isotopes cannot easily that For certain far more economically and in amuch more in and readily morefar economically - major diagnos all obvious that fact Itform. an is for is is preferredinduced reactions generally are whenever However, presentlyis commercial not use. in it is isotopes of reduced often are radioisotopic purity different nuclear reactions, differing not only in only not differing nuclear reactions, different decay times leads to products of sufficient purity, e.g. e.g. topurity, products leads ofdecay sufficient times projectile energy and the target material isotope, material target the and energy projectile proton bombardments: bombardments: proton mostfavours often protons. givenFor a projectile away tar from ofthe population isotopes further the becomesmore, possible allows spallation that proton bombardment on on bombardment proton quick access to unusual radioisotopes before acon accesstoquick unusual provideapplicationsto R&D greatinterestforof tionships as function of specific activity. of specific function as tionships separation Chemical stepstion more challenging. subsequent the makes but separa also universality tic isotopes for nuclear medicine imaging (SPECT isotopestic imaging for nuclearmedicine avail required isotopes the stable target are readily therefore protons.with achieved often Thus proton- or, unit are more power per beam unit importantly, current per beam production yields highest the comparable At productiontargets. cross-sections in range largest lowest the loss the and energy tiles, but also in the mass and charge of the projectile. projectile. of the charge and mass the in but also by proton-induced heavier reactions, projectiles available way from reactor-derived are warranted. The main alternatives to protons The main warranted. are and and PET) simplyand and made most are by efficiently chemical asuitable bebombarded in able can and production choice the of projectile purity high and ofrela dose–effect studies systematic e.g. activity, specific high particularly applications requiring gen of the selectivity acceptable chemical the since shorter-lived decayall after of ones). generatorAlso 2.1.4 energy, protons have, compared to heavier projec step. erator purification provides additional an chemi of combination a sometimes but element, chemical element chemical on-line separation possible, is e.g. and chosen irradiation suitably separation with cal removecannot radioisotopic same of the impurities get. Spallation with GeV with protons Spallation get. produces a large 99m Most by bemade of isotopes anumber can Physical mass separation in combination with combinationPhysical separation with in mass 67 201 Light ion induced reactions induced ion Light Cu (the longest-lived copper isotope remaining Tc, can that Tl. The only important exception to this rule rule exception this important to The only Tl. be made efficiently and pure and be efficiently made by 11 C, C, 100 13 Mo, but still is made is Mo, but still N, N, 18 F, F, 99 67 Mo. Ga, Ga, 111 In, In, 123 I ------The optimum half-life of an imaging isotope for imaging an of half-life The optimum (p,n) reactions e.g. but may provide yields, higher ( Neutron-induced (n,n’), reactions like (n,2n), (n,p) where where fluorine (F fluorine for for isotopes challenges the chain from production, via chain the isotopes challenges nium targets exist for alternative (p,xn) reactions. exist targets nium non-enriched targets instead of requiring highly highly of requiring instead non-enriched targets dose one should select the shortest-liveddose one the select should isotopes it to given takes is time by the purposes diagnostic produced produced water targets. in taken. are measures the reducing thus channels, exit many populate of the radioisotope remains longer in the body (not body the longer radioisotopeof in the remains (n, or traces oftraces stable F the corresponding corresponding the ion heavy heavierthe reactions (Liand projectiles) topes like 2 minute 2minute topes like to photon ( induced reactions as such forused radioisotope production. same The applies nosince stable emitter polo alpha promising to this reaction the Thus, protons two target. the more with ucts than bombardment considered is too expensive or techni be used for the same purpose but they may but lead they to purpose forsame be used the or ventilation few seconds for as short lung be as reactions regularly these are afew cases in but only radionuclidic impurity is impaired if no additional no if additional impaired is impurity radionuclidic available yield in each channel and the resulting resulting the and channel each in available yield are deuterons and alpha particles. Triton deuteronsare particles. alpha and and an issue for ventilation studies). Hence, to minimise for issue studies). ventilation an Hence, to minimise achieve arepresentative can This biodistribution. 2.1.6 2.1.5 handling to injection into the patient. Indeed iso patient. Indeed intothe to injection handling enriched enriched enhanced radiation doses to the patient if a fraction patient dosesto afraction the radiation if enhanced enriched enriched lead to the same target–productlead same to the combinations as specific activities compared activities reactions, specific standard to chemical processes comparedchemical fluoride to the (F while use, scale large to warrant challenging cally compatible agiven application. with Longer-lived studies. isotopes can perfusion cardiac g ,p). The Alpha-induced reactions provide accessto prod Also the the Also In other cases deuteron cases other induced(d,2n)In reactions On the other hand the use of very short-lived of very use the hand other On the 44m Radionuclide generators Other reactions Other a 14 Sc productionSc from ) give access to additional products or higher products or higher ) give accessto additional 14 N is abundant (99.6%) abundant N is expensive rather than N(d,n) 15 18 18 N (0.4% abundance) required natural for 2 O for the ), an advantage for certain subsequent advantage for), certain an F will be readily available in form of in available bereadily F will 209 20 Ne(d, Bi( 15 O reaction uses natural nitrogen natural O reaction uses 2 a are added to the gas target the the target gas to added are the 15 ,2n) 15 N(p,n) a O are used for PET imaging, for used O are PET imaging, 18 ) 18 O(p,n) 211 F reaction makes use ofF reaction use makes At is the only direct way direct only the is At 44 15 Ca targets. O reaction. 18 F reaction. When F reaction. When g , g ’), ( ’), g ,n) or or ,n) 3 He He - ) - - - - 113 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 114 Nuclear Physics for Medicine – Chapter III – Radioisotope Production would indeed be better to transport the cow the to the to transport bebetter indeed would from which the wanted product can be “milked”. If If be“milked”. wanted product the can from which importance it today. has importance generators Such are beseparated again. can and in generator. from (“eluted”) the extracted is After chemi loadedis onto a “generator” usually is and invention enabled of that introduction an the isotope generators more often is challenging nuclear reactors with particularly high neutron flux neutron flux high particularly reactorsnuclear with daughter isotope ( isotope daughter decay of the mother isotope, the daughter which which decay daughter mother ofisotope, the the decays wanted shorter-lived tocontinuously the milk were some perishable as it radioisotopes as are, milk produce efficiently provide more energetic arerequired projectiles to more away “exotic”, from stable isotopes further i.e. production. Most of mother isotopes the are slightly separation added performed before just This use. probably would medicine have not reached the short-lived since interesting isotopes particularly anddecay significant is challenge ment logistical the or during loading of the generator) of the loading providesor during often Here a logistics. patients and ments in for use require half-life of contradicting dilemma of the topes isotopes. Hence, production imaging of the to direct equip this room even and with PETto the imaging but only a few nuclear medicine departments are departments afew nuclearbut medicine only rapid transport systems from the central cyclotron central from the rapid systems transport additional chemical separation step during elution, elution, separation step during chemical additional atavailable remote The most locations. prominent to makeshorter-livedare essential isotopes easily are required to produce the generator efficiently iso production requires their moreand compared effort product. of the activity has to be produced than that which is actually used. actually is which tohas bethat produced than has chemical properties different fromthe mother properties different chemical has enhanced radionuclidic purity and high specific specific high and purity radionuclidic enhanced SPECT isotopeexcellent to remote nuclear places, example the is appropriateequipped cyclotrons” or with “bedside each separation new daughter activity will grow will activity new separation each daughter losses are unavoidable, i.e. far more radioactivity more unavoidable, far losses are radioactivity i.e. lives after the end of irradiation. theHence, end generatorsirradiation. of lives after longer-lived mother isotope produced is that step (in addition to performedstep aseparation (in before addition isotopes daughter by sufficient have accumulated can be extracted again and again, even half- many again, and again be extracted can After to stay bound there quasi-infinitely. cally customer rather than the milk. the customer rather than The price to paythe forconvenience of radio Various chemical methods are used for used are theVarious methods chemical A convenient side effect of a generatorthe is Radioisotope generators a Radioisotope “cow” called often are Radioisotope generators wayRadioisotope elegant out an are 166 Dy, Dy, 188 W or 99 Mo/ Figure 2.2 Figure 229 68 Ge, Ge, Th and larger acceleratorsandlarger that Th 99m Tc its generator. Without 82 Sr, etc. ). Theisotope mother - - - - - These generatorsare theplacedclose user,end to i.e. Longer-lived beshipped to remote can daughters directly directly (green). of decay the to comparison in time of function as Figure 2.2. it often more is the convenient genera to centralise to minimise department, nuclear medicine the in 82 decay losses after “milking the cow”.the decay If decay“milking losses after daughter isotopes respectively:daughter product isotope, attached generator or the directly is which form of the “kits” in departments medicine min short-livedproduct very is (5 s product is tested regularly (e.g. beforeproduct daily) of tested use is regularly used for simple chemical processing. The chemical chemical The processing. forused simple chemical to an often automated radiochemical often system. processautomatedto an radiochemical user perspective it is more interesting to classify the the perspectiveuser it moreto is classify interesting From etc. systems, the gas–liquid distillation, tion, tor operation and the subsequent quality controltor operation subsequent the and quality scheme assurance quality Hence, astringent use. the generatorthe for humans. reactants are either readily supplied nuclear to the are either readily reactants are always kept in central locations that have locations that kept central always are the in are simply mixed with the eluted the or preprocessed with simplyare mixed providedas generator by the generator the and is has to be respected where the quality of the eluted of the to berespectedhas where quality the leaving no time for a quality control step before for aquality no leaving time a) Generators with short-lived daughter isotopes daughter short-lived with Generators a) separation of mother and daughter isotopes: liquid isotopes:separation of daughter liquid mother and steps. Hencesteps. generators providing chromatography, liquid–liquid extraction, sublima chromatography, extraction, liquid–liquid customers excessive without decay Therefore losses. patient, to the connected more or less “directly” generators of mother and half-life to the according b) Generators with longer-lived daughters longer-lived with b) Generators Rb), form a simple product the in chemical used is Somewhat longer-lived products (such 68 as 68 Ga, 45 min 45 min Ga,

99m Tc activity (blue) available from a from available (blue) Tc activity 213 Bi or even 10 min 191m Ir, 13 s 90 99 Y, Y, Mo/ 99m 223 62 Tc produced 99m Cu) be can Ra or Ra 81m Tc generator Tc generator Kr, 75Kr, s 225 Ac Ac - - vide vide US and Canada. The logistics effort is clearly smaller smaller is clearly effort The logistics Canada. US and ficiently different chemical an to enable different properties chemical ficiently Certain isotopes haveCertain good properties for imaging from distributed or central or central from distributed c) In-vivo generators In-vivo c) irregular use of an own generator own of an use decay if losses and irregular former (weekly the of case radioactive in dispatch Future isotopes. during distribution of distribution during more make can effi system latter the day) while packages versus shipping daily or several times per per or several times daily versuspackages shipping or therapy respectively but aresimply too short-lived the in practised is mainly model This on demand. targets in nuclearreactors. in targets tope shipped customer and to the required amounts the the mother and daughter isotopes have should daughter mother and suf the short-livedto desired the the emits that daughter decay then required, as localise patient will the that human the in destination to be brought to their be produced daily by neutronbe produced capture on stable daily body in time before they decay. In certain cases cases before decay. time they certain in body In radiation. In contrast to vivo ex In generatorsradiation. where for long-lived the permits mother required handling a longer-lived into beinjected mother isotope can in product the dispensed is then eluted, regularly are distributors. at central remain also efficient separation, for in efficient vivo in separation, for generators similar generators the Alternatively needed. when eluted toerators end where are users they distributed are cient end have mother ofisotope users the the use if where beplaced radiopharmacies at central they can groups 1 and 2 In Europe and Japan Europe and groups 2 In 1 and “strange” chemical element not chemical present“strange” nature. in National Laboratory developed Laboratory toNational amethod The misjudged generator misjudged The In 1957 Brookhaven atIn the radiochemists Filing of apatent pat BNL by refused the was Filing of patenting” of great technetium-99 for market of apotential poses in the laboratory” pur experimental probably mostly for be used nuclear medicine and 30 million patient doses million 30 and medicine nuclear enough to encourage one to undertake the risk the risk to undertake to encourageone enough ply of asimplemake reliable generator and forsup the of of radioisotope generators workhorses the are of “the product will will product “the argument the entwith office Another boundary case is the therapeutic the is iso case boundary Another 99m 99m 44 188 Tc with 6 hours half-life is at the boundary of Tc boundary at is the half-life 6hours with Sc without a local cyclotron probably would a local without Sc Re (T Re Tc eluted are year. every 99m Tc, one just radioisotope time of at the a 1/2 [Ric82]. Today such =17 hours) either be eluted can that 44 Ti/ 44 99m Sc generatorsSc pro could that and “We not are aware and Tc acceptable. remain 188 W generators or even even or generators W 99 Mo/ 99 Mo/ 99m 99m Tc gen Tc 187 Tc Tc Re Re ------• • • • The 75s) positron emitter, (chelator). This issue is particularly (chelator).problematic for is particularly issue This 188 188 188 from a is a chemical homologue of molybdenum and rhe homologue and of molybdenum achemical is on section therapeuticemitters. alpha the in nium is a homologue of technetium; hence ahomologue is of the technetium; nium daughter remains at the intended at place the where remains daughter the months, thus giving convenient giving in-house to access thus months, one particular In mother isotope delivered. was myocardium and allows evaluation and quantifi and evaluation allows and myocardium for agiven better application). beslightly might of of tages as compared as tages to monophotonic such emitters reactors. flux to beproduced high in post-concentration radiochemical time-consuming convenient since elution volumetle particularly are (eventions decay of the parameters isotopes other if release of the daughter from the delivery vehicle delivery from the release daughter of the a therapeutic isotope. This explains why explains a therapeutic isotope. This where emitters violentalpha the recoil may break as as of potassium, analogue an has to verify that the nucleardecay not the does that break to verify has high specific activity activity specific Ci/g)(≥ 1 high that is has required even strong chemical bonds. Details are discussed are discussed Details even bonds. strong chemical eluted eluted separator technology (adsorption on acid alumina (adsorptionseparator technology on acid alumina short-lived Tungsten isotopes not does exist. always suspected coronary disease. As a short lived (T As disease. coronary suspected steps not are However, required. cation of myocardial perfusion in patients with patients with in perfusion cation of myocardial column) is identical to the well-known Mo/Tc well-known to the column) identical is wherecountries ajust-in-time network of delivery lead to could uncontrolled which bonds chemical properties the required are that to ensure chemical cardiology for more than 20 years in the USA. As As USA. the years in for 20 morecardiology than generator. Moreover the labelling chemistry of the of the generator. chemistry Moreover labelling the emerging in popular generators particularly are The possibility for quantification possibility The Lower radiation dose to the patientsLower dose to the radiation Better correction ofBetter attenuation the of photons in Shorter duration of the examination (rest examination ofShorter duration and the for overweight patients and women with large and for overweightand large patientswomen and with dense breasts dense the tissues leading to fewer false positive to fewer results false leading tissues the stress examinations can be made in aboutmin) 30 in bemade can examinations stress Re often the prime choice for therapeutic applica therapeutic for choice prime the often Re W/ Re can be eluted once or several times daily beeluted daily once can Re or several times 99m 188 188 82 82 Sr/ W these generatorsW these for beused several can Tc and 188 W/ Sr/ 188 188 Re generators providing high activity in lit in activity generatorsRe high providing 82 188 82 Re correspondsRe of to that W/ Rb generatorRb Rb generator nuclear Rb in been used has Re generator 188 201 Re generator.Re half-life 69 days With Tl: 82 Rb presents advan several Rb 82 Rb is extracted by the by the extracted is Rb 188 W of relatively 99m Tc, making 188 W/ 188 1/2 1/2 Re Re = - - - - - 115 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 116 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 100 µA). After irradiation, an extraction and purifi extraction an irradiation, 100 After µA). The The very corrosivevery con aniobium in becontained must which targets the cancer cells. The big advantages The advantages big cells. cancer the targets which has resin This adsorbed. is strontium the which oxideresinon stannic of consists ashielded which across has of section aboutwhich 100 mb. Large Below this energy, no Below this Due to its short half-life, rubidium cannot beeffi cannot rubidium to half-life, itsshort Due 68 for positron To tomography emission imaging. do is well suited for use with peptides and several appli and peptides with for suited use well is 82 diation (T diation during during manium is extracted and purified before purified shipment and extracted is manium protonproduced below MeV using 30 beams on a molecules. Due to its half-life (T to its Due half-life molecules. patients. production of protons energy (>produced high using MeV). 40 of neuroendocrine tumours. neuroendocrine of of increasing the melting temperature and allows temperature allows and melting the of increasing from time destruction to target observed leading of of cases, both In targets. as used are metal or rubidium to the generatorto the manufacturer. to take target rubidium the placed is behind target solution The other thepresents to advantage time. corrosion be cracks Despite can tainer. and this, the properties to retain strontium isotopes strontium not and properties tothe retain the generator to fill generatorto the manufacturer nuclear reactionthe of interest (p,4n) the is reaction the using rapid via chelators efficient and to coupling biologic ratio (89%) a allow properties that its chemical and ready to be injected topatient. the A generator typi adoseof isotopes. When rubidium reaction on enriched advantage of the remaining energy of protons the energy advantage of remaining the irra under themelts target case, first the In alloy. and 6 weeks depending on the number ofon the injected 6 weeksand depending safer irradiation especially in the case where case the the in especially irradiation safer so, the the so, the and column the NaCl injected is through sterile cations have been developed to be used in imaging cations have been developed imaging in to be used cally contains 4 GBq and can be used for between 4 for4 be used between can and 4GBq contains cally cation of the product ciently produced but a direct obtained is as gallium target, either in elemental form or as Ni-Ga form Ni-Ga elemental or as eitherin target, gallium get is made of rubidium. Rubidium chloride (RbCl) chloride Rubidium ofget made is rubidium. Ga is eluted is Ga from generators. Rb is eluted. The solution containing The solution eluted. is containing Rb 68 Different generatornowadaysexist based designs 68 68 68 Ga are related to its high positron branching positron related are Ga branching to itshigh Ga can be produced directly using a(p,n) using be produced can Ga directly Ge/ Ge/ 68 82 Ga must be attached to beattached avector must Ga molecule 68 Sr production. After irradiation, the ger irradiation, Sr production. After 68 82 melt Ga generatorGa Ga generator is mainly used in oncology oncology in used generatorGa mainly is Sr/ 82 =37°C) and liquid gallium which is is which =37°C) gallium liquid and Sr is needed. This product is then sent productis This needed. Sr is 82 82 Sr requires high intensity beams (> beams intensity Sr requires high Rb generator. Rb 82 68 Sr can beproduced.tar The Sr can Zn targets but most targets often Zn 82 68 Sr (T Sr Ge (T Ge 1/2 = 68 min), = 68 82 1/2 Rb is needed, needed, is Rb 1/2 82 =25.5 d) is Rb is then then is Rb =271 d) is 68 Ga Ga ------Alpha particles are emitted directly from the from the directly emitted are particles Alpha vivo generator. A phase I clinical trial is currently currently is vivo trial generator. Aphase Iclinical US breeder molten salt reactor research programme (d,2n) reactions on (T1/2=0.3µs). It is obtained through the decay(T1/2=0.3µs). of the through It obtained is Non-Hodgkin’s Lymphoma different the among are with high energy protons. energy high with working on producing working and tumours brain Leukaemia, level. clinical as well - be eas can and rare earth lightest the is Scandium from from ily attached via chelators via attached tovectors. biological The ily in 36% of the case or after thedecay beta to or after case of 36% the in 213 212 212 225 nium series. series. nium decay of 7340-years decay of 7340-years performed with this isotope at the preclinical as as isotope preclinical at the this performed with medium half-life (T half-life medium eluted the some requirements, cases, in maceutical HCl solutions.performed To using meet radiophar produced (p,2n) in reaction on manipulation of large amounts of amounts of large manipulation approach applications. Another of consists medical of of on TiO on of V, Fe Thus or Cu. of a ter ter (post module).processing module purification tional using using have of that cancer been studied. types beam dumps that have that dumps beam for long been time irradiated both nuclides are members of the extinct neptu members are nuclides extinct ofboth the antibody fragments. antibody ated by protons, raysneutrons to or produce gamma available are for quantities small only available and stored currently at is ORNL. and as for for as similar to that of to that similar solution from the generator passes through an addi solution an generator from the through passes case, the proton the beat 100 must least case, energy MeV. generator. The long-lived long-lived generator. The geted therapy. alpha have studies Several been Pb (T Pb Bi is an alpha emitter with a half-life of 61 a half-life with min. emitter alpha an Bi is Bi is an alpha emitter that can be used for beused tar can that emitter alpha an Bi is Ac directly or as adecay or as product of Ac directly 68 Actinium-225 is currently obtained from the obtained currently is Actinium-225 44 In recentIn several laboratories years, have been 44 225 212 44 232 Ge can be loaded on agenerator. can Ge is Elution Sc can be directly produced through (p,n) produced and through bedirectly can Sc Ti/ Sc makes it interesting to peptides or label it makes Sc interesting Pb/ Ac/ 233 226 Th target in high energy accelerators. In this this accelerators.In energy high in target Th 229 2 1/2 U as the first alphadecay daughter, and first the U as Ra (T1/2=Ra irradi material 1600y) target as 44 , SnO Th, the availability is restricted and theand is restricted the availability Th, 212 213 Sc generator =10h) the and Bi generator Bi generator 233 2 U, which has a fission characteristic characteristic afission has U, which or organic resins. Up resins. to 3.7 GBq or organic 235 44 U, was produced as part of the ofU, the produced was part as 1/2 Ca or obtained from a orCa obtained 229 225 44 =3.9 h) positron of the emit Th. Thorium-229 originates originates Thorium-229 Th. Ti can be extracted from be extracted Ti can Ac from proton irradiation 212 44 Pb/ Ti (T Ti 212 45 Sc or by spallation or bySc spallation Bi is used as an in in an as used Bi is 229 1/2 226 Th is not easily is Th not easily =60 y) be =60 can Ra is tricky. is Ra 225 44 Ra. But But Ra. Ti/ 212 212 44 Po Po Sc Sc Bi Bi ------The two main tools isotopes, to tools produce two main medical The flux that allows the production quantities large of allows that flux Certain research reactors neutron provideCertain a high fundamental neutron reac physics irradiation and fundamental 2.2 in turn from turn in 228 224 neutron beams that serve for neutron scattering and for serve and neutron that neutron beams scattering dent scenarios, neutron dent scenarios, sources for extracted intense ments, components of existing and future reactor future and componentsments, of existing 2.3 Figure applications. medicine of new reactor concepts (e.g. neu fast reactors with at aimed of reactors not are that primarily types ous applications. other of and radioisotopes for medical US for the breast expressing in cancer ongoing the HER-2 antigen using the trastuzumab anti trastuzumab the HER-2the using antigen tron spectrum, molten reactor, salt tron etc.), spectrum, reactors for set large of a radioisotopes for offering nuclear tary types), for neutron of doping semi transmutation tors have positionswhich with in-pile irradiation body. In order to transport the body. the order In to transport research reactors accelerators, and complemen are Thus rium. a generator which in turn derives from agenerator…a generator turn in which 2.2.1 high flux for test irradiations of materials eleof materials irradiations for test (fuel flux high electricity production. There are often prototypes are There production. often prototypes electricity studying certain aspects of reactor aspects physics or acci certain studying steps raw separated from to the radio the material chemical solution readychemical for labelling. Ra retrieved from the natural decay chain of tho decay chain retrieved natural Ra from the Ra/ The generic term “research reactor” covers vari Production facilities Production Radioisotope production in nuclear reactors 212 Pb generator provided. is 212 Pb agenerator is from isotope deriving 228 Th decay and the anddecayTh 212 Pb to hospitals, a a hospitals, to Pb 224 228 shows the main shows main the Ra is extracted extracted is Ra Th stems from stems Th ------“useful” fissile fissile “useful” The neutron flux in the reactor is deliberately limited limited the in deliberately reactor is The neutron flux (low enriched uranium with <20% enrichment of enrichment <20% with (low uranium enriched ( which require appropriatewhich materials. construction and flux the effectively usable flux varies strongly with with varies strongly flux usabletheeffectively flux Some reactors provide in-pile irradiation positions positions irradiation in-pile provide reactors Some in the design to avoid design the in acombination of thermo- 235 neutron flux at limited thermal power thermal generation limited neutronat flux nuclear power even and for comparable maximum mass is compensated by higher enrichment of the of compensated the is enrichment mass by higher massive pressure of vessels most power reactors are The damage. radiation high with stress mechanical maximum neutron flux does not scale with the with does not neutronscale flux maximum the core different todesigns production. very Due higher neutron require flux highest the providing to tens of kg of uranium are used, but this lower but this used, are to of tensof uranium kg distinct. of research reactors usually are types the available irradiation positions. Reactors with positions. Reactors with available irradiation the power relativelythe low contributes thermal to the ble neutron fluxes are optimised antipodal powerto antipodal bleare neutron optimised fluxes be exchanged. reactor of the cannot and lifetime forentire the built reactors. The aim is to produce the maximum useful useful is to reactors.producetheaim maximum The ability of different ofresearch different reactors for radioisotope ability entire coreentire more up afew kg far are compact. Only temperature pressure high and at high extracted exceptional inherent safety of research reactors.exceptional inherent safety (upenrichment and to 93%).fuel of mass tiny The sion of heat to electricity.Therefore is the coolant conductors and finally for radioisotope production. conductors finally and Table 2.1 Table U) is used for used mostU) is research those reactors while There is no straightforward ranking of the suit of ranking Thereis nostraightforward Research reactors that aim at the highest possi athighest the reactorsResearch aim that Power conver reactors at efficient aimed are extracted neutron beams while the first listed first the neutron while extracted beams ). Therefore the fuel elements and the). Thereforeelementsand fuel the 235 U. Today generally so-called LEU U. LEU Today so-called generally example of of example the at isotopes produced steps for accelerator or reactor Figure. 2.3. 18 Typical process process Typical FDG and and FDG 177 Lu. - - - 117 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 118 Nuclear Physics for Medicine – Chapter III – Radioisotope Production Thus operators can access the top of the pool during theThus operators thetoppool during access of can where reactor the core control and situated are rods FRM2) have a very high neutron flux just outside the neutronoutside just have flux high FRM2) avery that is usually accessible for production of medical radioisotopes is given. is radioisotopes medical of flux production for neutron thermal accessible usually is that unperturbed maximum The [RRDB]. production radioisotope for used are that reactors research 2.1. Prominent Table fuel element (e.g. flux trap in HFIR). Reactors with with Reactors elementHFIR). trapin (e.g.fuel flux is situated in a closed cooling circuit operated circuit at aclosed cooling situatedis in in pool reactor”.in Heavy-water moderated reactors pressure same core. the the vessel Alternatively as in diation positions distributed over positions volume. distributed diation alarger multiple fuel elements (e.g. BR2, HFR, NRU) not do HFR, elements (e.g. fuel multiple BR2, only the core the aonly pressure placed is in vessel but the reactor” moderator the placed is a “tank of bar. In lines. or fishing shield. efficientof 6mor more an radiation as acts tion positions from the top with long manipulators long manipulators positionstion top from the with positiontion recovered and irradiation. after irradia introduced into the beeasily can targets the reactor operation and load and unload the irradia the reactor operation unload load and and but provide flux peak reachmore same irra far the requires a faster waterrequires afaster flow. Therefore the core a single compact fuel element (e.g. HFIR, RHF, RHF, element compact (e.g. fuel a single HFIR, also use this concept to precious enclose this the use heavy also open bottomat reactor of the Awater an pool. layer higher water pressures up of tohigher afew bar tens surrounding elements stay in an open pool: a “tank open a“tank pool: elements an stay in surrounding core (at 10 hollow the cminside distance) to and 20 LVR-15 BRR RA-3 Maria OPAL OSIRIS FRM2 NRU SAFARI HANARO MURR HFR BR2 RHF SM-3 BOR-60 Research reactor HFIR At higher power efficient cooling of the powercore of efficient higher At cooling The easiest access is in “pool-type reactors” “pool-type in access is easiest The For radioisotope production that it essential is NRI KFKI CNEA Polatom ANSTO CEA Saclay CEA TUM AECL NECSA KAERI Univ. Missouri NRG SCK-CEN ILL SSC RIAR SSC SSC RIAR SSC Laboratory ORNL Ř Budapest, Hungary Ezeiza, Argentina Ezeiza, Poland Ś Australia Heights, Lucas Saclay, France Saclay, Garching, Bavaria Chalk River, Canada Chalk Africa Pelindaba, South Daejeon, South Korea South Daejeon, Columbia, USA Petten, Netherlands Mol, Belgium Grenoble, France Dimitrovgrad, Russia Dimitrovgrad, Dimitrovgrad, Russia Dimitrovgrad, Location Oak Ridge, USA Ridge, Oak wierk-Otwock, wierk-Otwock, ež, Czech Republic Czech ež, - - - Alternatively the tank has to be equipped has with tank the Alternatively water in the surrounding pool. surrounding the water in separate it thus from light and the a tank water in flux, the main why reasons power the main are reactors not flux, from the tank while the tank is not under pressure, not is under tank the while tank from the from the reactorfrom the core (several W/g core close to the in boiling water reactors and CANDU reactors but water reactors CANDU and boiling in positions for suitable are productionirradiation such reactor when the not Thus, is i.e. operating. neutrons through a target does not does heat atarget latter the neutrons through feasibility. nomic diation samples during reactor operation. samples during diation remove to introduce and inserts irra dedicated the different from cyclotron targets. Unlike charged fromcyclotronUnlike targets. different mensurate with the operation the reactor. of cycles the mensurate with of longer-lived half-lives com radioisotopes with particle beams the simple passage of thermal of simple thermal the passage beams particle nuclear reactors in production quite are targets operation cycles are, together with the lower the operation neutron together with are, cycles used for production of medical isotopes. Conceptual forisotopes. Conceptual used production of medical samples havethe to beremoved loaded into and so far noneso far projects of demonstrated these has eco significantly. However, rayssignificantly. gamma by the heating havestudies been performed for core during operation together with the very long very the operation with together core during The difficulty of accessing positionsthe close to of accessing difficulty The When producing radioisotopes in tank reactors tank radioisotopes producing in When The technical challenges for radioisotope challenges technical The 1.7 1.4 2.4 2.5 2.5 2.7 4 (fast), 1.34 (fast), (th.) 4 4 4 4.5 4.5 10 (tank), 3.6 (pool) 3.6 10 (tank), 15 19 20 (fast) (10 Thermal flux 25 14 cm -2 s -1 )

10 10 10 30 20 70 20 135 20 30 10 45 100 58 100 60 85 (MW) Power 99 Mo production

- - - values of the reactor ofvalues the core. Therefore nuclear reac with advanced systems for nuclear safety: multiple multiple for advanced nuclearsafety: systems with Table 2.2. neutrons. In certain cases (e.g. cases certain neutrons. In duced directly by neutron capture. The maximum by neutron maximum The capture. duced directly diation times are used for higher throughput. for used are higher times diation resonance of capture epithermal due to additional power) fissile heatThus provide load. significant of large activities of radioisotopes. activities of large reactors) flux theoftheand high self-heating of time would be impractically long (many years) beimpractically would totime predestined for production safe tors naturally are reach saturation activity, thus in reality shorter irra reality in thus activity, reach saturation radioisotope reactor inventory used and of operating achievable specific activity was activity) activity (saturation achievable specific respective of represent the fraction aminor only ally high neutron capture cross-sections to be has conhigh liquid effluents, etc., assure safe managementsafe the assure of etc., effluents, liquid and of supervision gaseous tight shielding, logical samples irradiated for radioisotopesamples irradiated production usu massive bio building, the including barriers safety sidered. reactors Nuclear equipped inherently are positions reactor close tosamples the or irradiation that reach targets kW/g for fissile sample (mainly cm neutron forof fluxes thermal calculated 10 anddose rates radiotoxicities of cores. activities, The cooling. sample for forced convection require core usually 169 169 166 153 117 103 99 90 89 64 60 32 isotope Product 195 193 192 188 186 177 -2 Table 2.2 Table Mo Y Sr Cu Co P Finally the self-shielding effect of materials with with of materials effect self-shielding the Finally Pt Pt Ir Re Re Lu Yb Er Ho Sm Sn Pd s -1 -1 respectively. Experimental values may differ may values differ respectively. Experimental Radioisotopes produced directly by neutron capture reactions. reactions. capture neutron by directly produced Radioisotopes shows a list of shows radioisotopes pro a list 4.02 d 4.33 d 73.8 d 17 h 3.72 d 6.65 d 32 d 9.4 d 26.8 h 46.3 h 13.6 d 17 d 66 h 64 h 50 d 12.7 h 5.27 a 14.3 d Half-life 60 194 192 191 187 Co) the irradiation irradiation Co) the 185 176 168 168 165 152 116 102 98 89 88 63 59 31 isotope Target Pt Pt Ir Re Cu Co P Mo Y Sr Re Lu Yb Er Ho Sm Sn Pd 14 and 10 and 33 0.78 37 63 37 2.6 0.13 27 100 27 15 1.0 69 100 100 24 100 83 % abundance Natural 15 ------

However, in reality it becomes more challenging to However, it becomes more reality challenging in thermal neutron flux of 1.5 flux neutron thermal a bottom its at providing tube V4 the thimble is image the of centre the below point blue bright The light. Cherenkov by “illuminated” is latter the of bottom The pool. water alight by surrounded is middle the in tank water heavy 7.5 water. The light mof through Figure 2.4. and unloaded with irradiation during shuttles reactor operation. flux the quality of product will remain the same. the same. remain will of product the quality flux material has to be has removed)material requirements the and of but even rise, at lower material) of will target mass the chemical purity of target material and chemicals chemicals and material of target purity chemical the order,to first With notthedepend on neutron flux. achieve a higher separation factor (moreachieve a higher stable target higher flux the yield (i.e. the activity producedyieldthethe per activity (i.e. flux higher In the indirect route the final quality (n.c.a.) does, does, (n.c.a.) quality route final the indirect the In 35 470 190 0.8 21 80 0.003 1.9 0.009 0.6 70 24 4.3 14 0.3 0.08 0.8 0.004 GBq/mg Φ Specific activity Top view of the central part of ILL’s reactor seen ILL’s of seen part reactor central the Top of view = 10 14 cm -2 s -1 × 10 15 cm -2 s -1 . It can be manually loaded loaded manually be can . It 300 1500 260 8 200 640 0.03 18 0.02 6 90 230 40 30 3 0.8 8 0.04 Φ GBq/mg = 10 15 cm -2 s -1 119 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 120 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 10 Irradiation in still lowerispossible fluxes still for in (e.g. Irradiation Figure 2.5. reactions. capture neutron by indirectly produced Radioisotopes 2.3. Table Table 2.3 lowerfor a batch with Table activity. impurities at an acceptable at an level. impurities neutron fluxes ranging from neutron5×10 ranging fluxes neutron flux is not very relevant for the quality is thenotneutron relevant quality for very flux may differ due to additional resonance capture of due to additional may differ product isotope iso of 100% per mg target enriched production is performed in high flux reactors flux at production high performed is in of produced radioisotopes. Large scale industrial of industrial produced scale radioisotopes. Large times weretimes chosen to keep co-produced radioisotope tope) neutron of fluxes for thermal were calculated separation process of traces the since rise in used epithermal neutrons. Typicalepithermal decay and irradiation list of radioisotopes produced indirectly by of neutron radioisotopes producedlist indirectly stable impurities becomestable impurities relatively more important capture reactions. The achievable yields yields achievable The reactions. capture (GBq of Indirect production via(n,f) Indirect production via(n,γ)β 47 133 131 99 227 199 177 161 131 131 125 188 166 isotope Product Production via(2n,γ)reactions 14 Sc Mo Xe I Ac Au Lu Tb Cs I I W Dy As for other indirect production routes for indirect other theAs and 10 and Typical sizes of IBA cyclotrons providing proton energies of 11, 18, 30 and 70 MeV from left to right. to 11, of left 70 from MeV 18, and 30 energies proton providing cyclotrons IBA of sizes Typical 15 3.3 d 2.8 d Half-life 5.3 d 8.0 d 21.7 a 3.1 d 6.7 d 6.9 d 9.7 d 8.0 d 59.4 d 69.8 d 3.4 d cm -2 s -1 -1 respectively. Experimental values values respectively. Experimental 235 235 235 226 198 176 160 130 130 124 46 186 164 isotope Target Ca U U U Ra Pt Yb Gd Ba Te Xe W Dy - 0.004 % abund. Natural 0.72 0.72 0.72 0 7.2 12.8 22 0.11 34 0.10 28 28 13 to 2×10 to isotope mediate Inter- 227 199 177 161 131 131 125 47 187 165 shows a a shows Ca 14 Ra Pt Yb Gd Ba Te Xe W Dy cm -2 s -1 - . Half-life 4.5 d 42 min 31 min 1.9 h 4 min 12 d 25 min 17 h 0.99 d 2.35 h Today two types of particle acceleratorToday for of used are particle types two degree linear accelerators, butdegree linear new developments This requires of massivediation targets. fission difficult. the cooling of the fissile targets gets increasingly increasingly gets targets of fissile the cooling the are not fluxes favourable higher since Still targets. radioisotope production; to alesser cyclotrons and reactors) but tothe alessuse efficient leads of additional investments such as forced cooling, investmentsforced as such cooling, additional are underway. are 2.2.2 handling the heavily shielded transport containers. transport shielded heavily the handling local monitoring of fission gas release, additional additional ofgas fission release, monitoring local supply or regional oflocal shielding and correspondingly heavy equipment for for equipment heavy correspondingly and shielding by accelerators Not research reactor every equipped is for irra Medical isotope production production isotope Medical d Φ T 10 7 7 7 100 7 14 14 7 28 7 100 10 irr =

10 14 cm T 1 7 12 1 d 30 0.5 1 0.5 7 2 7 10 1 d

-2 s -1 0.5 3 0.7 5.7 GBq/mg Yield 0.02 0.7 0.6 0.4 0.7 0.1 6 0.002 2 99 Mo with medium-flux medium-flux with Mo 10 T 28 7 14 14 7 28 4 50 5 d Φ irr =

10 15 1 30 0.5 1 0.5 7 2 7 10 1 T d cm d

-2 s -1 5 0.03 7 4 4 7 1 20 0.1 100 GBq/mg Yield 235 U - 10 µA to 1 mA range. 10 µA to 1mA 2013 [Sch13].2013 a cyclo use facilities Most driven of beam the ( Cyclotrons against their maximum proton beam energy. beam proton maximum their against Figure 2.6. Cyclotron manufacturers 2.4. Table providers worldwide, see of their maximum proton energies world-wide maximum of their in tron. They are commercially available from several areavailable commercially They tron. ating for medical isotope production as a function isotope production forafunction medical as ating size is compact is size plugpower and modest needsare Figure 2.5 Sumitomo, Tokyo, Japan Sumitomo, Germany Erlangen, Healthcare, SIEMENS France Peynier, EuroMeV), (formerly Alcen PMB Korea Seoul, KIRAMS, Belgium Louvain-la-Neuve, (IBA), Applications Beam Ion Sweden Uppsala, Healthcare, GE Russia Petersburg, St. (NIIEFA), Institute Efremov China Beijing, (CIAE), Energy Atomic of Institute China Canada Vancouver, (BCSI), Inc. Systems Cyclotron Best TN, USA Louisville, (ABT), Technology Biomarkers Advanced Canada Richmond, (ASCI), Inc. Systems Cyclotron Advanced Figure 2.6 Figure Number of cyclotrons operational worldwide in 2013 in worldwide operational cyclotrons of Number ). Available beam currents are in the the in are ). Available currents beam shows of number cyclotrons the oper Table 2.4 Table [Sch11]. The The [Sch11].

- - 1/A, number. mass the Abeing 11–19 SPECT isotopes MeV, the can all almost while An extended version extended ion acceleration forAn is light linac). tube (drift A mobile –DTL version Alvarez Los Alamos) or MMF (INR Troitsk) (INR or Alamos) MMF Los produce med Dedicated medical ion linacs have ion linacs been developed medical Dedicated PET isotope 2.7). production (Figure It of consists Compared to contribution cyclotrons the of linear Ion Linacs Ion facilities like BNL Brookhaven, LANSCE (LANL (LANL Brookhaven, BNL LANSCE like facilities ical isotopes that require higher energy protons energy isotopes require higher ical that ion accelerators isotope production to medical is installed on a truck has been 2007. available since has on a truck installed duced by cyclotrons, in particular by negative ion particular duced in by cyclotrons, most cases modest. The most modest. isotopesPET cases (except gen proton-induced reactions for radioisotope produc accelerate that H machines to the present fleet of “medical” and “industrial” “industrial” and presentto the fleet of “medical” Moreovertion. required proton the energies in are consequence of trons adirect dominance is of the H to under development. under than available from standard medical cyclotrons. cyclotrons. medical from available standard than be produced MeV by 30 lead has fact protons. This been developed for lin A/q these ratios up to 3. All USA. by ACCSys, Pleasanton, CA, rather small. Some accelerator proton at large linacs rather small. at reduced performance also light ions. For singly For ions. singly light at reduced also performance acs driven by multi-cell cavities deliver beams at cavities a beams deliver by driven acs multi-cell (radioa 4-vane RFQ frequency quadrupole) an and (electron ECR an cyclotron resonance) ion source, erators) protons accessible invariably are with below charged ions the maximum ion energy scales with with ionscales energy ions charged maximum the cyclotrons. constant final beam beam velocity,that at a con means constant final A compact 7MeV for proton optimised is system Intense protonIntense conveniently are beams pro In Europe and in Japan, compacthave in Europe ion and linacs In Cyclotrons are able to accelerate protons and protons and accelerate to able are Cyclotrons + for extraction. The predominance of cyclo The of predominance for extraction. - ions which are stripped are ions which [http://www.accsys.com] ACCSys. from production isotope PET for linac 2.7. Proton A7MeV Figure ------121 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 122 Nuclear Physics for Medicine – Chapter III – Radioisotope Production • The two above sections The cyclothatshow clearly very A×MeV linacs is another H- type drift tubestruc drift A×MeV H- another is type linacs A×MeV A×MeV A/q ratio ( given is design by the Frankfurt in cooperation with GSI Darmstadt, Darmstadt, GSI cooperation in with Frankfurt Darmstadt and IAP Frankfurt, Germany, serving as as Germany, serving Frankfurt, IAP and Darmstadt Comparison of cyclotron with ion linac linac ion with cyclotron of Comparison 11.7 MeV to 24.3 MeV within a tank length of 2.9 m. 2.9 of 11.7 MeV length atank within 24.3 MeV to Figure 2.9. Germany. HIT, Heidelberg, centre therapy cancer the at linac 7A×MeV the of View 2.8. Figure

Germany ( Germany injector Heidelberg at the Ion Therapy centreHIT, development within the GSI FAIR project at IAP FAIR GSI project the development at IAP within becomeisotope for attractive medical might design production. The reasons are:production. The reasons beadaptedproduction it to end too can other as trons significantly dominate in medical isotope in medical dominate trons significantly A70 MeV, cross-bar structure. CH the ture, 25 been reproduced for therapy other four centres. This installations and a 3.7 m IH-DTL. This 21 MV injector since MV has 21 This a3.7and mIH-DTL. energies or max. A/qenergies or by max. values industry. long linac based on that technology is under is technology basedon that long linac stant energy per nucleon. The maximum accepted per nucleon. energy Themaximum stant consists of an ECR ion source, a 1m 4-Rod RFQ ion ECR RFQ a1m ofsource, consists an 4-Rod Very compact at most ofrequested design the beam energies beam A new development towards compact 100 325 MHz prototype CH – cavity accelerating from from accelerating –cavity CH prototype MHz 325 12 C Figure 2.9 Figure 4+ linac (217 linac MHz) developed by GSI ) [Cle11]. ) Figure 2.8 Figure ). The7 m - - • • • • • • The natural limitations in beam current at cyclocurrent at in beam limitations The natural MeV protons) [Jen12], but lower operate these with Electrostatic acceleratorsElectrostatic play at present no role in with onion like shaped [Bea11] onion electrodes like with that However, develop by the concept the challenged is novel Their developmentHealthcare. of the Cockcroft Walton design is known as the ONIAC, the Cockcroftas ONIAC, known is design Walton New developments for ion beam production beam ion for developments New pared to cyclotrons. to pared ment compact of very low cyclotrons (<8.5 energy of ( PET SPECT radionuclides and to cyclotrons are: cyclotrons to trons no are problem most cases. in tor principle is currently being revisited by being ajoint tor principle currently is beam currents. beam by a factor of 3–5, but the linac rf power rf are by needs afactor of 3–5, but linac the radioisotope production (except for injectors into into (except injectors for production radioisotope accelerator for local “point of demand” production accelerator “point of for demand” local H a compact, high-current of Oxford University,activity SIEMENS and STFC have reduced and/or size the power rf requirement still about an order of magnitude higher when com higher order about an of magnitude still cyclotrons or linacs), but Tandem the accelera could serve as alow-energy as proton serve could deuteron and 10 years, could reduce the difference in investmentin 10 reduce could difference the years, The plug power efficiency of linacs increases with with increases linacs power The plug efficiency of ACCSys for PET isotope production on atruck Mobile light weight solutions as realised by solutionsrealised weight as Mobile light Long experience by experience commercial manufacturers Long Helium anions exist only in a metastable atomic ametastable in only exist anions Helium Low rf power requirements significantly reduce power rf Low requirements significantly Further drastic price reductions state of solid drastic Further investment operation and costs not competitive for producing alpha beams. In not In competitive for beams. alpha producing power amplifiers, as has been observed in the last thelast in been observedas has power amplifiers, end-users.many positive ion cyclotrons the extracted beam cur positive beam ion extracted cyclotrons the tive for very high currents (mA). currents However,tive high for very such more are Hence competi current. linacs beam the tralised production facility over region awider to production facility tralised of interest only are for and longer-livedtechnology radioisotopes that can be distributed from acen bedistributed radioisotopes can that rents are usually limited by beam losses on the losseson the by beam limited rents usually are are in competition with very compact very low-energy competition in with are helium and heavier and more projectiles helium efficiently. efficiency. Thereforenegative cyclotrons ion are state and productionstate of and He septum. Linacs can accelerate of can beams intense Linacs septum. currents can only be used with appropriate with beused only target can currents costs morecosts favour in of linacs. cyclotrons. Recent technical improvements in linac design improvements design Recent linac technical in Cases where linac solutions might besuperior solutions might whereCases linac – Tandem Accelerator - beams has very low very has beams Figure 2.10 Figure ). ). ------( with such amachine. such with avail possible irradiance highest the when using hadrontherapy precise requires very While wide. However, shots possible are per day afew laser only 2010) Munich, LMU thesis, PhD Henig, Andreas of (courtesy acceleration Figure 2.11. accelerator. electrostatic ONIAC Aprototype 2.10. Figure foils hit by an intense, well focused laser beam beam laser focused well intense, by hit an foils for clinical applications (~GBq) be reached. could for clinical per afew Bq and productionfor purposes practical ing from some MeVing to some of tens MeV have been [Led10]. ahigher operate can Once with lasers such proof-of-principle experiments have demonstrated have demonstrated experiments proof-of-principle that the PET the isotopesthat beam energies, a wider energy distribution is usu is distribution energy awider energies, beam repetition rate suitable (kHz), activities saturation able at the large VULCAN petawatt laser [Led10]. petawatt laser VULCAN able large at the order of the at activities of ~ acceptable for production of radioisotopes. First ally quite usually is spectrum achieved but energy the laser shot have been obtained with 100 TW lasers lasers shot 100laser have TW with been obtained Figure 2.11 Another trend is acceleration behind thin trendthin acceleration is Another behind More compact “table top” required are lasers Advanced approaches to high intensity laser-driven ion ion laser-driven intensity high to approaches Advanced ) [Led10]. Proton energies rang beam 18 F and F and 11 1 MBq per laser shot per laser 1 MBq C could beproducedC could - - - • • • This limits theefficient limits toapplication longer-lived This The most apparent fis- theneutron sourceis nuclear (laser) itself. However, more R&D is needed to solve solve to needed is R&D more However, itself. (laser) BR2, FRM2). Since these irradiation positions are irradiation these Since FRM2). BR2, fluxes of fast neutrons are available in a few ded ina are few neutronsfast of fluxes available Given that the technological developmentGiven technological the that of high Neutron beams Neutron icated reactors fast (BOR60) irradiation or in isotope production target to the primary laser target target laser isotope primary to productionthe target duction as apriority. as duction However, projects these may reactor ofduration the cycles. multi-purpose irradiation reactors (SM3, HFIR, reactors (SM3, irradiation HFIR, multi-purpose core the corepositions close to orthe in very of power lasers follows a kind of Moore’spower akind follows lasers law it possi is only be loaded and unloaded during areactor stop. during unloaded beloaded and only the efficient of radio as open such issues coupling (compact) the only area may target get activated optimised for medical isotope production. Main isotope production. for Main medical optimised these projects is optimised to medical isotope pro to medical projectsthese optimised is ble that in future table-top complement could future lasers ble in that by accelerators. not of that any One to recognise has radioisotopes with half-lives comparable to the the to comparable half-lives with radioisotopes and need radiation shielding, and not the machine not machine and the needand shielding, radiation located inside the pressurised primary cooling cir cooling primary pressurised located the inside suited fluxes for isotope production. Significant forisotope fluxes suited Significant production. well neutronssion with reactor thermal providing cuit, access is less straightforward. Often they can they can Often access less is straightforward. cuit, accelerators. conventional concepts are: concepts given the large beam divergence. beam given large the give a hint on options to be further developed and ongive options to ahint befurther 2.12 MeV) neutrons. Today spallation neu athermal Initially neutrons of severalMeV gen are energy Initially Deuteron acceleration MeV up to 40 and Proton deuteron and accelerators up to afew MeV Switzerland is used for production of experimental for used is productionSwitzerland of experimental tar heavy neutron sources irradiate Spallation operated at FZK on a single operatedended electrostatic on a single at FZK tron irradiation position at the spallation neutron position spallation attron the irradiation neutron sources spallation Thus energies. thermal to generate neutrons (p,n) by the (d,n) –and pro breakup reaction on target: under construction construction breakup under reaction on target: reactors but in addition also higher energy (>10 energy higher also reactors addition but in at SPIRAL2 at GANIL, Caen, France Caen, (see at GANIL, at SPIRAL2 a 2MeV linac. rf with accelerator, Frankfurt in construction under erated which can besubsequently moderatederated can to which source SINQ at Paul Scherrer Institut, Villigen, Villigen, Scherrer at Institut, Paul source SINQ can provide slow neutron spectra similar to fission providecan slow neutron similar spectra respectively, like cess, targets with gets with protons with gets of MeV several hundred energy. There are also alternativedriven neutron also are sourcesThere A potential advantage accelerators of A laser potential that is ) and SOREQ, Israel. SOREQ, ) and 9 Be or Be Figure Figure 7 Li as as Li ------123 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 124 Nuclear Physics for Medicine – Chapter III – Radioisotope Production • TRIUMF where a 50 MeV electron linac will pro where MeV a 50 will electron linac TRIUMF Figure 2.13 (see 10 ofvide electron beam mA Figure Electron beam generated rays beam Electron via Gamma Bremsstrahlung can also be used directly for isotope directly beused also can Bremsstrahlung Gamma induced nuclear reactions nuclear induced Gamma beams at 40 MeV as well as light and heavy ion beams with up to 1 mA current at up to 14.5 MeV per nucleon. 14.5 to up per MeV at current 1mA to up with beams ion heavy and light as well as MeV 40 at beams Figure 2.12. 67 production; (γ,n) reactions induced by 10 to MeV 50 rays can also be used to bephoto-fission, used induce e.g. rays also can ray beam will rapidly evolve to an equilibrium of rapidly evolve equilibrium to an ray will beam Moreover,reactions. incident gamma- an matter in con low cross-section, generally their reactions is at ALTO-IPN Orsay and in the ARIEL project at ARIEL the at ALTO-IPNOrsay in and electron beams and leading to isotopes like to isotopes like leading and electron beams siderably lower compared to neutron-induced Cu or While the time-averaged the neutronof pure flux While (ADS) reactors. The future European ADS facil ADS European future (ADS) reactors. The fluxes for fluxes andradioisotopeis foreseenproduction future EURISOL and ESS facilities. ESS and EURISOL future ity MYRRHA at SCK-CEN Mol in Belgium will will at Belgium SCK-CEN Mol in MYRRHA ity provide very competitive thermal and fast neutron fast provide and competitive very thermal the in production ports neutron by fast irradiation to eventually replace the BR2 reactor for replace routine BR2 the to eventually research reactors, flux it can highest of the that be further boosted by combination with a fissile boosted by a fissile combination with be further radioisotope production. radioisotopes. There for ispotential radioisotope spallation neutron sources is generally lower than lower neutron than generally sources is spallation core in so-called accelerator-drivencore so-called in subcritical A general drawback of gamma-ray induced 111 The light and heavy ion LINAC of the SPIRAL2 project at GANIL, Caen, France. It will be capable of delivering up to 5 mA deuteron deuteron 5mA to up delivering of capable be will It France. Caen, GANIL, at project SPIRAL2 the of LINAC ion heavy and light The In are being studied at Kharkov. studied Gamma being are In ). 103 Pd, Pd, - - - The term “targetry” usually denotes complexsystems usually “targetry” The term (γ,γ’) or (γ.n) reactions resonantlyatappropri the (γ,n) Apossibility limited. reactions inherently is with charged particles (protons, deuterons, deuterons, (protons, particles charged with for bombardment production via of radionuclides transitions resonant suitable Provided facility. ray fluxes gamma the beams for particle charged 2.3 oactive targets, e.g. e.g. oactive targets, conventional with radioisotope produc quantity quasi-monoenergetic gamma beams to inducequasi-monoenergetic beams gamma therapy [Hab11].therapy promising the give tion butproviding cases access to can specific ELI-NP future at the e.g. electron beams, tivistic of intense use the is to overcome limitation this of radioisotopes producedin activity specific the Consequently be powerdissipated. the can that by limited inherently are targets thick usable with by Compton backscattering of laser light from rela light by of Compton laser backscattering are found, such a production will not compete in aproduction such will found, are beproduced can beams ate gamma Such energies. higher specific activity activity specific (e.g. higher efficient transmutation of special rare rare efficient and/ortransmutation of special radi causing important energy deposition. Hence, as energy important causing production gamma-rays latter energetic the and electrons, Targetry for radionuclide 225 Ac generator for targeted alpha alpha targeted for generator Ac 226 Ra(γ.n) 195 10 MV at a length of 1m. of alength 10 at MV to up provide will cavity 9-cell Vancouver, Canada. Each TRIUMF, at linac electron Figure 2.13. Pt(γ,γ’) 225 Ra as asource for as Ra 195m The 50 MeV MeV 50 The Pt) more or 3 He, α - - - - – solid, liquid and gas. Charged particle beams are are beams particle Charged gas. and liquid – solid, • • • • validated and each batch of target material tested batch material each of and target validated yield while maintaining an acceptable an radionu maintaining while yield In the case of medical radionuclide production, radionuclide of case medical the In Since many parameters, e.g. radionuclidic purity, are purity, are radionuclidic e.g. parameters, many Since for use (it is in particular true for short-lived true radio (itfor use particular in is in the choice the forin acomplex- solution sys of atarget it matrix: from target itsseparation from the ing radionuclides for productionindispensable of all nuclides), whole the production process be must desirable for PET/SPECT diagnostics. much attention must be paid to optimising the the much to attention be paid optimising must medicine, economic aspects play an important role important play economic an aspects medicine, routine to the production.Due prior to regular the of a release radiopharmaceutical after measured ofmajority accelerator-produced is radionuclides (e.g. emitters). Auger purposes peutic and α- The emission photon single for radionuclides many must be compatible with further production of a be compatiblemust further with of labelled compounds with high specific activity activity specific high with compounds of labelled non-carrier-addedparam in This obtained quality. to: forused positron tomography emission (PET) and the activity obtained at the end at of the irradiation: obtained activity the too. tem, form result of aradionuclide chemical optimal the that could disturb labelling or cause toxic effects. or toxic cause effects. labelling disturb could that not must processing for exceedused target levels route to available parameters increase there four are radiopharmaceutical. Finally, presence Finally, of chemi radiopharmaceutical. eter is undoubtedly very favourable very undoubtedly eter for is production enrichment. Another issue that must be solved must that issue is Another enrichment. etc.). Targets may be irradiated in all three phases phases etc.). three Targets all in may be irradiated clidic purity by taking into consideration target by taking purity clidic character of radionuclide production of radionuclide character for nuclear thera for and (SPECT) tomography computed cal impurities in the target matrix and chemicals chemicals and matrix target the in impurities cal (beam current, flow, current, (beam pressure or temperature of in particular gases) particular in dling and minimises personnel’s radiation burden, burden, radiation personnel’s minimises and dling automation and han design (facilitates target monitoring of parameters during irradiation irradiation ofmonitoring during parameters power, possible and processing recycling target mate formphysico-chemical ofirradiated the of materials) enriched beam and target) and beam rial (co-determines maximum applicable beam (co-determines maximum rial allows for optimal recycling of enriched material, of material, enriched recycling for optimal allows efficient cooling (co-determines maximum appli maximum efficientcooling (co-determines cooling media, pressure in gas targets) gas pressure in media, cooling position of by mutual but also systems, cooling cable power; beam it provided is by not only A target system should be optimised with respect with A be optimised should target system For given agiven and production radionuclide ------• • • • Recycling is easiest in the case of gases, where of case gases, cry the easiest in is Recycling Enrichment applies to all polyisotopic elements and applies to all Enrichment (e.g. production of However, or oxides of compounds other sometimes H few percent of the original amount. Liquids, like like Liquids, amount. few percent original of the forms a glassy material with much better thermal thermal much better with material forms aglassy in in related techni and to economic aspects directly is is also strongly related strongly to since production costs, also is impurities. production the ofincrease radionuclidic nuclides, is limited to ≈19 limited is nuclides, MeV protons. Ahigher duction ofduction duction ofduction more material, often expensive, and expensive,more more often efficient material, purity that meets criteria for application in humans criteria meets for humans that application in purity not investment expensive material, in primary particular metals with good thermal conductivity conductivity good thermal with metals particular on wet chemistry that results in losses of at a least in results that on wet chemistry quantitative almost for allows pumping ogenic or of monoisotopic arsenic). monoisotopic of of higher however, effectively; quite are slightly losses target allows for better utilisation of the integral integral of the for utilisation better allows target productionthe of same the elementthe (e.g. itself TeO forms of tar chemical the Among for gases. than beam energy loss requires a thicker target layer, target loss requires athicker energy i.e. beam but it certain below has excitation the function, recovery (e.g. material enriched of the it requires hand, other on the purity; radionuclidic resistance than elemental elemental than resistance always available, and its effective recycling. In many In many its effective and available, recycling. always a target isotope display much better properties than properties than isotope much better display a target gases. inert or points, melting high sufficiently and lived medical radionuclides, irradiation longer irradiation radionuclides, lived medical limits. The maximum available beam energy, e.g. beam available maximum The limits. contrast, recycling of solid targets is usually based based usually is targets of solid recycling contrast, way to only it accomplish radionuclidic the is cases, the also It feasibility. improvescal usually and yield cyclotron operation rather is expensive. For shorter- tar the heat in dissipation due to higher cooling compact cyclotrons for production of PET radio get layer. Finally use of a wider energy range may range energy of awider use get layer. Finally in pure elements dominate, get naturally matrices Entrance energy and the total beam energy loss energy beam total the and energy Entrance of isotope pure of use ele target and Enrichment Beam current. Duration of bombardment. of Duration in the target. the in ment of its compounds. instead 2 18 124 123 [ The time time bombardmentof time) The (irradiation the in loss energy beam increasethe total The of 18 O, production of I; enriched Te, production of direct and O] for production of 76 81 Rb or Rb Br than elemental elemental than Br 76 SeO 124 18 F from water highly enriched enriched F from water highly 123 Xe forXe production of 2 is also more suitable for pro for more suitable also is I from highly enriched I from highly 124 18 Te for used production F, can also be recycledF, also can 76 2 with ca 6% of Al with Br via Br via 76 Se and Cu and Se 99m Tc from 3 He activation activation He 82 Kr for proKr 123 3 100 As for As I). In 124 Mo). Mo). 2 Xe Xe O 3 ------

125 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 126 Nuclear Physics for Medicine – Chapter III – Radioisotope Production • • • via the stripping method, which results both in high high in both results which method, stripping the via with the best possible thermal conductivity. Some possible best the thermal with Internal targets are located directly in the cyclotron the in located are directly targets Internal fore, vacuum frequently prepared by electroplating, preferably metallic layers with the best possible best the layers preferably with metallic parameters), beam the or located end at the modify external only offer usually position.per They foil rather applicable determined is current maximum of a beam line whose elements allow for shaping the for whose shapingthe elements allow of line a beam thick perpendicular targets have and targets no backing perpendicular thick thereare, They backing. their contact with thermal or windows. matrices entrance target on solid cooling application and of helium targets, to no possibility practically (leaving chamber uum vac to attached positions,either the closely target is produced the activity time, irradiation the than profit. 1–2 For little than brings half-lives generally beam. The external location enables installation of locationinstallation enables external The beam. low extremely with slanted targets as be designed system of atarget construction and design by the radionuclides with a half-life significantly longer longer significantly half-life a with radionuclides Figure 2.14 Figure shown example is in An angles. Modern compact by targetry. and the cyclotrons time. irradiation proportional to the directly almost all kinds of target systems, i.e. also liquid and gas gas and liquid also i.e. systems, of target kinds all beam the deuteronsand negative as extract ions and ences the target’s characteristics. Solid targets are are targets Solid target’sences the characteristics. stripflexible in variedenergy, the and by efficiency production are targets slanted examples of internal evaporation or sputtering on a metallic backing backing evaporation on ametallic or sputtering systems for systems the fact, to this Due supply up to 1mA. beams chamber, and thus limited to solid targets. They can can They targets. to solid limited chamber, thus and layer. properties target of the the combined with accelerator by the performance limited is current, get systems. The most widespread The most are:get systems. According to the position with respect to the beam respect beam to positionthe to the with According respect to location the with to their According According to the phase (solid, liquid, gas). (solid, phase to the liquid, According (perpendicular or slanted, fixed or fixed rotating). or slanted, (perpendicular tors always use external targets. external tors use always cyclotron (external or internal). Linear acceleracyclotron (external or internal). Linear There are several ways to classify targets andtar targets Thereare several ways classify to The phase of the target matrix strongly influ strongly matrix thetarget The phase of Modern compact cyclotrons accelerate protons the beam variable, final of the Maximisation 67 Ga, Ga, 111 In, In, 201 Tl or Tl 211 At. . Typical Typical . ------Metals with poor thermal conductivity and/or conductivity low poor thermal with Metals with low deuterons energy with for production of production of of production for (right) chamber niobium its and Figure (left) 2.15. target Liquid production of of production fully used for the pilot production for pilot used the of e.g. fully ing, only the activated the layer only for etched used is and ing, ing the chamber volume (e.g. chamber to spare gas the enriched ing or compounds alloys. inorganic 82 nuclides. millilitres (see millilitres elements or areoften non-metallic points, melting of enriched filling. It significantly reduces radiation reduces radiation It significantly of filling. enriched of of researchers: These were solutionsuccess - targets. tioning of a target in the beam, as this affects the affects this as beam, the in of a target tioning favourable for short-lived particularly is that radio recycling automated, including be easily can targets due to diameter beam of increase the gradual the of tion have attention targets the ontion attracted liquid be re-used several times (e.g. irradiation ofbe re-used (e.g. several times irradiation burden and shortens the whole process, something whole the shortens process, something burden and minimis while filling, gas the in straggling beam in order often conic very to is compensatebody for are directly cooled from the back during process cooled from back the during directly are ally at 5–15ally bars) avolume of afewof tens with entrance window.entrance varia Recently, interesting an separation of a radionuclide, and the target can then then can target the and separation of a radionuclide, concentrated solution of of solution concentrated of solution concentrated volume closed by an ofchambers afew millilitres converted or more oxides, to rarely to their other Kr for productionKr of 123 Another aspect related to targetry is the posi the is related aspect to targetry Another Figure 2.15 (see targets Liquid Figure Operation and processing of both liquid and gas gas and liquid Operation of processing both and (usu vessels medium-pressurised are targets Gas I). 89 Zr fromZr 68 18 Ga or or Ga F that can be also operated as solution target for for target solution as operated also be can F that Figure 2.16 Figure 86 Y (Nuclear Physics Institute AS CR, v.v.i., CR, AS Institute Physics Y (Nuclear 89 Y(NO 81 Rb and and Rb 68 86 3 ) ). Theshape thetarget of ZnCl Sr(NO 3 solutions. 124 2 ež) [Leb05]. Řež) v.v.i., CR, AS Institute 201 e.g. of suitable for production angle low extremely slanted solid target with internal a multipurpose Figure 2.14. , or for produc the ) are usually metal metal ) areusually Xe for production production for Xe 3 Tl (Nuclear Physics Physics (Nuclear Tl ) 2 or or 67 Ga, Ga, 68 Ga fromGa a 86 Example of of Example 111 Y from a In or or In 61 nat Cu). Cu). Ř Ni Ni ež). ------highly enriched enriched highly Figure 2.16. target filled with with filled target asimilar U-120M (bottom); cyclotron the of line beam external an Institute AS CR, v.v.i., CR, AS Řež). Institute face, thereby heatface, the of reducing power per unit deposition over surface. target the port of the irradiated target to processing in hot to in processing target irradiated of the port sur target on a larger project diameter beam the or grazing angle targets) agood are choice angle for solid or grazing that only a few reaction channels that potentially potentially that afew reaction channels only that angles Small currents. high with irradiated targets beam energy loss. Both factors improve Both loss. energy cooling beam rarely goes beyond 40 MeV,rarely goes beyond 40 except for such cases only incident energy projectile the radionuclides, to spread beam or the power target the the rotating that targetry high-current slanted, require external of matrices for low target thermal rent, especially and increase the maximum applicable cur beam maximum increase the and as as required for optimal thickness target the area and contribute to formation of significant radionuclidic radionuclidic significant of formation to contribute cases. such in obviously is mandatory cells up dissipate to 12 kWcan of heat. Automated- trans conductivity. Cyclotron production of tar amount of the and necessary efficiency cooling get matrix. Slanted targets (also called tangential tangential (also called targets Slanted get matrix. 82 In routine cyclotron production ofIn medical For of completeness, we mention possibility the Figure 2.17 Sr production (see Figure Disassembled external gas target system filled with with filled system target gas external Disassembled 82 124 Kr for production of of production for Kr Xe is used for production of of production for used Xe is 81 Rb (top) and its position on on position its and (top) Rb 123 I (Nuclear Physics Physics I (Nuclear ). This means means This ). 99m Tc wou ld ld wou Tc - - - ver this method provides radionuclides of almost provides method ofver almost radionuclides this (tens of g/cm with a Ga target for for target aGa with RbCl targets for for targets RbCl with capsules steel stainless two of cooling water 4π with system target solid perpendicular external an of 2.17. Example Figure isotopes from hydrogen element up target to the are This product of different nuclei. to amixture ing energy, projectile rising With opened. are impurities produced simultaneously. In this case, it is necessary it necessary is case, produced this In simultaneously. (GeV energy projectile protons) targets thick very more opened are more and lead reaction channels onuclides. But the gain in usable target thickness thickness usable target in gain But the onuclides. more thereby exotic forming radi of beta-stability tion to be able to extract single radionuclides. In the the In radionuclides. single totion beable to extract separa chemical to combine separation with mass all virtually fission and reactions spallation tation, high of very case extreme the In selectivity. in tion and higher product yield is accompanied product is by areduc yield higher and valley from the further to range system the allows even short-lived very isotopes accessible; are moreo so-called isotope separation (ISOL) on-line so-called method carrier-free quality. 82 Sr production and an additional niobium capsule 2 ) can be irradiated and via fragmen via and beirradiated ) can 68 Ge production (ARRONAX Nantes). (ARRONAX production Ge ------127 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 128 Nuclear Physics for Medicine – Chapter III – Radioisotope Production value and cost-effectiveness and value perfusion of myocardial (GEP-NET) frequently show overexpression of pep (peptide receptor therapy) radionuclide today is III trials were performed with trials III DOTATOC DOTATATE. and these of The results versus conventional (non-nuclear) conventional (non-nuclear) versus Correct disease staging helps to avoid staging opera needless Correct disease treatments Side effects are mild and reversiblemild areand quality-of-life Side effects role in important play an PETSPECT and imaging 3.1 l l l ies. Zevalin ( Zevalin ies. [Mar08] for been reviewed, in has example, imaging patients with advanced follicular lymphoma were that advanced follicular patients with of the patientsof improved is the [Kha11]. therapeutic) treatments: median progression-free progression-free median treatments: therapeutic) treatments, for example with fortreatments, example with receptorstide by be targeted radiolabelled can that forpatient the and beaggravating might which tions can for certain and, of disease correctthe staging blood cells. B cells show overexpression Bcells blood CD20 cells. of the antigen that can be targeted by betargeted appropriate can that antigen antibod agement is discussed in [Buc10]. in agement discussed is applicationand of PET PET/CT and man cancer in are costly for the healthcare system. The clinical clinical The system. healthcare for the costly are excellent results in a randomised phase III trial of trial III phase arandomised in results excellent either treated by an induction treatmenteither treated (chemother induction by an survival of 32 3to 18 months vs. months [Kwe08].survival somatostatin analogues. This so-called PRRT so-called This analogues. somatostatin compare favourably alternative (chemo very with cer types, also in the early detection of detection recurrence. early the in also cer types, considered the best systemic treatmentconsidered option systemic best for the sur nuclear medicine applications applications medicine nuclear gically unremovable GEP-NET. Clinical phase II and unremovable and phase II GEP-NET.gically Clinical Examples and specific topics 3. 3. Lymphoma is a blood cancer affecting the white thewhite Lymphoma affecting ablood is cancer Gastroenteropancreatic neuroendocrine tumours tumours neuroendocrine Gastroenteropancreatic Examples of success of of success Examples 90 Y-ibritumomab) has demonstrated Y-ibritumomab) demonstrated has 90 177 Y and Y and Lu-DOTATATE, Lu-DOTATATE, 177 Lu labelled Lu labelled ------Treatment with Zevalin showedTreatment acomplete Zevalin remission with vides an improved of 58months versus an 31vides survival versus 61 monthsforcontrol the group [Cha06]. no durable treatmentvisible metastases options exist USA but not in Europe due to radiation protection protection radiation to due Europe in not but USA Promising results were also obtained in trials using using trials in obtained were results also Promising Zevalin or Bexxar as first line therapy line lymphomaof first as or Bexxar Zevalin versus 3.0 years for control the groupZevalin [Mor13]. for this type of cancer. Treatment type for this with its complications. The definition of “symptomatic of its complications.definition The next treatmentnext 8.1 was years for patients treated with developed liver metastases is surgical resection of developed surgical is liver metastases patient. prostateand areoften duedisease cancer tobone control the months in group [Lie07]. [Bod13]. ( Bexxar of prostate cancer and other cancers. Deaths from of prostate Deaths cancers. other and cancer of extraction from surgical treatment. Apart oiodine that additional treatment with treatment with additional that chemotherapy not but did additional metastases the not does respondthyroid that cancer radi to normal after tion beam therapy for pain management or management tumour- therapy forbeam pain rate of 87% after 3.5rate after of 87% years [Mor08].time to Median restrictions requiring longer hospitalisation and isola and longer hospitalisation requiring restrictions employed the in mainly is that radioimmunotherapy related orthopaedic surgical intervention. These intervention. related surgical orthopaedic apy) plus Zevalin or the induction treatment alone. treatment induction alone. or the apy) plus Zevalin antibody provided an overall survival of 110 providedantibody survival overall an months events are decisive for the quality of life of a cancer of acancer of life events decisive are forquality the leading to paralysis, severe pain requiring external external severe requiring pain to paralysis, leading show improved survival. A small trial demonstrated trial show Asmall improved survival. spontaneous bone fractures or spine compressionspontaneous bone fractures event”skeletal covers seriousevents very as such Medullary thyroid arare carcinoma is form of Medullary Bone metastases occur frequently in the late stage late stage the frequently in occur Bone metastases Standard treatment of colorectal cancer that has treatment has of that Standard colorectalcancer 131 I treatment. I 131 I-tositumomab) alternative an is 131 I-labetuzumab proI-labetuzumab 131 I-anti-CEA I-anti-CEA - - - European countries. The DDM2 project countries. [DDM2]European 9.8 months [Par13], a significant gain in particular 9.8 [Par13],in months particular gain asignificant (14.9 versus 11.3 months) [Par13].the to time The No other therapy modality has provided similar suc provided has similar No therapy other modality when considering the impact on the quality of life. of life. quality on impact the the when considering In the previous vari the a large chaptersIn we discussed However, frequency practice the present in clinical first of all a comprehensiveall and preof the viewfirst past of first “symptomatic event” first skeletal was 15.6 versus Figure 3.1. 3.2 intervals and where and combination treatmentsintervals with demonstrated in a recent phase III clinical trial trial arecentdemonstrated clinical in III phase other drugs are explored. It is expected that these these that It explored. are expected is drugs other possible future trends in radionuclide needs requires needsrequires radionuclide in trends possible future improve the further outcome. could modifications on the number of nuclear medicine procedures of number on nuclearmedicine and the assessment of an Making variable. highly is of use that are used to produce used are relevantthat the radionuclides. where treatmentunderway the not is stopped after bone metastases from metastatic prostate from metastatic bone cancer metastases a median overall survival benefit of 3.8 benefit months survival overall a median in Europe: evolution trends in Europe: and ety of nuclear medicine procedures and the methods of procedures nuclear methods medicine the ety and sent use. Unfortunately, regular and detailed data data detailed and Unfortunately,sent regular use. (previous cycles but regular trial) continuedsix in are present At Europe. and USA new the trials in sale consumed radionuclides is only available for few few for available only is radionuclides consumed 2013 In approvedwas Xofigo disease. this for cess in The alpha emitter Xofigo ( alphaXofigo emitter The

Procedures p er m illion i nhabitants a nd y ear use of radionuclide Statistics 10000 20000 30000 40000 50000 Use of diagnostic radioisotopes in European countries, Japan, Canada and the USA. 0

AT BE BG CH CY CZ DE 223 DK RaCl EE

ES 2 FI against ) used FR GR HR HU IE - - IS - IT Thus, as approximation the Belgian contribution to as theBelgian approximation Thus, valuable input. No data was available for Belgium. for available Belgium. was No input. valuable data years can reach a factor two to four. Also reach to four. afactoryears two can Also reference hence differing bias dueyears, to the the (1998-2002) or higher had similar show Belgium that It is thus the best publicly accessible publicly best source for the data It thus is Luxembourg. See “Contributors” chapterSee for end at a of the this ing from 2004 (for to 2011. UK) from 2004 the ing induce may This interpretation. the in taken is draft report were draft complemented additional, with dures in 2010 in dures updated was from [Ste11], even the if methodology of this reference is not fully traceable. reference of this not is fully methodology more recent from sources. national obtained data per capita use as Luxembourg. This appears justified appears justified This per capitaLuxembourg. as use fre thegather to precisedata ahuge made effort for per capita use of nuclear medicine procedures than per capita procedures of nuclearmedicine use than quency, doses for employed radiation and activity the European average was estimated taking the same same the average taking European the estimated was procedures Europe. in diagnostic most important the between the countries participating in DDM2, rang DDM2, in participating countries the between rapidly changing consumption. For most in example, rapidly changing after the after a strongbias for with procedures radionuclides and caution some provided comparison comprehensive a listing of persons and institutions that provided that of persons institutions and listing sumption may differ significantly before, during and during before, significantly maysumption differ since data from the previousfrom 1 project the Datamed data since Dose LT to six three of PET use the doubledcountries within LU The year of data collection varied considerablyvaried data The collection of year Where possible the data taken from the DDM2 DDM2 from the taken possible data Where the LV numberof the PET proce UK and IT For FR, MD

ME 99 Mo crisis.

MK PET 99mTc 201Tl 131I 123I 67Ga 111In Other MT NL NO PL PT RO RS SE SI SK UA UK EUR JP 99m CA con Tc US

- - - - 129 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 130 Nuclear Physics for Medicine – Chapter III – Radioisotope Production These data cover less than 20% of the European theEuropean of 20% data cover These than less Again a country-dependent bias cannot be excluded bias cannot acountry-dependent Again (both only PET only and (both Figure 3.2. Cumulative distribution of radionuclides used in Europe. 3.2. Figure for ex vivo counting (seefor vivo ex counting 1.3). section nuclear medicine procedures as a function of radi procedures afunction medicine nuclear as population base and do not allow determination of determination not do and allow base population LV, GR, ES, Bavariapatients), and SI MK, EE, DK, of radiotracers activities small procedures use that onuclide in Europe, the United States and Canada United the Europe, Canada States and in onuclide tic radionuclides which were which radionuclides nottic covered by DDM2. by 80% by 80% as well as the non-European the as comparator well as Japan. a meaningful arithmetic average. Still, some trends average. Still, arithmetic a meaningful secutive years are so far only available for available afew only secutive so far are years synovectomy) not are included. always procedures (such radio and SIRT certain since as shows the European averageshows European dominated is the which certain countries “other” also contains diagnostic diagnostic contains “other” countries also certain countries: CH, CZ, DE hospital (only stationary CZ, CH, countries: In addition statistics were for therapeu collected statistics addition In Figure 3.1 Figure Detailed time series covering five time or moreDetailed con 99m Tc about and 10% PET isotopes. For shows the number of diagnostic shows numberof the diagnostic 99m Tc) Japan. and Figure 3.2 Figure Other PET 123I 131I 201Tl 99mTc - - - -

vs. vs. PET tracers or PET scanners are installed they are soon are extensively they installed are PET scanners 67 67 for for isotopes. towards cost-effective expenses healthcare their ing in recentin years. 201 ners. Certain PET radiopharmaceuticals have PET radiopharmaceuticals ners. Certain diagnostic and therapeutic procedures. and However,diagnostic dominated by FDG. Next are are Next by FDG. dominated despitethe recent replacement during effects medicine procedures, in particular in countries with with countries in particular procedures, in medicine perfusion, does not- does yet statis show European perfusion, up in others can provide superior results with respect provide to others can with superior results unique properties (FDG, FLT, properties (FDG, unique soforth) while and evolutionthe considerably varies radio for different tics since since tics showedthat most rapid the PET among isotopes rise of PET procedures 90% more available, are tics than statis where countries on the Based detailed used. SPECT tracers corresponding ( the rise in the last decade (aboutdecade last the in per year)rise 20% is that give and alowerresults dose to patients. radiation observed is a decline over risen while decade, last the replaced by Technegas or and Tetrofosmin)and provideimaging superior often consistent most countries. evidentare of and these in are performed with performedare with correlated with the number of installed PET scan of number installed the correlated with The corresponding crisis. orient are cost-conscious that systems healthcare Ga is being replaced as an inflammation marker by replaced inflammation being an is Ga as Ga. In lung ventilation studies studies ventilation lung In Ga. Tl for myocardial perfusion imaging is declining declining is imaging perfusion for myocardial Tl The number The of number PET proceduresshowed a rapid Among single photon of use single the emitters Among 99m Overall there is a continuous rise in nuclear in there a continuous rise is Overall 201 Tl and, even more and, pronounced,Tl for Tc-phosphonates,whenever etc.). Thus, new 82 Sr/ 82 99m Rb generatorsRb available at a only are 82 Tc labelled leucocytes. The use Tc of The leucocytes. labelled Rb, a PET Rb, tracer for myocardial 18 F-tracers, and these are largely largely are F-tracers, these and 99m 81m Switzerland. in isotopes therapy important most three the of use the Figure 3.3. Tc radiotracers (MIBI Kr respectively and Kr 11 C-tracers and 68 Ga vs. vs. Ga Evolution of of Evolution 133 Xe is being being is Xe 133 111 Xe and and Xe 123 In, In, 99m I has has I 68 Ga Ga 18 Tc Tc F - - - - -

Today worldwide the supply of RIT), RIT), ( will be used (see beused 3.7). section will Hospital of Basel is one of the European pioneers oneHospital is of European of Basel the Figure 3.3 Figure The pathway of the produced produced the of pathway The 3.4. Figure Office of Public Health).Office of Moreover, theUniversity 3.3 first for(by locoregional treatment of gliomas first facilities. Its production is essential for provid Its production essential is facilities. Once approved trials. certified as of clinical frame for of Many these new therapeutic radionuclides. It a supply-limited clearly is hospitals. few European ing nuclear medicine with with nuclear medicine ing important rise in relative terms is expected for relative newly expected is in terms rise important therapies: radionuclide novel in more available more become generators if issue: nuclide isotopesmostnuclide the for medicine: nuclear might eventually overtake of that eventually might of therapeutic radionuclides in other countries, once countries, other in of therapeutic radionuclides the corresponding radiopharmaceuticals become radiopharmaceuticals corresponding the “early this of treatment ofstatistics The lymphomas. temporal evolution of therapy use of isotope, the bone metastases) rapidly and to rise expected is by radiopharmaceuticals they can be applied in more beapplied in can they radiopharmaceuticals ade the worldwide of the ade use are so far only available in a few hospitals in the the in afew hospitals available in only soare far approved even PET SPECT tracers and more and approved use. for regular future for the provide thus adopter” guidance can tumours, neuroendocrine for then administration) hospitals and more countries. Thus in the next dec the next in more Thus and hospitals countries. reactor vs accelerator vs reactor limited number of number research reactors limited processing and by complemented later FOPH from available are the lent statistics (Federal 90 Y-ibritumomab) and 131 Therapy procedures are still largely dominated dominated largely Therapy areproceduresstill To summarise the future prospectsTo of radio future the summarise

99 I for thyroid treatment. As an example forI for the an thyroid treatment. As 177 Mo/ Lu (for PRRT and RIT) and of and Lu (for RIT) and PRRT shows where from data Switzerland excel 99m Tc issues: supply 177 177 Lu-rituximab are used for are used Lu-rituximab 90 Lu-DOTATOC. Zevalin Zevalin Lu-DOTATOC. Y (for SIRT, and PRRT 99m 99 Tc form the of in Mo/ 99 90 131 99m Mo on a relies Y-DOTATOC, Y-DOTATOC, I. Tc from the irradiation facilities to the users. the to facilities irradiation Tc the from 223 Ra (for Ra 82 Rb Rb - - - - Africa), MARIA (Poland), LVR-15Africa), MARIA (Czech Republic) (53%),America Europe (23%), (20%) Asia the and MALLINCKRODT (The Netherlands), IRE IRE Netherlands), (The MALLINCKRODT (3100 to be produced end at TBq) of the irradia (AIPES). Their priority is to achieve optimal coordi is to achieve optimal priority Their (AIPES). (Belgium) and NTP (South Africa). Worldwide NTP and (Belgium) which the the which HEU to LEU targets to address non-proliferation non-proliferation address to targets LEU to HEU BR2 (Belgium), OSIRIS (France), (South (Belgium), OSIRIS SAFARI BR2 *  is used in more than 80% of diagnostic nuclear of diagnostic 80% more in used is than in the large scale production (>95% scale large the in of world supply) procedures. These applications representimaging nation of their operating periods to ensure a secure asecure to ensure periods operating nation of their processing facilities: AECL/NORDION (Canada), AECL/NORDION processing facilities: policy issues policy 99 99 of of supplyous of of Imaging Producers Equipment Suppliers and of Imaging tion, depending on the time needed for time processing on the depending tion, end ofthe processing)required is to supply North brated represents a rest of world the (4%). The cali Ci 10.000 ‘6-day’ reactors, processing facilities and and reactors, facilities processing and/or low enriched uranium (LEU) targets from and/or (LEU) targets low enriched uranium (HEU) highly OPALirradiate and (Australia). They shipment.and Given half-lives short of the about 10.000 (i.e. calibrated Ci‘6-day’ 6after days worldwide examinations approximately million 30 and Isotopesand Working Group of Association the hours) itsdaughter and every year.every Therefore, a weekly erator manufacturers) represented are Reactor the in supply of of supply central radiopharmacies is required is radiopharmacies ( central real proliferation risk real proliferation a not and issue policy a pure indeed itis that stressed be to It has be needed to make a nuclear bomb. anuclear make to needed be 235 of 4grams just Mo converted production presently is being from Mo/ 99 The main actors in the supply chain thesupply in chain (research actors main The Today research eight reactors only involved are Mo: NRU (Canada), (The Netherlands), HFR 99m Tc generators. Technetium-99m itself 99 99 Mo worldwide. However, current the Mo is subsequently extracted in four four in Mo subsequently extracted is * . 99 U while many thousands of such targets would would targets such of thousands many U while Mo/ since one 99 one since 99 99m Mo activity of about Ci 85.000 Mo activity Tc generators or to hospitals 99m Mo production target contains contains target production Mo Tc (6 hours), acontinu 99 Mo production of 99 Mo/ Figure 3.4 Figure 99m 99 Tc gen Tc Mo (66 (66 Mo ). - - - - - 131 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 132 Nuclear Physics for Medicine – Chapter III – Radioisotope Production Medical Radioisotopes” to support actions relating to relating support actions Radioisotopes” Medical Europe is planning to develop replacement irra planning is Europe NEA. Practical measures –near, and measures medium Practical NEA. OECD/ by the created was (HLG-MR) 2009 in fleetand someof them research of ageing reactorsis duction within the decade. the within duction [Pon10]. Group High-Level reason, the on For this ply chain that directly impact on healthcare needs. needs. on healthcare impact directly that ply chain the economicin changes significant ply, including of of to urgent issues concerning the the to concerning urgent issues of Supply Radioisotopes of Medical Security the are expected to stop irradiating targets for targets to stop expected are irradiating experienced in the supply the ofexperienced in lished to address the key for issues the supply to a secure address lished long term –have for beena identified sup reliable structure [NEA11]. principlesstructure have Six been estab created the “European Observatory on the Supply on the created Observatory of “European the cost recovery, reserve capacity, [NEA12]. etc. The chemical element technetium was discov elementwas chemical The technetium who separated technetium isotopes chemi who separated technetium in Ernest Lawrence’s Ernest Overin cyclotron. famous molybdenum foils in cyclotrons. in foils molybdenum alternative method an process of industrialising exclusively was producedmedicine, nuclear in to produce reactors. Today the nuclearphysicists in are recent decades as deflector as thereby irradiated) became (and ered in 1936 by Carlo Perrier and Emilio Segrè Segrè ered 1936 in by Perrier Emilio Carlo and cally from a molybdenum foil that had served that from foil a molybdenum cally Back to the roots the to Back 99 Furthermore, in 2012 the European Commission 2012 Commission in Furthermore, European the Since 2008 several severe have shortages 2008 Since been Mo/ 99m Tc, implementation the of full- including 99m Tc by… for Canada irradiating 99m Tc, workhorse the of nuclear 99 99 Mo and and Mo Mo/ 99m 99 Mo pro Mo Tc sup Tc 99m Tc Tc ------• • • • • • Argentina, Brazil and the Republic of Korea Republic the and have Brazil Argentina, alarge building is ANSTO 2015. The OSIRIS 2015. shutto scheduled reactoris down OSIRIS The (The Netherlands) and MYRRHA (Belgium) to (Belgium) MYRRHA (The andNetherlands) Besides OPAL reactor. Other countries like Russia, China, China, OPAL Russia, reactor. like countries Other ing conversioning by 2015. targets to LEU FRM-II The in alternative production routesin of (France). Cadarache in replacement Other projects diation capacity based on based capacity conservativediation production [Kri13]. In the meantime the annual irradiation irradiation [Kri13]. annual the meantime the In major options were ( identified tion capacity for the irradiation of LEU targets from targets of LEU forirradiation capacity tion the (fission of technologies to fully exploit the production capability of the exploit production the capability to fully construction under reactor currently is that JHR the reactor Bavaria) (Garching, irradia developing is an replace HFR in 2022 and BR2 in 2023, respectively 2023, in BR2 and 2022 replace in HFR and new and projects of new reactors for construction also the PALLAS investigated as such being are currently endat of the 2015, bereplaced 2017 in but will by commissioned in the period 2016 the commissioned in to 2018. capacity of BR2 is being increased. In Australia Australia In increased. being is ofcapacity BR2 Neutron fission induced of 100 100 100 Direct cyclotronDirect production of Photofission Photofission Production of Production of Cyclotron production of driven neutron sources. neutron driven or or The recent supply shortages also raised interest The raised also recentsupply shortages Mo(γ,n) in resulting Mo(p,2p), reaction. Mo(p,2n) 98 Mo via the the Mo via 235 99 U fission in nuclear reactors the following in the nuclear reactorsfollowing U fission Mo processing facilities which would be be would which Mo facilities processing 238 98 99 Mo(d,p) or or Mo(d,p) 99 U(γ,f) or the photonuclear reaction reaction photonuclear the or U(γ,f) Mo by neutron activation of 98 Mo in the the Mo in Mo(n,γ) reaction. Mo(n,γ) 235 99 U), involving the challeng the U), involving Mo. 100 99 nuclear reactions leading to Figure 3.5. 100 99 Mo or or Mo 99 Mo(d,t) reactions. Mo plant separation Mo(n,2n) reaction. Mo in Mo in Figure 3.5 Figure 235 U by accelerator- 99m 99 Tc respectively. Selection of of Selection 99m Mo and and Mo 100 Tc the via Mo(p,pn), Mo(p,pn), ): nat 99m Mo Mo Tc. Tc. - - – will stop its global stop its global – will 1 TBq of 1 TBq The GovernmenttheThe that decided has ofCanada ACSI respectively) a fleet existing arepreparing of via the the via 30 MeV)30 for (Missouri). for cyclotron production, As the NRU reactor – a major player supply the chain in Non-fission routes havethe advantage of radioactive will be extracted from this low specific activity low activity specific from this be extracted will or only reductionwaste mainly since with automated two-column selectivity inversion selectivity automatedwith two-column Light Source, is working on the photonuclear on the working is Source, reac Light ing and day) and ing helps reduce investment operation and oneprovide could up to control transport, ity and of efficientin recycling duction of duction of suit study the interest in stimulated drawbacks most routes of and these duction prefer or require duced butthe nohand, other fissionOn products. [Qai14]. The [Leb12]. more stable molybdenum compared to fission pro fission to compared molybdenum more stable targets, one could obtain up to 2 TBq of up to 2TBq one obtain could targets, tion tion tively.the ledCanadian by one Thus consortium, needarea. metropolitan of alarge daily the typically (proton endthe of MeV, irradiation 24 energy beam the of low activity specific in result they the specific activity of activity specific the morn night)(duringthe PETthe and radionuclides cyclotrons same forthe production of the photonuclearthe reaction become too low for the labelling of certain kits kits of certain become too low labelling for the reactors, so-called aqueous homogeneous reactors. reactors. homogeneous aqueous so-called reactors, accelerator production of and new cyclotronsrelatedand Tc plus the and target accelerators. Two and (led consortia by TRIUMF qual packing, processing, for 6hours target another of lowand breakthrough sorption capacity able generator high with matrices advanced project will irradiate natural Mo or natural irradiate advanced project will has funded efforts to establish the feasibility of the feasibility establish to efforts funded has enriched highly extraction technology for direct for direct technology extraction enriched enriched set up domestic domestic up set costs. The optimum proton The (between optimum costs. andenergy 16 Governmentcover Canadian domestic needsthe 6h). time Assuming irradiation µA, 500 current generators. A longer-term using at project also aims The Various to USA the in projects underway are Another project solution proposesAnother LEU critical 99 Mo is typically diluted with a thousand times times athousand with diluted Mo typically is 100 100 100 Mo(γ,n) 99m 98 Mo(p,2n) Mo(p,2n) cyclotron pro reaction allows Mo in the MURR reactor Columbia in MURR the Mo in Tc to nuclear medicine departments, i.e. Tc i.e. departments, to medicine nuclear 99m 99m 99m Tc. Using high-current cyclotron cyclotron high-current Tc. Using Tc debate under production still is Tc but energy with increases yield 99 99 98 Mo driven by 40 kWMo by driven electron 40 Mo/ Mo or 99m 99 Tcuse reaction.The jointof Mo 2016. production in To 99m 98 99m Mo or 100 Tc production.The most Tc might decreases and 100 99 99 Mo respectively. These Mo [Das13] as well as Mo(γ,n) Mo and and Mo 100 99m Mo respectively. Tc production 99 99m 99m Mo. 99 99 Mo where where Mo Tc (during Mo pro is Tc respec 99m 99m Tc at at Tc 99 Mo Mo Tc Tc ------These These have to be for a keptcouple critical days, of (100 mA) (300 low keV) energy deuteron beam without intermediate radiopharmacies. Hence, radiopharmacies. intermediate without Intense NeutronIntense at Emitter) project aims that for for formation of of formation neutrons that irradiate in turn undercritical LEU LEU undercritical turn in neutrons irradiate that production easier is to implement it since affects may far exceedmay far production of costs patients costs per day, transport therethat arisk is for remotely fewer located with users particular 99 99m of a once weekly delivery of agenerator.of aonce delivery weekly Hence, in end the but radiopharmacies not the directly only of to direct generator or aswitch technology for production target of gas 14 MeVonto atritium only a small fraction of these reactions can be seri of reactions these can fraction a small only tics: one or more daily shipments one oftics: or more daily However,users. regions other Europeand the in the extract tors which radiopharmacies placed are in accelerators electrostatic using intense to send an activity specific produced the then high regions. In North America the the America North regions. In require a radical change of the distribution logis of distribution the change require a radical are many possible nuclear reactions that result in possible many are in result nuclear reactions that extracted from the liquid core. liquid from the extracted solutions to produce surrounded by stable isotopes. Consequentlysurrounded there cyclotron production of “instant cyclotron production of “instant Mo/ With the end of the cold war and the signature signature the end and cold of the the war With US and the Soviet Union, war nuclear the many US and flux reactors producing medical isotopes. Thus, isotopes. Thus, reactorsflux producing medical for high flux reactors and as targets for targets as andreactors flux for high to for addition nuclear power In fuel stations. irreversible disarmament 20,000 warheads, each each warheads, 20,000 irreversible disarmament disarmament helps medical isotope helps production medical disarmament ment! are HEU production. Every several ten year kg of the nuclear disarmament treaties between the the between treaties disarmament nuclear of the used for for used “Megatons famous to Megawatts” prothis to produce uranium natural with tents “mixed” nuclearcon the and were dismantled uranium, and the latter contributes latter the toand durable disarma heads had to be dismantled. To hadheads to bedismantled. truly ensure hundred kilograms for fuel elements of high elements for of fuel high kilograms hundred containing on average 25 kg of highly enriched enriched on average 25 ofcontaining highly kg Megatons to Megacuries Megacuries to Megatons gramme, disarmed warheads also serve as fuel fuel as serve also warheads disarmed gramme, Tc change a Thus it ship end to users. and the A variant is the SHINE (Sub-critical Hybrid (Sub-critical SHINE the is A variant It should be noted that the boundary conditions It be noted should boundary the that 99m 99m 99m Tc is in the middle of the chart of nuclides, of nuclides, Tc chart of the middle the in is Tc use are significantly different in various various in different Tc significantly are use Tc generators shipped are end to users the 99 Mo production targets and several Mo and production targets 99m Tc or its precursor 99 Mo. 99 Mo/ 99 99m 99m Mo. However, However, Mo. 99m 99m Tc. Tc” wou ld ld wou Tc” Tc instead Tc genera Tc 99 99 Mo is is Mo Mo Mo 99m Tc Tc ------133 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 134 Nuclear Physics for Medicine – Chapter III – Radioisotope Production The administrative effort of validating and adding adding and validating ofeffort The administrative (kerosene) goods brought is by that dangerous Nuclear medicine is today recognised as an essential essential an today as is recognised Nuclear medicine PET-MR, etc.), requires specific “fuel” PET-MR, radio (the “fuel” etc.), requires specific Economic issues of radionuclide production radionuclide of issues Economic Secondly a new method has to it demonstrate has anew that method Secondly involved radiation exposed enhanced to often are related to directly aspect an viable, economically is nuclides) that is carried by special dangerous goods goods dangerous nuclides) by special carried is that millions of users. It is instructive to compare this to compare this It instructive of is users. millions the of respective files master radiopharmaceuticals. and criteria thequality established product satisfies of disciplines in medicine or achieving therapeutic or achieving medicine in of disciplines drug the in included theto be has new method often production. Before consideredously for industrial to various supervisory bodies and the personnel the and bodies supervisory to various subject regulated, highly are activities both that trained highly and to its destination transporters to service safe technicians) and to provide regular nuclearmedicine (medical doctors, experts trained highly needs and to itsdestination transporters tech equipment (SPECT-CT, high uses PET-CT, the market radionuclide. of value the the regular and safe service to millions of users. Note of users. to millions service safe and regular a new method is only justified if it can if contribute it can justified only a new is method radionu contribute can a new to method industrial and cost-efficient method of supporting a variety cost-efficientand variety a of method supporting huge demand forhuge demand high tech equipment (airplanes), specific “fuel” tech equipment (airplanes),high “fuel” specific experts (pilots, air traffic controller, traffic etc.) air to (pilots, provide experts situation to the aviation industry that also uses uses also that aviation to the situation industry Nuclear medicine success where fail. othermethods The demand. toor regional global substantially clide production it to bedemonstrated has clide its that 99m Tc puts this hurdle quite high. Tc high. quite hurdle puts this - - fields. of of production cyclotron by self-sufficient assumed is 2016.of Canada given region. a in consumption the to proportional is circles red the of diameter the and visibility) for shifted HFR and (BR2 reactors the of capacity production annual the to proportional is circles blue the of diameter Expected Expected 3.8. Figure 3.7. Present Figure operational by 2016. by operational be can projects US proposed the of which reliably judged be cannot Figure 3.6 profession. exercising their Figure doses while shows a comparison of the cost distribution in both both shows in a comparison of cost distribution the 99m Tc, reducing the demand for for demand the Tc, reducing 99 Mo production capacity and demand. The The demand. and capacity production Mo 99 Mo production capacity and demand end end demand and capacity production Mo 99 Mo accordingly. At present it it present At accordingly. Mo 99m average an for taken were medicine nuclear for numbers The industry. aviation the to nuclear medicine compared of economy The 3.6. Figure gov www.eia. (from kerosene for margin refinery the and KLM annual reports of Air France/ the from 2012to taken was 2007 from average an costs industry aviation the for while to 2011.to Tc scan from [NEA10], [NEA10], from Tc scan ) was averaged from 1995 1995 from averaged ) was

As Paracelsus, a cofounder had of medicine, modern Paracelsus, As 3.8 Rising doses provide therapeutic buteffect higher Rising where a good therapeutic effect is achieved with wherewith is achieved therapeutic agood effect Switzerland, Germany and some Scandinavian 3.4 in particular for all cancer therapies: cancer general alow in for all particular in the unless deserve they introduced or reach use the ness, it must be made clear that these cannot be cannot these that itness, beclear must made dose does not cause a durable therapeutic effect since not dose does since adurable therapeutic cause effect but considered are directly, asimple as auxiliary protection issues, and for cost-effectiveprotection and overall issues, may be destroyed, while aproportion repairable. are may while bedestroyed, taken. is action producers” no political if problems, been the has that physical or technical plastersof syringes, to disposable similar material of other promising radionuclides that have that radionuclides of advan promising other of the healthcare system such as the USA, Japan, USA, the as such system healthcare of the tion. Thereforetion. there appears (see by acknowledged and therapies recognised better is properties forpatient, tageous the radiation appre not is widely nuclear medicine, in “fuel” the they nuclear medicine aviation, in in expenses the the cancer cells, thus the curves of therapy effect and of therapy effect curves the thus cells, cancer the concentration better poison of on the therapy allows “therapeutic window” so-called the range, middle the recover mechanisms repair from cell’s cancer the not is poisonous.”principle This applies athing that “non- to certain favour market would the delivery bandages. It is mainly this economic aspect, and not and economic aspect, this It mainly is bandages. ruptions in the past. When discussing the prospects the discussing When past. the in ruptions root supply for cause radionuclide occasional dis acceptable More side targeted effects. (“selective”) therapyAny in tries stayto side effects. higher also dose makes the poison. Only without is nothing and 1538: poison are in recognised already things “All a procedure medicine nota nuclear are reimbursed 1% for case the less than are in healthcare systems! healthcare ery. With medium doses a proportion of the cells a proportion doses cells of medium the ery. With structures different with exceeded countries in nuclear medicine of in value radionuclides essential suggests that perhaps that of value radionuclides, the suggests side effects are better separated and the therapeutictheareand separated better side effects dose completely.high damage Asufficiently small atsupports present own their can destroy all cells without the possibility of recov possibility the without cells destroy all can in used radionuclides the countries many In ciated. countries. Interestingly none countries of these Interestingly countries. 99m .) a clear risk that in times of global undersupply of global times .) in that risk aclear While “fuel” costs represent costs of about aquarter “fuel” While It is noteworthy that the averageIt the noteworthy is that of costs OECD Theranostics Tc procedure given above diagnostic largely are 99 Mo or 99m Figures 3.7 Figures Tc This scans. 99m Tc produc and and ------Thus uptake into the tumour can be visualised and visualised be can tumour theinto Thus uptake Also for non-radioactiveAlso therapeutics it be would window becomes ( window wider dose that causes acceptable side effects. side acceptable causes that dose a at results therapeutic better gives i.e. window, therapeutic larger a provides side) (right pharmaceutical selective Amore 3.9. Figure ing optimum use of the therapeutic window. This therapeutic of window. the use This optimum ing used and be quantified can organs dose-limiting in vector question. isotope in coupled targeting to the dance. This is done by injecting a PET doneSPECTis or injecting by This dance. dose consisting of atherapeutic isotopedose consisting coupled to from one another.patient to differ Thereforeis it preferable uptake before the tumour to the know - theranos called is medicine ofmethod personalised therapies. for nuclearmedicine particular unwanted excessive uptake in healthy tissue can be be can excessiveunwanted tissue healthy uptake in the required markerthe present is abun sufficient in tics (fromtics [Bau12]. ‘therapy on based diagnostics’) thereby mak to therapy adapt the dose individually, most patients treated are those who will only that ensures This vector injected. is targeting same the These congeneral therapy patients. for best is the are sidereduced effects the therapeutic result or at treatment, but without radioactive probes this is is treatment, but probes radioactive without this a quantitative analysis of the scout dose, i.e. the con the scout of i.e. the dose, analysis a quantitative therapeutica giventhe level success of side effects excluded. Only after this verification the therapythe verification this after Only excluded. likely benefit from benefittreatment.the likely PET even enables siderations are valid for all types of therapy, types but in forsiderations all valid are crucial to verify before to aselective verify therapy that crucial centration of the targeting vector in the tumour and and tumour vector the in centration of targeting the beimprovedcan selective respectively.highly Thus The abundance of certain tumour markers may tumour of certain The abundance Figure 3.9 ). Thus, at a given at a ). Thus, - - - - 135 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 136 Nuclear Physics for Medicine – Chapter III – Radioisotope Production vivo. Ideally one should use radioisotopes one use of should the vivo. Ideally (see not does that amount the as (MTD) determined is dose is reduced and a better therapeutic effect can be achieved. be can effect therapeutic abetter and reduced is dose the of scatter the theranostics patient-specific With curve). (blue correspondingly scatters dose resulting the radiopharmaceuticals) for activity pharmaceuticals, normal of (mass amount administered agiven for thus patient, to patient from varies pharmaceuticals of distribution the theranostics: of 3.10. Principle Figure difficult to realise non-invasively tosur realise without (i.e. difficult of the therapy. the of from varies patient to patientof pharmaceuticals the fact that the scout dose of the imaging isotope scout the imaging dose of that the fact the the therapy, the before patient individual an in tion behaviour. This explains the particular interest for the particular explains behaviour. This reduction of the therapy success. The distribution distribution reduction of therapy the The success. and the therapeutic the dose behaveand way same in the improve doseand optimum success achieve the the to accordingly be tailored can amount administered advantage of nuclearmedicine. non-invasive represents studies allowing adecisive lead fixedlead tothe excessiveand for is side effects same elementsame biochemical identical to ensure so-called “matched pairs” of one diagnostic and and “matched of one pairs” diagnostic so-called clinical application. This concept will obviously obviously will concept This application. clinical gical sampling). Thus the use the of probesradioactive Thus sampling). gical In clinical trials the maximum tolerated dose maximum the trials clinical In Obviously the theranostics approach theranostics Obviously on the relies Figure 3.10 Figure on average to an under-treatment to an to a thus and ). By measuring the real distribu real the ). By measuring - - Thus deviations in the be compensated uptake can in deviations Thus This seems sufficient seems for present PRRTThis applications With aconvenientWith of alow 6.65 half-life days, beta Usually such therapies are fractionated into smaller therapies such fractionated are into smaller Usually ( (SPECT) with (PET) or ( 131 177 would profit from higher specific activity and pre activity profit specific would fromhigher 68 3.5. for in the subsequent the for treatment in cycle. ing of the biodistribution with the therapeutic dose. therapeutic dose. the with biodistribution of the ing elements, e.g. similar isotopes from chemically ing particularly stable labelling with macrocyclic macrocyclic with stable labelling particularly ing degree of chemical resemblance has to be validated resemblancedegree ofto has be validated chemical matched pairs are are matched pairs moment of production. Thus, after delivery the ratio momentdelivery after of production. Thus, Ci/mg20 of about theprovides at activity aspecific ment been reported. has of bone metastases or planar gamma cameras, therapeutic isotopes cameras, that gamma or planar one to often “nearly matchedresorts pairs“ of radio or one a “matched element cov that with quadruplet“ or one therapeutic isotope element. same Real of the of radioactive radioactive of the “useful” 7/2 “useful” the activity. specific higher with targeting on enriched ture therapeutic isotope. Moreover the has lutetium by in vivo experiments for every targeting vector targeting for every vivoby experiments in branch of the neutron ofbranch the reactionnot capture leads to radionuclide therapies. Even successful use for therapies. use treatradionuclide Even successful administered activities that are repeated are that activities regularly. administered low emit rays intensities of gamma also imageable depend element Some combination. chelator and and treatment of bone metastases but certain RIT RIT treatment butand of certain bone metastases energy (0.13energy MeV mean) (< range and 2mm) a and encies have uptake the Since been observed. indeed nuclear medicine: decay in modes used ers all ligands. This makes it an optimum isotope an for optimum makes it appli This ligands. rays of gamma SPECT imageable low abundance lowest ionic radius among all lanthanides, ensur lanthanides, lowest all among ionic radius can also be followed to a certain degree by SPECT befollowed to acertain also can clinical PRRT experiments demonstrated improvedexperiments PRRT clinical targeted other and RIT, PRRT cations including physics and radiochemistry physics and 153 b Ga (PET) Ga with I ( - Lu has excellent nuclear decay nuclear excellent properties for Lu has a ) or Sm, Sm, 149 64 Direct production Direct In the direct production of c.a. production of c.a. direct the In b Cu (PET) with

Tb ( Tb 177 - ) or 203 166 Lu, ashowcase for nuclear Pb (SPECT) with Ho, Ho, a 155 125 ). If real matched pairs are not are matched real available ). pairs If Tb (SPECT) Tb with I (Auger),I 177 177 186 + Lu, Lu, groundstate of 90 Lu to total Lu is about Luis 1:6Lu to total to 1:8. Re or Re 176 Y ( 123 186 Lu targets in high flux reactors flux high in Lu targets 67 I (SPECT) or of c.a. of c.a. Re, b Cu ( Cu 86 - ) or 188 Y (PET) with 188 Re ( Re b Re, 177 212 - ), ), 177 Lu ( Pb ( Pb b 44 161 211 - Lu by neutron cap ), ), Sc (PET) Sc with 177 Tb ( Tb At) allow monitor At) allow b 111 a Lu (T - ). Thereis even 124 ). However, the the However, ). In (SPECT)In or b I (PET) with 177 90 - plus Auger) Auger) plus Y ( 1/2 Lu a0.1% =6.65 d) d) =6.65 b - ), ), 152 99m 61 47 Tb Tb Cu Cu Tc Tc Sc Sc ------1878, it took nearly thirty years before chem three 1878, it took nearlythirty virtually free of virtually RIT), patients will rapidly excrete excess activ the patients will RIT), (T It was not until the 1990s that large-scale chemical chemical large-scale 1990s that the It not was until Lu/Yb separation is particularly challenging since since challenging particularly separation is Lu/Yb Charles James)Charles to separate independently managed impractical to water keep waste for the years impractical many ists (Georgesists Auer von Carl Urbain, Welsbach and certain in radioactive waste, islation concerning in is separately latter The collected urine. via ity nuclear medicine departments of hospitals and only only and of hospitals departments medicine nuclear decay path, indirect production also requires a production also indirect decay path, powerful radiochemical separation method. The separation method. radiochemical powerful ments that contains c.a. c.a. ments contains that only to the wanted ground state and does not does wanted state ground and popu to the only of to let let to the remaining activity has dropped has below free the activity remaining the treated with thus demonstrating its existence as separate element. as itsexistence demonstrating thus from lutetium ytterbium, similar very chemically the similar very chemically neighbouring, are these problem. waste tive” radioisotope. promising applicationthe of this but to the longer-lived 23/2 the to but released after sufficient decaysufficient released after half-lives)(>>10 when of relative activity rules of decay 9/2 beta that ensure rules indirect element, by Jean-Charles Galissard de Marignac in in Marignac de Galissard element, by Jean-Charles may easily. This represent a bottleneck serious for late the high-spin state high-spin late the lanthanides. After ytterbium was first chemically first chemically ytterbium was After lanthanides. Given of long half-life the limit. separation of pure lutetium became possible, thus possible,separation became of thus pure lutetium discovered anew thus chemical as and separated, countries sewage water depart sewage ofcountries nuclearmedicine 1878. It took nearly thirty years until chemists chemists years until 1878. It took nearlythirty Ytterbium was first chemically separated, and separated, Ytterbiumchemically first was ytterbium within hours. within ytterbium A long and tedious challenge for chemists for challenge tedious and A long its existence as separate element. In 2007, separate element. as In its existence a managed to separate the chemically very similar similar very tochemically separate the managed of patient doses that now allows clean separation of hundreds separation of clean hundreds nowthat allows element, in discovered anew chemical thus as lutetium from ytterbium, thus demonstrating demonstrating thus from ytterbium, lutetium scale radiochemical separation was developed developed was separation radiochemical scale century after discovery of lutetium, a large- discovery a of lutetium, after century 1/2 Thus, depending on the free limit and local leg and local limit freethe on depending Thus, 177g In addition to a nuclear suitable reaction and addition In Fortunately Fortunately =160 d).c.a. Thus 177m Lu during transport is considered. is When transport Lu during

production Lu decay. 177 Lu for systemic therapyLu for (PRRT systemic or 177 177m 177 Lu can also beproduced by also an Lu can 177m path. Here selection spin path. the Lu and solvesLu and “administra the Lu from grams of irradiated of irradiated Lu from grams Lu, or moreLu, decay when the 177m 177 177 Lu cannot be disposed of be disposed Lu cannot Lu contains at 10 least Lu contains Lu. Hence, n.c.a. Hence, n.c.a. Lu. - high-spin isomer isomer high-spin 177m + Lu it be would

177 Yb decays decays Yb 177 177m Lu is Lu is Lu Lu -4 ------

Therefore accelerator with production (d,p)and (d,n) ytterbium within hours. Today hours. - of mas within irradiations ytterbium (about 2gmass) neutron for flux aweek athermal in would be produced. Irradiating the same target target same the beproduced. Irradiating would HFR Petten, SAFARI Pelindaba, etc.) followed by Pelindaba, SAFARI Petten, HFR Since itsbeen “inception”,Since has nuclearmedicine 3.6 functions for for functions duction and accelerator-based and duction the production in deuteron available from accelerators currents and of separationof hundreds developed now that allows metallic [Man11].measured Even of 0.1 deuteron if mA cur productpopulated by final the (n, paths patient doses of pure discovery the of after 2007,mentation. In a century ments required The that stronger sources. radiation product of French (in brachytherapy via treatments for practice of this material enabled material new,of this more complex experi were that techniques and discoveries outstanding 10 of target/product combination. However, (d,p) the triggered the development the triggered of radiochemi areal numerous physics nuclear achievementsuses in and nuclear interwovenphysics radio with and tightly be produced research reactors. in rent is sustained over enriched rent one sustained is week on ahighly assures separation at Garching ITG radiochemical Grenoble, Mol, ILL BR2 Munich, reactors (FRM2 recognised by Nobel Prizes in Physics in Chemistry. by and recognised Nobel Prizes a dozen more these among than radiochemistry, reactions not is competitiveisotope same can the if a regular supply of n.c.a. supply of n.c.a. a regular accessible directly by (d,n)accessibleexcitation The directly reactions. amounts of amounts example of enabling production of LSO crystals for PET instru production crystals of LSO enabling lutetium, large-scale radiochemical separation was separation was radiochemical large-scale lutetium, sustainable by the targets. For indirect production For indirect targets. by the sustainable sive sudden need for large quantities of need sudden quantities for large therapie) Curie called with still and nuclear physics nuclear and cal “industry” for large scale separation of gram scale for large “industry” cal could bereplacedcould by (d,p) same the reactions with close collaboration ofclose collaboration physicists nuclear nuclear and covered, were these rapidly introduced into medical Today’schemistry. directly of nuclearmedicine use cross-sections are generally lowercross-sections so the are are generally and When the effects of ionising radiation dis wereradiation of effects ionising the When It is interesting to compareIt interesting is reactor-based pro Synergies of nuclear medicine medicine of nuclear Synergies 176 14 cm Yb targets by anetwork targets of several research Yb 176 -2 232 s Yb target, only about of GBq 80 only target, Yb 226 -1 -1 177 Th present in minerals like Pechblende) Th minerals presentin 176 would producewould more ten times Ra. In turn the industrial availability availability industrial the turn In Ra. Lu. In principle all (n,γ) principle all In Lu. reactions Yb(d,p) and and Yb(d,p) 177 Lu from grams of irradiated of irradiated Lu from grams 177 Lu in GMP quality. GMP Lu in 176 Yb(d,n) were recently recently were Yb(d,n) 226 Ra sources. The The sources. Ra 226 Ra (aRa decay g ) b - is also also is 177 177 Lu. Lu. Lu Lu ------137 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 138 Nuclear Physics for Medicine – Chapter III – Radioisotope Production • • • • • • United States and in Europe in 1920–1930,United Europe in in States and main the Nuclear medicine is arelatively is sub-speciali Nuclear medicine young IAEA soon played amajor development role the in IAEA anti-prolifera not only call this in including IAEA, first medical applications taking place in both the both in place applicationstaking medical first invited formation the of what to was become the nostic radiology. This is normally seen as the result the as result seen is normally nostic radiology. This nostic and therapeutic radioisotopes. Although some therapeutic radioisotopes.nostic Although and developed rapidly into an important sibling to diag sibling developed important rapidly into an physics most notably national and various from the the by justified enough strangely world, and medical “Atoms the and programme for Peace” concept. In physicians enabled of many radiology and medicine of this production capacity by supportof of this research world needs of medical for the the diag of satisfying research world many reactorsof the the capable in threat posed invention bythreat the of nuclearweapons. outside the initiated was towards nuclear medicine this Within publication programme. important the research many reactorsthe isotopes radioactive that topes ( would Experts of mankind. pursuits peaceful the to serve allocated fissionable be would material this nuclearpower but and tion also: measures, discoveries 20 of the ground-breaking the became available at a large scale and on demand. The The on demand. and scale at available alarge became to apply of needs to the be mobilised atomic energy Manhattan wake of the the in came breakthrough agriculture, medicine and other peaceful activities.” peaceful other and medicine agriculture, all the way the back to- George Hevesy’s dis all centennial and training programmes, by conferences programmes, by and training and cyclotron-produced and activity neutron-rich iso his famous speech in 1953 speech in famous his president Eisenhower early pre-1960early work radium-derived done was with whereby methods beto devise would agency energy entific and technological developments fromand technological basic entific sation of medicine. Although its roots can be traced betraced its roots can Although sation of medicine. covery 1913 principle tracer of the in some and of the context, it is worth remarking that the IAEA’s effort IAEA’s effort the that remarking it worth context, is The presently used labelling methods for methods Theused labelling presently The discovery of neutronuse andThe moderationits Later on the onLater the Discovery neutron of the by Chadwick. Discovery of artificial transmutation by Joliot- Discovery of artificial Curie. Szilard-Chalmers reaction (atSzilard-Chalmers ahospital). from medical medical from was by Fermi transmutation morefor efficient developed Centre Jülich. NuclearResearch at the developed Brookhavenat the Laboratory.National based on a Rn/Be source with the the source with based on aRn/Be “The more important responsibility of this atomic atomic this of moreimportant responsibility “The This advance of nuclear medicine driven advance sci by of This medicine nuclear During the following years, nuclear medicine nuclearmedicine years, following the During 32 P, P, 24 Na, etc.) it was only after the advent etc.)Na, after itof only was 99 226 Mo/ Ra sources. Ra 99m Tc generator were FDG and 222 Rn recovered recovered Rn th century: 18 F were were F ------• • • • worth remembering when considering the future future the remembering when considering worth On the basis of this pattern it can be reasonably it pattern can of basis this On the into medicine and healthcare should be recognised be recognised should healthcare and into medicine medical applications. This ‘food chain’ of innovation innovation of chain’ ‘food This applications. medical tist in basic physics sooner or later starts to think of basic physics to in think soonertist or later starts throughout the EU. the throughout basic science driving medical advance can benoted: advance can medical basic science driving role of nuclearphysics. research in nuclear and particle physics. It seemsan particle nuclearand research in almost universal truth that the experimental scien experimental the that truth universal almost fromfundamental advanced spin-offs by important argued that the medical field and in general the in general and field medical the that argued health of the public has been and will continue to be will been and has public of the health laboratories is seen as a general pattern, which is is which laboratories ageneralpattern, seen as is The gamma camera and the well counter came in in counter came the andwell camera gamma The universal developmentThe This cyclotron.the of While the PET scanner concept PET the scanner emerged more or While workhorse of medical isotopeworkhorse production of origi medical Laboratory and the entire field of cyclotron design cyclotron field entire design of the and Laboratory PET/MRI integration had important input from from input important had integration PET/MRI nated at the University of California Radiation Radiation nated University at the of California during the period of the Manhattan programme. periodManhattan of the during physics. the detector groups at CERN, Fermilab etc. Fermilab detector groupsthe at CERN, development, from CT inspiration under it can same the in working 1950sthe Anger from Hal be strongly argued that the present the that block- day argued be strongly ring PET PET/CT and ring detector development had and isotope-producing targetry evolved isotope-producingand rapidly targetry less directly from the medical physics world medical from the and less directly strong roots in the vast detector of vast arrays nuclear the strong roots in The discovery of natural radioactivity, of meth radioactivity, discovery of natural The group as the Radiation Lab. Radiation group the as (at the time mainly brachytherapy) (at triggered mainly time the well equipped medical faculties by borrowing by borrowing faculties equipped medical well Frequently nuclearphysicists profitedfromthe industry that provided that isotopes these masse. en industry 226 not have occurred so quickly without this close this not without have so quickly occurred quickly found medical applications. medical found quickly strongsources of isotopes like to extract ods the Szilard-Chalmers separation method would separation would method Szilard-Chalmers the neutron Fermi or activation by Enrico through developmentthe of averitable radiochemical purposes of sources such use forthe medical like the production of artificial radioisotopes production the of artificial like synergy. In turn the nuclear physics nuclear the discoveries turn In synergy. Discoveries research. sources forsuch their From nuclear physics to medicine and back and medicine to physics nuclear From Very examples of developments important in Ra and and Ra 210 Po derived and neutron and sources, - - - The complexity of instruments, the methods applied, applied, the methods instruments, The of complexity The role of nuclear medicine and PET in in and PET medicine role The of nuclear variety of applications ( applications of variety (HFR, BR2, NRU, SAFARI, MURR and many and MURR NRU, SAFARI, BR2, (HFR, New pharmaceuticals areby impor themselves very New pharmaceuticals However, isotopes a serve the produced at HFIR Isotope Reactor) Ridge. Flux Oak (High in HFIR General Atomic) reactors carry ‘isotopes’ in their their Atomic)General in ‘isotopes’ reactors carry one nuclearreactorOnly isotope worldwide carries 3.7 isotopes ( medical etc.)isotope with batteries for satellites, nuclear medicine techniques, and the pharmaceuti the and techniques, nuclear medicine name and indeed part of the fleet of over 40 TRIGA fleet ofTRIGA of the 40 over part indeed and name departments. more) usually serve a variety of purposes at the of purposes avariety serve more) usually particular in emerging countries. emerging in particular the its name, in purpose production its main as companies even havepharmaceutical PET own their of these sensitivity the compete can with modality of concentrations picomolar even of measurements modern PET scanner this quantitative aspect is quantitative aspect this PETmodern scanner of modern pharmaceuticals. No other imaging No imaging other of pharmaceuticals. modern used forused bore hole petrol probes industry, the in to utilise the strength of the technology. of Some the big strength the to utilise discovery,the development approval and process sensitivity. PET high very and registration tomical leveltracer compound concentrations, unperturbed economic and growth. healthcare fortant future reactors worldwide operating contribute to local on based radiochemistry and its companion science of clinical physiology its companionand science of clinical and regional radioisotope regional and supply in for medicine, volume. irradiated of the a minority isotopes for superheavy elementactinide research, compound. organic any almost the In animals. in as well as man vivo, in in and production of training, structure underlying the and have relied upon quantitative measurements of pharmaceutical discovery and development and discovery pharmaceutical research and radioisotope radioisotope and research for accelerators and reactors still supports development supports of new pharmaceuticals. still cal industry is embracing embracing PET is universities centres in industry cal applications. However infrastructure this clinical development scanner and capacity now is by driven production combined with good spatial resolution good spatial ana combined and with This has made PET a very important tool in tool important made has a PET very This Also TRIGA (Training, Research, Isotopes, Research, (Training, TRIGA Also From the outset, diagnostic nuclear medicine nuclear medicine From diagnostic outset, the Other research reactors with less explicit names research names reactors less explicit Other with Joint exploitation of research of Joint research exploitation 188 W, W, 186 Re, 117m Sn, etc.)Sn, representing only 252 11 Cf for neutron sources, sources, neutron for Cf C or 18 F allows in vivo in F allows - - - The LINAC supplies polarised or unpolarised prounpolarised or LINACsupplies The polarised Alternating Gradient Synchrotron (AGS)Alternating ulti and were essential (LANL) Laboratory National Alamos The acceleratorsThe of US DOE the laboratories viding 800 MeV protons to the LANSCE spallation MeV spallation 800 protonsviding LANSCE to the MAPLE) in Canada failed due to technical, regula due to technical, failed Canada in MAPLE) 202 MeV202 Brookhaven to diverted the are LINAC Medical Isotope Reactors, previously known as as Isotope previously known Reactors, Medical Excess proton beams with energies between 66 and and 66 energies proton between Excess with beams where neutrons aprobe the as serve for fundamen Isotope Producer (BLIP) stationfor production of Brookhaven (BNL) Laboratory National Los and OPAL at ANSTO, ORPHEE at LLB, etc.) serve at LLB, OPAL ORPHEE at ANSTO, facilities (RJH, MYRRHA, PALLAS). MYRRHA, (RJH, facilities for medical applications beforefor medical dedicated sufficient industrial isotopes, transmutation doping of sili doping transmutation isotopes, industrial important but notimportant exclusive use. injector for the Booster synchrotron that can fill the fill can that synchrotron injector Booster for the for development the supplyin chain of a regular 82 neutron The source. MeV100 protonsarethe sent to multipurpose reactors more is multipurpose sustain efficient and notproduction could cover alone for medicine the problems radioisotope that when it clear became are neutron to that supply beams extracted mainly elements, fuel production of of certification ples, mately the Relativistic Heavy Ion Collider (RHIC). (RHIC). Ion Heavy Collider Relativistic mately the production not is covered cyclotrons and by medical Today cyclotrons available. became medical there physics labs were to used produce new radioisotopes tory and political problems, but also faced problems, economic but also political and tory for used are radioisotopethat production. have reactors positions these also irradiation in-pile condensed physics, matter in applied and studies tal technique important an forused neutron scattering, tons booster for to the nuclearphysics experiments of the use joint exploitation the ofthus nuclear physics accel branched off from the linear acceleratorthatis linear pro branchedfromthe off rising project costs. Given this historic precedent project historic Given costs. rising it this requires protons MeV 60 of more than for efficient able. Consequently it been adopted has for future and the NASA space radiobiology programme. programme. space radiobiology NASA the and radioisotopes whose of anumber interesting still are erators helps to fill thesegaps. erators helps to fill seems today evident that the model of of model shared use the todayseems evident that sam irradiated (materials research time with same chemistry, biology, However, science, etc. chemistry, materials con, etc.) isotope where production medical an is Sr, At LANL a 100 MeVAt LANL proton be can beam accelerator proton as used is alinear BNL At The project to operate two MMIR (MDS projectThe to operate MMIR two Historically the accelerators the of nuclear many Historically Certain research reactors (FRM2, RHF at ILL, at ILL, RHF research reactors (FRM2, Certain One example is the productionOne the of example is 68 Ge and other radioisotopes. other and Ge 85 Rb(p,4n) and 87 Rb(p,6n) reactions. 82 Sr that 82 Sr. ------139 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 140 Nuclear Physics for Medicine – Chapter III – Radioisotope Production Accelerator Centre), of the Facility aNational Agency. A commercial radioisotope manufacturer, Agency. Acommercialradioisotope manufacturer, TRIUMF’s nuclear medicine programme is actively actively is programme nuclear medicine TRIUMF’s MeV can be performed simultaneously with ongoing ongoing MeV with beperformed simultaneously can Russian Academy of Sciences in Troitsk, Russia, Troitsk, in of Russia, Sciences Academy Russian National Research Foundation of South Africa, Africa, South of Foundation Research National Nordion, co-located is site at the where oper they 123 with the University the Columbia of (UBC)with British was designed from the outset to from beamultidiscipli the designed was melanoma. where patients treated are for ocular Isotope Production Facility (IPF) for regular pro (IPF)Isotope for Production Facility regular Department of Medicine and the BC Cancer BC the and of Medicine Department PET cyclotron exclusively is for used radioisotope is currently 300 µA and up to four targets can be can up and totargets four µA 300 currently is including including nuclide targetry to support its collaborators and targetry nuclide nary facility for applied basic physics and nuclear facility nary diverted from the linear accelerator that is driving accelerator driving is that linear fromdiverted the weekMeV the a66 neu protonduring with beam duction ofduction ment stations, of which two can be simultaneously besimultaneously can two ment of which stations, production receives that production. Radionuclide presence international and anational in maintain radio and technologies new labelling pursuing addi In locations. other two physics in experiments proton ofMeV 94 beams to 158 MeV be can operated, for production used routinely are the of 72 these research arenas. these active proton there an tion is therapy programme 500 MeV cyclotron to designed is topes. TRIUMF’s tinely and production and of tinely Moscowthe Meson Factory. dedicated proton for therapy while therapy tron this effort TRIUMF has a strong collaboration strong a collaboration has TRIUMF effort this beam current on the vertical beam target station target beam vertical on current the beam bombarded simultaneously. bombarded research, radiotherapy with protonsresearch, radiotherapy with neutrons, and about 40% of the SSC beam time allocation shares shares allocation time beam SSC of the about 40% and radionuclide production. These three main dis three main production. radionuclide These and production the of thus intensities, and ate 3 cyclotrons producing a number of products, keeping with sciences. In basic life researchand in application of for physical medicine techniques the of its mandate physics part as has particle and exclusively at five nuclear physics facilities, clinical exclusivelyclinical at five physicsnuclear facilities, energies multiple proton ofextract varying beams scheduled blocks are earmarked. Three bombard Three blocks earmarked. are scheduled sector cyclotron (SSC) acommercial 11 while MeV ciplines share the beam from the K=200 from the separated beam share the ciplines Se, etc. has been demonstrated. has etc. Se, I, I, At the Institute of Nuclear Research of of the Nuclear Research Institute the At While While TRIUMF, Canada’s National Lab for nuclear nuclear for Lab National Canada’s TRIUMF, iThemba LABS the as National (formerlyknownLABS iThemba 82 Sr, Sr, 68 201 82 82 Ge, Sr was produced in the last decades produced last Sr was the in Tl, Tl, Sr, 67 68 123 Ga, Ga, Ge and many more many and Ge radioisotopes. I, I, 111 22 In, In, Na and 117m 103 Pd, Pd, Sn, Sn, 82 18 Sr is producedSr is rou 67 225 F. The maximum F. The maximum Ga and other iso other and Ga Ac, Ac, 82 223 Sr at 70-90 Ra, Ra, 109 Cd, Cd, ------Ring Cyclotron feeds the Swiss Muon Cyclotron Swiss (SμS) Source the feeds Ring (cross-section measurements) [Had11]. will be the first such machine fully dedicated dedicated to fully machine such first be the will with six beamlines available for experiments using using availablefor experiments beamlines six with France, can provide simultaneously two proton two provideFrance, can simultaneously Cyclotron post-accelerated and to 590 MeV. The Switzerland, operates two cyclotrons in series: the series: operates the cyclotrons in two Switzerland, isotope pro for several stations medical and SPES neutrons for neutron scattering, neutron radiogra neutron scattering, neutron for neutrons duction capacity. This triggered thedevelopment triggered capacity. duction of This duction (LARAMED). duction plus other medical isotopes ( medical plus other part of the 72MeV of the part proton besent the into can beam production by (n,γ) splitter a beam Via reactions. phy, neutron radioisotope physics and experiments probes, SINQ, and muons magnetic sensitive as local of of trials demonstrated impressively value added trials the the purchase of purchase a70the MeV proton cyclotron which beams with upto each produce to 375 with µA beams beams to 72 MeV that are injected into the Ring to 72 MeVbeams Ring injected are into the that radionuclide production vault. PSI currently pro currently PSI productionradionuclide vault. additional dedicated and shared facilities. and dedicated additional a continuous spallation neutron source providing a continuous spallation drive Laboratory, National at Legnaro Italy, will entific research in radiolysis and physics nuclear in radiolysis research entific accelerator for used sci is this etc.). addition In so-called Injector 2 which accelerates 2.5 mA proton accelerates Injector 2which 2.5 mA so-called simultaneously the radioactive ion beam facility radioactiveion facility the beam simultaneously commercial radioisotope production. first dedicated dedicated first improved specificity and accuracy comparedimprovedand accuracy specificity injected into the patients. Production patients. of injected into the 82 not available from usual medical cyclotrons. For cyclotrons. medical not available from usual now coming on-line. now coming to the usual SPECT isotopes in heart perfu heart SPECT isotopes in usual to the therefore nuclear physics accelerators and so- and accelerators physics nuclear therefore automated an it system is patient. With to the requires energetic protons (>60 MeV) are that rising demand for this promising isotope promising the for demand this rising eluted from energy physicsenergy laboratories respectively. With long time all five all long time sion studies and, due to its short half-life (75due to its short half-life and, sion studies seconds), a minimisation of radiation exposure of exposure radiation seconds), a minimisation called injector accelerators for nuclear or high high or nuclear for accelerators injector called From injectors for injectors for injectors From 82 The 70 MeV cyclotron ARRONAX in Nantes, in Nantes, The 70 MeVARRONAX cyclotron Multiple beams from anew 70Multiple beams MeV cyclotron Recently Zevacor Molecular, USA, announced announced USA, Zevacor Molecular, Recently Paul Scherrer Institute (PSI) in Villigen, (PSI) Villigen, Scherrer in Institute Paul Rb, a short-livedRb, positron emitter, showed Sr and today demand outpaces by far the pro the outpaces by today demand far Sr and 82 Sr/ 82 82 Sr production machines are Sr production machines 82 Sr producers worldwide were Rb generators and directly directly and generators Rb 64 Cu, Cu, 67 Cu, Cu, 44 82 Sc, Sc, Sr, Sr, 82 68 47 Sr Sr Ge Sc, Sc, ------The Technology of where binding new methods Řež, Debrezen, etc. can also beexploited to pro also can Debrezen, etc. Řež, MEDICIS is now under construction. It will make make It will now is construction. under MEDICIS Recently the K=160 the Recently complemented cyclotron was (mainly in Copenhagen, Hannover Orleans). and Copenhagen, in (mainly beoperated negative can in and (e.g. ARRONAX) with chemically selective ion on-line sources and chemically with for medical applications are only available afew available applications only are for medical Therefore facility. unique radioisotopes from this beams alpha cyclotrons accelerating few medical supply of PETfor radiopharmaceuticals. aregular for the ics heavy ion cyclotrons usually operate positive in ics ion heavy cyclotrons usually in radiobiology and preclinical studies before a studies preclinical and radiobiology in isotopes saturation activities in purposes for R&D univer by combining non-carrier-addedin quality beams alpha of supplying have capability the will ity thereforeion can and mode accelerate beams. alpha nuclear solid state physics, solid nuclear etc.) depend on beams produces butnuclear physics also experiments, dedicated productionbeen developed. dedicated has method duce silver coated TiO or using directly duces methods can be supplied for fundamental research besupplied for can fundamental methods radio purity It separation. givesmass accessto high for effi essential positive being latter ion the mode, other medical radioisotopes. medical other of Warsaw K=160 the ion heavy cyclotron serves to further research in radiopharmacy and medicine. and radiopharmacy research in to further targets for additional beam dump irradiations of irradiations dump beam for additional targets ayear. times troscopy, nuclearastrophysics, measurements, mass up to ≈1that radioisotopes Thus promising GBq. production for of large-scale potential the use of the protons of the use have that traversed ISOLDE the by a PETtrace medical cyclotron, intended mainly by intended cyclotron, mainly aPETtrace medical at CERN provides over radioisotopes at CERN 1000 different It has current. up to 1mA with energy at tunable emitter alpha high affinity to the receptors of glioma cancer cells. the to cancer gliomareceptorscells. of affinity high lations play a significant the roleproductionis lations playof asignificant sal production via 1.4 GeV production via sal proton reactions induced apeptide with Pis Substance tested. Pare substance and of NuclearChemistry samples Institute at the cient required are that acceleration ofbeams alpha cannot be easily produced production by be easily established cannot The isotope separation on-line facility ISOLDE ISOLDE isotopeThe separationfacility on-line The linear accelerator of the new SPIRAL2 facil acceleratorlinear the SPIRAL2 The of new The physicscyclotronsnuclear Oslo at University, At the Heavy Ion University of the At Laboratory the example whereAnother nuclearphysics instal To overcome a new restriction project called this Several disciplines (nuclear atomic spec and disciplines Several 211 211 44 At is then extracted from the irradiated Bi irradiated from the extracted then is At 209 At and thus complement thus and At production at the Sc, Sc, Bi( 64 a Cu and Cu and ,2n) reaction.However, nuclearphys - 211 At. Only few modern cyclotrons few modern Only At. 161 Tb regularly to aid its users its users to aid regularly Tb 2 nanoparticles to to nanoparticles 211 At and and At 211 211 At. At. At At ------110 cyclotron for post-acceleration of radio these The Cyclotron The Centrethe Research of University of Vancouver, of host along tradition has Canada, Applications) subsequently developed that smaller Molecular, the radioisotope the production branchMolecular, Europe and Asia and 13 radiopharmacies in the USA USA the 13 and in radiopharmacies Asia Europe and (still carrying TR in the name to acknowledge the to name the acknowledge the in TR carrying (still (Advanced 1987 Cyclotron in Systems Inc.) built (11 MeV 18 and MeV) (70 larger and MeV, MeV) 230 will become available much more frequently.will with about 800 employees. 800 about with com and of prototype anew powerful the also was was the origin of several spinoffsup companies origin the was Louvain-la-Neuve, Belgium, is well known in the the in known well is Louvain-la-Neuve, Belgium, field of nuclear physics as the birthplace field post-of theof physics nuclear birthplace as 3.8 isotopes. This Cyclone 30, first operating in first Cyclone1986, operating 30, isotopes. This is the world-leading producer the is of accelerators and ing on-site radioisotope productioning and medical 211 protons for radioisotopes producing aCyclone and plying medical applications. Based on TRIUMF’s TRIUMF’s on Based applications. medical plying of negative ion cyclotron type forpact medical ogy as part of its ISAC science part Present as programme. ogy two cyclotrons, aCyclone cyclotron cyclotrons, providing 30 two consideration. under isotopes ISOLDE greatthe quality choice of high the high power cyclotron TR30, the first industrial industrial first the power cyclotron TR30, high the developed MeV fortechnology its 500 negative ion spinoffIBA company the year (Ion same Beam the by the moreby the compact TR-19 TR-24 and cyclotrons complemented was programme the Later beams. radiotherapeutic isotopes using the ISOL technol ISOL the radiotherapeutic isotopes using radioisotope production. Yves Yongen founded in accelerated radioactive ion beams by first coupling accelerated coupling by ion first radioactive beams recoveredare byisotope off-line Thus separation. thesetar irradiation appropriate After materials. and services overaccelerators services and 600 world-wide. IBA production, radioisotope for equipment associated hadrontherapy and industrial applications of sterili hadrontherapy industrial and efforts are aimed at the spallation production of the spallation aimed areat efforts employees, revenues of 215 M€ and has installed installed has employees,revenues215 ofand M€ sibility studies for the production and isolation of isolation production for and the studies sibility sation and ionisation. Today ionisation. sation and group he 1300 IBA has cyclotron to deliver over 1 mA of extracted protoncyclotron of toover extracted deliver 1 mA cyclotron (the world), the cyclotron in largest ACSI operates production sites 36 in byco-owned IBA, Todaycyclotrons accelerator plus other types. IBA nuclear physics laboratories physics nuclear gets are recovered are gets radioisotopes the of and interest At. Additional a Additional At. TRIUMF has also recently embarked also on has fea TRIUMF The nuclear physics laboratory TRIUMF in in physics nuclear The TRIUMF laboratory Examples of spinoffs from from of spinoffs Examples - and b - and -emitting isotopes are -emitting ------141 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 142 Nuclear Physics for Medicine – Chapter III – Radioisotope Production TRIUMF technology). In response technology). In “molybde to the TRIUMF R&D facilities that manufacture and commercialise and commercialise that manufacture facilities R&D - to (CERN), develop innovativeResearch diagnos European pharmaceutical group founded in 2002 as a a as 2002 group in founded pharmaceutical European years with Carlo Rubbia at CERN on the ARC on the Rubbia Carlo at CERN years with (electron cyclotron resonance) ion source invented (France, Italy, Germany, Switzerland, Spain, Poland, Poland, (France, Italy, Spain, Germany, Switzerland, was that method Crossing) Resonance (Adiabatic National CyclotronNational Network by 2015. which one third are for medical applications, deliv for are medical one third which Buono, physicist, anuclear had worked for 10 Portugal, Israel, USA, Canada). USA, Portugal, Israel, PANTECHNIK was created was from acooperative PANTECHNIK known as “CycloTec”, as known to meet a good aims that from PANTECHNIK are in use world-wide, use in are of from PANTECHNIK fraction of Canada’sfraction focuses on molecular imaging, in particular the the particular in imaging, on molecular focuses intense beams of highly charged ions is the ionsECR charged the is of highly beams intense - ions interdis for and physics nuclear experiments num crisis” ACSI launched in 2009 aproject, today 2009 ACSI crisis” launchedin num ment of serious diseases. AAA’s CEO Stefano CEO ment of diseases. AAA’s serious products, and over 260 employees in over 10 and products, 260 countries on and production of PET radiopharmaceuticals, or superconducting coils for low and high charge charge foror low superconducting coils high and ion ECR sources and to commercialise of GANIL then further developed by AAA. After After 10 of years developed by AAA. further then therapeutic applications and products. AAA tic and both diagnostic and therapeutic nuclear medicine medicine nuclear and therapeutic diagnostic both 1991 In Geller. by spinoff Richard the company radionuclide therapyradionuclide for the personalised treat equipment, lines beam related diagnostics beam and Kirams. accelerators at HIT, Siemens CNAO, MedAustron, hadrontherapy for proton beams and carbon and world the is solutions. PANTECHNIK turnkey and patent licences and IN2P3/CNRS with agreement existence AAA currently has 16 production has 16 and currently AAA existence intense ering leader for ECR ion sources with permanent magnets leader permanent formagnets ion ECR sources with spinoff from the European Organisation forfrom the European spinoff Organisation Nuclear state ion beams. Todaystate ion beams. over ion ECR sources 60 ciplinary applications. Key for the availability of for availability applications. Key the ciplinary Advanced a is Accelerator Applications (AAA) GANIL in Caen, France, Caen, accelerates in heavy GANIL 4 He 2+ beams to IBA XP cyclotrons XP to IBA beams 99m Tc needs by production a in - - - [Dad08] (2008). Dadachova E. Radioimmuno- [Cha11] Champion al Jet other and gallium-68, [Bau12] Theranostics, [Bat06] [Cle11] al et [Cha06] JF Chatal al et E. Cardis, [Car06] [Buc10] [Bod13] al Cet Bodet-Milin [Bey04] Beyer GJ Beyer al et [Bey04] [Bea11] al [Ara07] Let Arazi References 14984. J Nucl Med J Clin Oncol 5025. Int JCancer JNuclMed MolEur Imaging Beams Radioimmunotherapy of B-cell non- B-cell of Radioimmunotherapy New York, p. 1876. USA, with the French the Tumorwith Endocrine Group. Hodgkin’s Front lymphoma. Oncol Diagnostic accuracy of rest/stress accuracy Diagnostic ECG- Springer (2012).Springer for proton ion low and acceleration the in Chernobyl from the accident. fallout improvement in patients with medullary improvement medullary patients with in designed to study astatine chemistry in in chemistry astatine to study designed treatment; and recent in results diagnosis pretargeted anti–carcinoembryonic-antigen anti–carcinoembryonic-antigen pretargeted therapy of infection with Bi-labeled with therapy of infection thyroid who carcinoma undergo evidence for vivo:therapy single in direct release of recoiling by interstitial tumors radionuclides: A pathway to personalized Apathwayradionuclides: to personalized antibodies. antibodies. room temperature crossbar-H-mode cavities radioimmunotherapy: A collaborative study study collaborative A radioimmunotherapy: Phys Rev STAccel PhysRev range, beta medium and Phys Chem Chem Phys Chem PhysChem solution. aqueous an effective quasirelativistic methodology accelerator. Proc of PAC 2011 Conf, a novel voltage electrostatic compact high evidence and methodologic approaches. methodologic evidence and ofevaluation PET PET/CT and oncology: in sestamibi SPECT.sestamibi Cardiol Nucl J Phys Med Biol Med Phys emitters. alpha short-lived comparison with ECG-gated Tc-99m ECG-gated with comparison cancer burden in Europe from Europe radioactive burden in cancer cancer cell kill using 149Tb-rituximab. 149Tb-rituximab. using kill cell cancer cancer research. Eds Baum R, Rösch FP. Rösch R, Baum research. Eds cancer gated Rb-82 myocardial perfusion PET: perfusion myocardial gated Rb-82 et al et TM Bateman Clemente G et al. (2011).Clemente G etal. Development of al et Buck AK Beasley P,Beasley Heid O. Progress towards

14 : 110101. : 51 Curr Radiopharm Curr 119 24 : 401. : : 1705. : . (2007). Treatment of solid : 1224. : . (2010). Economic Economic (2010). . . (2004). Targeted alpha Targeted alpha (2004). . . (2006). Estimates of the of the Estimates . (2006). . (2006). Survival Survival . (2006). . (2011). Assessment of . (2006). (2006). . . (2013). (2013). . 31

1 : 547. : : 234.

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3 : 24. : 177. :

13 52 : : [Mae11] (2011). Reubi JC. Maecke HR, [Leb12] [Kha11] (2011). Setal. in Khan of life Quality [Kas11] [Kri13] [Das13] Dash A, Knapp Jr FF, Pillai MRA. (2013).[Das13] MRA. Jr Knapp FF, A, Pillai Dash [Jur02] [Jur02] [Jen12] [Hab11] Habs D, Köster U. (2011). Production [DDM2] doses population on European Study [Led10] [Lew05] Lewington VJ. (2005). for VJ. [Lew05] Radioisotopes Lewington [Lie07] [Leb05] [Kwe08] Kwekkeboom DJ al et -beams of high intensity and large brilliance. brilliance. large and intensity of high -beams Oncol Ann Surg Appl Radiat Isot Radiat Appl Appl PhysB 143 J NuclMed 265 patients with gastroenteropancreatic or or gastroenteropancreatic with patients 265 with [ with with the radiolabeled somatostatin analog analog somatostatin radiolabeled the with Laser-driven particle and photon and and Laser-driven beams particle Somatostatin receptors forSomatostatin targets as Supp C:C9. Supp for NuclMed Rev PET radionuclides. 2 Datamed Dose exposure. from medical internal target system for system production target of internal 211 nuclear reactors for radionuclide targeted produced draft report from report 25.1.2013.draft http://ddmed.eu metastases: comparison of outcomemetastases: to a of radionuclidic impurities in cyclotron in impurities of radionuclidic 99 particle immunotherapy for myeloid myeloid for immunotherapy particle [ of medical radioisotopes with high specific specific high radioisotopes with of medical Nucl Med Biol 40 NuclMed Biol options. technology bronchial neuroendocrine tumors treated treated tumors neuroendocrine bronchial the palliation of metastatic bone of a cancer: metastatic palliation the therapy with with therapy therapies. therapies. activity in photonuclear γ in reactions with activity Radiat Prot Dosim Prot Radiat radionuclides. emitting JClin Oncol survival. efficacy, and leukemia. leukemia. salvage resection ofsalvage colorectalliver systematic review.systematic JNuclMed 46 JPhys12 New applications. some cellular radiobiological effects for Auger Auger for effects radiobiological cellular contemporaneous control group. group. control contemporaneous carcinoembryonic antigen radioimmuno- antigen carcinoembryonic 177 Mo/ At on the cyclotron onAt U-120M, the Lu-DOTA0,Tyr3]octreotate: toxicity, et al Oet Lebeda et al et AI Kassis et al Get Krijger Jurcic JG al et (2012).Jensen M. accelerators Particle Ledingham KWD, Galster W. Galster (2010). KWD, Ledingham et al Tet Liersch et al Oet Lebeda : 241. : 177 99m Lu-DOTA0,Tyr3]octreotate. Tc assessment of separation: An 99m Trends Biotechnol Blood 52 103 Tc. Tc. 131 : 1361. : I-labetuzumab after after I-labetuzumab 14

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63 Nucl Med Biol Med Nucl 100 . (2002). Targeted alpha (2002).. Targeted alpha . (2011). and Molecular . (2013). The of necessity . (2007). Update of . (2012). Assessment . (2005). Anew : 2577. : : 49. : : 1233. : . (2008). Treatment

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[Man11] al Set Manenti [Qai14] supply The [NEA10]of medical OECD/NEA. [Pon10] Ponsard Mo-99 supply B. issues: report [Par13] Asupply demand and [NEA12] OECD/NEA. [NEA11] supply The of medical OECD/NEA. [Mue12] al Cet Müller [Reg27] Regaud C, Lacassagne A. (1927). A. [Reg27] Lacassagne C, Regaud [Mor08] al Fet Morschhauser [Mar08] al Cet Marcassa [Mor13] al Fet Morschhauser Eur Heart J Heart Eur Radiothérapie Radiothérapie Molybdenum-99/Technetium-99m Molybdenum-99/Technetium-99m 26 90-ibritumomab tiuxetan compared no with tiuxetan 90-ibritumomab Hodgkin Lymphoma: Updated after results Hodgkin La radiosensibilité envisagée dans ses ses dans envisagée radiosensibilité La Society, ENS RRFM 2010 Transactions. RRFM Society, ENS function for deuteron inducednuclear function international, randomized, phase III first- III phase randomized, international, ibritumomab tiuxetan consolidation of first of first consolidation tiuxetan ibritumomab in no-carrier-addedin form for metabolic nuclear medicine imaging and radionuclide radionuclide and imaging nuclear medicine derivative; derivative; production of high specific activity activity specific production of high production technologies. 2010.production technologies. New England JMed England New cancer. prostate update Molybdenum-99 of2012. market. the Radiophysiologie et Radiophysiologie generales. manifestations 99m perfusion scintigraphy: aposition scintigraphy: statement. perfusion treatment. treatment. on the specific activity of cyclotron-produced of activity specific on the implication its and Tc-impurity long-lived of therapy: an in vivo proof-of-concept proof-of-concept vivo in an therapy: quadruplet of terbium radioisotopesquadruplet for PET reactions on natural ytterbium for ytterbium reactions on natural radioisotopes. Review of potential of potential radioisotopes. Review radium-223 and survival in metastatic metastatic in radium-223 survival and 2011. toradioisotopes: reliability. path the and lessons learned, European Nuclear Nuclear European lessons learned, and trial of consolidation therapy with yttrium- with therapy consolidation of trial remission in advanced-stage follicular Non- follicular advanced-stage in remission radiotherapy. radiotherapy. and SPECT and for SPECT and a and follow-upa median of 7.3 years from the and and excitation functions of of functions excitation advanced follicular lymphoma. follicular advanced in first remission therapy after additional study with anew receptor-targeted with study folate JClin Oncol indolent trial. line cost-effectiveness, and safety of myocardial of cost-effectiveness,myocardial and safety Tc. Tc. : 5156. : et al SM et Qaim Parker al Cet 100 Appl Radiat Isot 85 Isot Appl Radiat Mo(p,2n) J NuclMed J NuclMed 29 Appl Radiat Isot 69 Isot Appl Radiat 1 : 557. : : 95. : 99m . (2013).. emitter Alpha . (2014). Evaluation of (2014). of . Evaluation . (2012). matched Aunique Tc reactions: Estimation . (2011). Excitation . (2008). Clinical value, value, . (2008). Clinical - and b - and 52 53 100 . (2013). . (2008). Phase III : 841. : : 1951. : Mo(p,d+pn) : 101. : -radionuclide -radionuclide 31 J Clin Oncol JClin Oncol 90 : 37. : : 1977. 1977. : Yttrium- 177g 369 99 Lu Lu Mo Mo : 213. : 143 Nuclear Physics for Medicine – Chapter III – Radioisotope Production 144 Nuclear Physics for Medicine – Chapter III – Radioisotope Production [Zal08] radiation. of ionizing effects [UNS08] and Sources [Ste11] [Sch13] [Sch11] Database Reactor IAEA’s Research [RRDB] [Rot13] [Ric82] Accel Sci TechnAccel Sci 1835. Annex D, Effects due to radiation fromthe due to radiation D, Effects Annex Western 2011. presented Europe, at EANM UNSCEAR 2008, volume II: Scientific Scientific volume II: 2008, UNSCEAR 2013 DJ, pers updatecomm. by Schlyer (RRDB). http://nucleus.iaea.org/RRDB (RRDB). with with Historical An (1982). Technetium-99m: first ionization potential of astatine by laser laser by astatine of potential ionization first Perspective. Chernobyl accident. UN New York,Chernobyl accident. UN 2011. Rev applications. Rev industrial and for medical for production the of isotopes radioactive ionization spectroscopy.ionization Comm Nature monoclonal antibody 81C6. JNuclMed antibody monoclonal treatment of recurrent brain tumor patientstreatment of tumor recurrent brain radionuclide production in member productionradionuclide states, in experience with a with experience et al et MR Zalutsky Stevens Anthony, Development of PET in of for cyclotrons used Directory IAEA Schmor P.Schmor (2011). of cyclotrons Review Rothe S et al. (2013). Setal. Rothe Measurement of the P,Richards Tucker Srivastava SC. WD, 211 At-labeled chimeric antitenascin At-labeled antitenascin chimeric lsot Int JAppl Radiat 4 :103. -particle–emitting 211At: . (2008). Clinical . (2008). Clinical 33 : 793. :

49 4 : : 30. : • • • • • • • • • • • • • Tom Ruth (TRIUMF), Lucia Sarchiapone (LNL), Paul Paul (LNL), Sarchiapone Lucia Tom (TRIUMF), Ruth Juan Carlos Alonso Farto (SEMNIM, Spain) Bernard Bernard Spain) (SEMNIM, Farto Alonso Carlos Juan Aubert (IRSN France), Ursula Bär (Federal Statistical Statistical (Federal Bär Ursula France), (IRSN Aubert Administration), Pedro Teles (IST/ITN Portugal), Teles Pedro (IST/ITN Portugal), Administration), Vermeulen labs).(iThemba Beasley Paul from received was input Valuable Congreso de los Diputados y al Senado Spain. Senado yal Diputados los de Congreso Germany), Office, Statistical (Federal Vierkant Gertrud for Office State (Bavarian Richter Sigrid Germany), Environmental (State Dreimanis Andrejs Cyprus), Office of Public Health, Bern, Switzerland), Dietmar Dietmar Switzerland), Bern, Health, of Public Office Office (Federal Cernohorski Dieter Germany), Office, of radionuclides in nuclear medicine: in nuclear of radionuclides use the on data statistical providing for organisations Etienne and (ACSI) Van Lier Erik (PSI), Meulen der of Economics and Export Control, Germany), Panicos Panicos Germany), Control, Export and Economics of (Siemens Healthcare) José Benlliure (University of of (University Benlliure José Healthcare) (Siemens We are very grateful to the following individuals and and individuals following to the grateful very We are Malta), Elena Shubina (Environmental Board, Estonia), Estonia), Board, (Environmental Shubina Elena Malta), Schaffer (TRIUMF), Peter Thirolf (LMU), Nick van van Nick (LMU), Thirolf Peter (TRIUMF), Schaffer (DOE), Garland (IPHC), Marc Brasse David Santiago), Stavroula Vogiatzi (Greek Atomic Energy Commission) Commission) Energy Atomic (Greek Vogiatzi Stavroula (H.U. la de Lopez España Marisa Latvia), Service, (Chapter III) (Chapter List of Contributors and Informe del Consejo de Seguridad Nuclear al al Nuclear Seguridad de Consejo del Informe and Association, Radioisotope Japan the Denmark, Protection Radiation of Institute State the Republic, Czech Control Drug for Institute State the as well as Protection Radiation (Slovenian Škrk Damijan Hospital, Dei (Mater Samuel Anthony Environment), (Federal Linder Reto Univ. Poland), of (Medical Krolicki Leszek Germany), Dresden, &TU (DGN Kotzerke Jörg France), (IRSN Etard Cécile Madrid), Princesa, Inspection, Labour of (Department Demitriades Noßke (Federal Office for Radiation Protection, Protection, Radiation for Office (Federal Noßke Thierry Stora,Switzerland NuPECC liaison –NuPECC Ari Jokinen,Finland Czech Republic Ondrej Lebeda,Czech Uli Ratzinger, Germany Ulli Köster, –convener France Sotirios Harissopoulos,Greece Itzhak Kelson,Israel NuPECC liaison Piet VanNuPECC – Duppen,Belgium Ferenc Tarkanyi, Hungary Bernard Ponsard, Belgium Mikael Jensen, Denmark Ferid Haddad,France –convenerMarie-Claire Cantone,Italy Annexes 146 Nuclear Physics for Medicine • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • I:Annex Contributors Annalisa Patriarca Katia Parodi Olko Pawel P. Josep Oliver Murphy Alex Christian Morel Guillaume Montemont Igor Mishustin Samuel Meyroneinc Alejandro Mazal ( Maj Adam Hamid Mammar Lebeda Ondrej Ian Lazarus Ulli Köster Gabriele-Elisabeth Körner Itzhak Kelson Ari Jokinen Mikael Jensen Sotirios Harissopulos Ferid Haddad Jean-Louis Habrand Thomas Haberer Christian Graeff Georg Dietmar Galès Sydney Fine Fiedler Fagotti Enrico Laura Evangelista Wolfgang Enghardt Marco Durante Dobeš Jan Dendooven Peter Ludovic Demarzi Guerra Del Alberto Taille La de Christophe Jürgen Debus Cuttone Giacomo Stephanie Combs Paolo Colautti Piergiorgio Cerello Marie-Claire Cantone Lucas Norberto Burigo David Brasse BrandenburgSytze Angela Bracco Marcus Bleicher Guido Baroni Balosso Jacques Faiçal Azaiez (France) (France) (Czech Republic) Republic) (Czech Poland) Poland) (Poland) (Poland) (Finland) (Finland) (United Kingdom) Kingdom) (United (Germany) (Germany) (United Kingdom) Kingdom) (United (Italy) (France) (France) (France) (France) (France) (France) (France) (France) (Israel) (Germany) (Italy) (Italy) (Italy) (Italy) (Denmark) (Russian Federation) Federation) (Russian (Italy) (Austria) (Austria) (Spain) (Czech Republic) Republic) (Czech (Germany) (France) (France) (France) (France) (Germany) (France) (France) (Germany) (Germany) (France) (France) (France) (Netherlands) (Italy) (Italy) (Germany) (Italy) (Italy) (France) (France) (Italy) (Italy) (Italy) (Italy) (Germany) (Netherlands) (France) (France) (France) (France) (Greece) (Italy) (Italy) (France) (France)

(Brazil) (Brazil) (France) (France) (Europe) • • • • • • • • • • • • • • • • • • Claas Wessels Duppen Van Piet Meulen der van Nick Udias Manuel José Irene Torres-Espallardo Thirolf G. Peter Ferenc Tárkányi Stora Thierry Solevi Paola Sabine Schott Christoph Scheidenberger Röhrich Dieter Frauke Roellinghoff Uli Ratzinger Magdalena Rafecas Pshenichnov Igor Marlen Priegnitz Bernard Ponsard (Spain) (Germany) (Switzerland) (Switzerland) ( (France) (France) (Norway) (Norway) France) (Germany) (Hungary) (Hungary) (Germany) (Belgium) (Belgium) (Belgium) (Belgium) (Russian Federation) Federation) (Russian (Spain) (Belgium) (Belgium) (Spain) (Belgium) (Belgium) (Spain) (Germany) • • • • • • • • • • • • • • • • • • • • • • Members: • Chair: AnnexCommittee II: NuPECC Utrecht (The Netherlands) (France) Strasbourg (Germany)Darmstadt (Norway) Bergen Kingdom) (United Liverpool (Italy)Bari Kingdom) (United Edinburgh (Croatia)Zagreb (Poland) Krakow Caen (France) (Switzerland)Basel (The Groningen Netherlands) (Finland)Jyväskylä Uppsala (Sweden) (Greece)Athens (Denmark) Copenhagen (Portugal) Lisboa Řež (Czech Republic) Gif-sur-Yvette (France) (Romania)Bucharest (Spain) Madrid Orsay (France) (Italy) Milano Raimond Snellings Christelle Roy Rosner Günther Nystrand Joakim Paul Nolan Eugenio Nappi Murphy Alexander Miljani Đuro Maj Adam Marek Lewitowicz Bernd Krusche Klaus Jungmann Ari Jokinen Tord Johansson Sotirios Harissopulos Jens Gaardhøje António Fonseca Dobeš Jan Philippe Chomaz Gheorghe Cata-Danil Borge Maria Faiçal Azaiez Angela Bracco ć • NSAC: • NPB/EPS: Observers: • • • • • • • • • European Science Foundation: • Secretary: Scientific NuPECC • ANPhA: GSI Darmstadt (Germany) Darmstadt GSI (Hungary) Budapest (Austria)Wien TrentoECT* (Italy) (Germany)Darmstadt (Belgium) Leuven (Germany)Jülich (Germany)Darmstadt Email: [email protected] Email: Tel: +33 388 76 71 48 67080 –France Cedex Strasbourg Lezay-Marnésia1 quai –BP 90015 Foundation Science European Coordinator Administrative Head of Science Support Office [email protected] Email: Tel: +49 172 89 15 011 /+49 89 2891 2293 85748 –Germany Garching Technische Universität München E12 c/o Physik-Department (China)Beijing (USA) Argonne Don Geesaman Don Peters Klaus Wolf György Eberhard Widmann Wolfram Weise Jochen Wambach Duppen Van Piet Hans Ströher Stöcker Horst Nathalie Geyer-Koehler Jean-Claude Worms Gabriele-Elisabeth Körner Ye Yanlin

147 Nuclear Physics for Medicine 148 Nuclear Physics for Medicine • • • • • • • • • • • • • • • • • • • • Annex III: Glossary CPO: CNAO: CCD: BGO: ASIC: 1 mCi =37 MBq. = 37 1Ci GBq, nuclearmedicine. in ( ( close to the range of the particle in the target. target. the in particle of the range close to the matter. It in very is energy release most of their position-sensitive APD). position-sensitive semiconductor. tissues (e.g. lung and kidney). (e.g. and tissues lung late responding observed in generally is and fractionation, with strong reduction effect of the alow α/β hand, other the ratio corresponds to a On colon) and (e.g. tumours. skin many and tissues normal responding early commonis in forand fractionation, sparing asmall implies the normal tissue. normal the receive would tumours alower dose-rate than Deeper tissue. dose rate healthy normal of the receiveswhere equivalent same atumour the BNCT,tissue in In thedepth at it defined is 18 CT: CS: CMOS: (Curie): Ci CdZnTe: CdTe: peak: Bragg Brachytherapy: (Becquerel): Bq BNCT: API: APDs: (ADDR): dose-rate Advantage-depth α/β of the dose (D):of the E=αD+βD function (E) effects radiation as a the to describe provided used parameters ratio by two of the the rotated around a single axis and numerically numerically and axis rotated asingle around angles at different taken are scans transmission 1 Bq =1decay1 Bq per second. medicine. to nuclear than closer to radiology discipline or body. body close to the into the Formerly a radiation, (short-range) ionising emit that http://protontherapie.curie.fr/ http://www.cnao.it FDG: ratio: Computed tomography. Several X-ray Several tomography. Computed Compressed sensing image reconstruction. Compressed image sensing Atmospheric pressure interface. Centre Protonthérapie de Orsay Charged coupled device. Charged Bismuth germanium oxide. germanium Bismuth Application-specific integrated circuit. integrated Application-specific Cadmium telluride. telluride. Cadmium Boron neutron capture therapy. capture neutron Boron Fluorodeoxyglucose with radioactive radioactive Fluorodeoxyglucosewith Avalanche photodiodes (PS-APD: (PS-APD: photodiodes Avalanche Centro Nazionale Adroterapia Adroterapia Nazionale Centro Complementary metal–oxide– Complementary Cadmium zinc telluride. zinc Cadmium A measure of tissue radiosensitivity radiosensitivity of Ameasure tissue A unit of activity that is still used used still is that of activity Aunit Region where charged particles where Region particles charged Introduction of closed sources, Introduction SI unit of activity. unit SI ). 2 . A high α/β ratio . Ahigh ). 18 F. • • • • • • • • • • • • • • • • • • • • • • • • • Dose: DOI: DESI: kVp: IMS: GSI: GPU: GaAs: GAGG: FWHM: FPGA: FFAG: FBP: 1 Gy =1J/kg. gray (Gy). It in measured is radiation. ionising 2 Gy for effective sparing of the normal tissue. the normal of 2 Gy for effective sparing of approximately fractions daily delivered in (up high Gy), very is to 60–70 but normally is Willkommen.113005.0.html ( It is generally measured in kilo-electronvolt per kilo-electronvolt in measured It generally is by particles. charged tissue the trackin per unit expressed in gray-equivalentexpressed in (GyE) or Gy(RBE). generally is product physical of dose xRBE the therapy, In account for quality. the radiation to RBE by the physical be multiplied dose must LET haveeffects, different biological different with Since radiation effectiveness. biological the scanning beam and of the target organ. target of the and beam scanning uncorrelatedcaused by motion the of the morphological image of the body. of the image morphological combined to a3D view.provides This a in Gy/min). rate: Dose equivalent: Dose Cyclotron: CZT: Linear energy transfer (LET): (LET): transfer energy Linear Interplay: IMRT: IMPT: IGRT: HIT: Fractionation: ENLIGHT: (www.gsi.de). from the centre along a spiral path. aspiral centrefrom the along accelerate outwards particles charged which Therapy (http://enlight.web.cern.ch/). Therapy synchrotron. http://www.klinikum.uni-heidelberg.de/ Heidelberg Ion TherapyCentre Helmholtz Centre for Heavy Ion Helmholtz therapy Peak kilovoltage. Peak Depth of interaction. of Depth Imaging mass spectroscopy. mass Imaging Cadmium zinc telluride. zinc Cadmium Filtered backprojection. Filtered Graphical processor unit. processor Graphical Image-guided radiation therapy. radiation Image-guided Desorption electrospray ionisation. electrospray Desorption Intensity modulated proton modulated Intensity therapy. Energy deposited per unit mass by mass deposited per unit Energy Intensity modulated radiation therapy. radiation modulated Intensity Fixed-field alternating gradient Fixed-fieldalternating Gallium arsenide. Gallium Field programmable gate array. Gd full width at half maximum. maximum. at half width full Inhomogeneity in treatment in plan Inhomogeneity European Network Ion European for Light 3 A type of particle accelerator of in particle Atype Dose delivered per unit time (usually (usually time deliveredDose per unit Al 2 The therapeuticdose The radiation Ga Physical dose corrected for 3 O 12 based scintillator. based ). Energy deposited Energy • • • • • • • • • • • • • • • • • • • • • • • • • • Annex III: Glossary OSEM: OS: MS: MRI: MR: MPPC: MLEM: ML: MIP: MC: MAP: LXe: LSO: Lesion: LC: absorbed dose. proportional to the directly always is risk cancer the that atrisk low It assumed is doses. radiation the to Agencies extrapolate Regulatory adopted commonly International by the organism. algorithm. attenuation correction of PET or SPECT. However,burden. for directly be used it cannot and no CT radiation than tissue contrast soft better provides with image amorphological ion charge and velocity.ion and charge (keV/ tissue micron in Nuclear medicine: (NTCP): probability complication tissue Normal NIRS: imaging: Multi-modality MS/MS: MRS: MBq: MA-PMT: MALDI: LYSO: (LNT): Linear-no-threshold radioactive decaysradioactive per second). maximisation algorithm. maximisation diagnostic or therapeutic applications. therapeutic or diagnostic for body human the sourcesopen in radiation Sciences (http://www.nirs.go.jp). doped)(Lu morbidity with the radiation treatment. radiation the with morbidity PET/MR, SPECT/CT, etc. ultrasound, as such PET/CT, modalities imaging different ionisation. local control. local Overall survival. Overall Maximum likelihood (statistical technique). (statistical likelihood Maximum Mass spectroscopy. Mass Magnetic resonance. Magnetic Monte Carlo Monte Liquid xenon. Liquid Maximum intensity projection intensity Maximum Nuclear magnetic resonance imaging resonance imaging Nuclearmagnetic Lutetium oxyorthosilicate (Lu oxyorthosilicate Lutetium Millions of becquerel (millions of of becquerel (millions Millions (Bayesian framework) maximum a-priori (Bayesian framework) maximum Magnetic resonance spectrograph. Magnetic National Institute for Radiological for Radiological Institute National Lutetium yttrium orthosilicate (cerium- orthosilicate yttrium Lutetium Multi-pixel photon counter. photon Multi-pixel Ordered-subsets-expectation- Maximum-likelihood-expectation- Any abnormality in the tissue of an of an tissue the in abnormality Any Matrix-assisted laser desorption Matrix-assisted laser Two spectroscopy. ‘tandem’mass stage Probability of inducing early or late early of inducing Probability Multi-anode photomultiplier tube. photomultiplier Multi-anode 1.8 Y 0.2 SiO Medical discipline using using discipline Medical 5 (Ce)). m m). 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149 Nuclear Physics for Medicine 150 Nuclear Physics for Medicine • • • • • • • • • Annex III: Glossary TCP: SRM: SiPM: as possible the dose to the OARs (low NTCP). possible OARs dose toas the the TCP) (high low keeping as PTV dose to the the attenuators. attenuators. or by passive changes either by active energy changed is depth the and stirrers, magnetic achieved is by scanning 2D target. into the superimposition of beams with different energy. different superimposition with of beams thereforemust bewidened by passive or active and too narrow is topeak cover tumours, large spatial resolution. spatial improved with imaging for functional 3D image are combineddirections to compute different a tomography. from images scintigraphic 2D Organ at risk (OAR): risk at Organ (PTV): volume target Planning (ITV): volume target Internal (CTV): volume target Clinical The treatment planning The treatment SiPM). Gross tumour volume (GTV): volume tumour Gross radiotherapy: in volumes Target (SOBP): Spread-out-Bragg-peak SPECT: Sparing effect: Scintigraphy Scanning: suitable collimators. suitable Positioncamera. resolution achieved is via agamma registered body the with in distributed emitter of agamma images planar 2D providing side effects. side bespared should to avoid which tumour to the therefore cannot be fully imaged. therefore befully cannot spread which disease for sub-clinical margin patient. of the imaging radiological the visible in quality. (α/βtissue ratio), dose/fraction, radiation and fractionationthescheme, on depends effect severe morbidity. tissue The normal sparing Fractionation radiotherapy to in avoid used is reduced (sparing generally is effect).damage 1day), biological several (typically hours the of at intervals multiplefraction, deliveredis in include target motion. target include treatment delivery. treatment or positioning, planning, in for uncertainties Tumour control probability. Probability Tumour Probability control probability. System response matrix. Silicon photomultipliers (dSiPM: digital digital (dSiPM: photomultipliers Silicon

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NuPECC Professor Angela Bracco NuPECC Chair Università degli Studi di Milano Dipartimento di Fisica and INFN sez. Milano Via Celoria 16 • 20133 Milano • Italy Tel: +39 02 50317252 Email: [email protected] Dr Gabriele-Elisabeth Körner NuPECC Scientific Secretary c/o Physik-Department E12 Technische Universität München 85748 Garching • Germany Tel: +49 172 89 15 011 / +49 89 2891 2293 Email: [email protected] www.nupecc.org

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