SEEIISTSouthEastEuropeInternationalInstituteforSustainableTechnologies

AFacilityforTumourHadronTherapy

andBiomedicalResearchinSouth-EasternEurope

U.Amaldia,J.Balossob,M.Dosanjhc,Ph.Lambind,J.Overgaarde,

S.Rossif,M.ScholzgandB.SingersSørensenh

withthecollaborationofA.Celebici

a TERA Foundation, Novara, Italy b Department of Radiotherapy, University Hospital of Grenoble, Grenoble, France c CERN, Geneva, Switzerland d Maastricht University, Maastricht, The Netherlands e Department of Experimental Clinical Oncology, Aarhus, Denmark f CNAO Foundation, Pavia, Italy g GSI, Darmstadt, Germany h Department of Experimental Clinical Oncology, Aarhus, Denmark i Clinic of Oncology and Radiotherapy, Podgorica, Montenegro

THISDOCUMENTHASBEENPRODUCEDUNDERTHEAUSPICESOFTHEMINISTRYOFSCIENCE,MONTENEGRO

(*)ReferencestoKosovointhisdocumentshallbeunderstoodinthecontextoftheUNSecurityCouncilresolution1244(1999).

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EXECUTIVESUMMARY

In 2016 at a Worksop of the World Academy of Art and Science held in DubrovnikProfessor Herwig Schopper proposed the creation in South East Europe of anInternational institute devoted to sustainable technologies. The objectives of SEEIIST(South East Europe International Institute for Sustainable Technologies) were, and are,both to create new opportunities of cutting-edge research and technology for thewelfareoftheRegion,andtohelpbuildingmutualtrustamongscientistsandengineers–andalsoamongadministratorsandpoliticians–ashasbeensuccessfullydemonstratedbythecasesofCERNandSESAME.

Dr.SanjaDamjanovic,MinisterofScienceofMontenegro,broughttheInitiativetothepolitical level by contacting the relevantMinisters of the SEE countries and convincingthemtoparticipateinitslaunching.

Giventhepositivereactions,inSpring2017IwasaskedtoorganizeandchairanEditorialCommittee aiming at thepreparationof the conceptual design reportof a“Facility forTumourHadronTherapyandBiomedicalResearch”(HTR).Dr.DieterEinfeldwasputinchargeofthesametask inconnectionwitha“4thGenerationSynchrotronLightSourceforScienceandTechnology”(SRL).

While the Editorial Committees were working on the conceptual designs of the twofacilities, ameeting of theMinisters of Science or their representative took place atCERN on 27 October, 2017. The goal was to sign a Declaration of Intent for futurecollaboration.Albania,BosniaandHerzegovina,Bulgaria,Kosovo*,theFYRMacedonia,Montenegro, Serbia and Sloveniawere represented; Croatia agreed ‘ad referendum’,whileGreeceparticipated as an observer. The final declaration stated that the PartieshaveacommonvisionandthattheInstituteshalloperatewiththemissionof“ScienceforPeace”. In the following, an Intergovernmental Steering Committee was created, andSanjaDamjanovicwaselectedasthechairperson.

Inthis frameworkonJanuary25-26aForumon“NewInternationalResearchFacilitiesfor South East Europe” was organized at ICTP (Trieste), where a first forty pagedocumentpreparedbythetwoEditorialCommitteesandentitled“BasicConceptsfortheSouthEastEurope International Institute forSustainableTechnologies”wasdistributed,presented and discussed. The Forumwas verywell attended and the discussionswerelivelyandproductive.

In the following twomonths theSteeringCommitteemet twice– in Sofia (January29,2018)andinTirana(March30,2018)–andcameunanimouslytotheconclusionthatthefirstFacilitytobebuiltintheRegionshouldbetheHTR.

MeanwhilethetwoEditorialCommitteeshavecontinuedtheirworkandproducedmoredetaileddocuments.ThisReportdescribestheconceptualdesignoftheHadronTherapyandResearchFacility. Ihopethatthiswillbeuseful,asastartingpoint,tothefull-timeexpertswhowillbeputincharge,forthenexttwotothreeyears,ofwritingtheTechnicalDesign Report that will cover all technical, scientific, financial and legal aspects of theInitiative.

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IthasbeenwiselydecidedbytheSteeringCommitteethatthesiteoftheFacilitywillbechosenat a later stageof theproject.Here Iwant to emphasise thatother importantdecisionswillhavetobetakenatthesametimebecausetwoNetworkswillhavetobeorganized and their hubs are better placed elsewhere so to involve in the InitiativemoreInstitutions,belongingtodifferentcountries.

TheNetworksareessentialforthesuccessoftheInitiative.IndeedTheClinicalNetworkwillallowtheradiationoncologistsoftheRegiontoworktogetherwiththeoncologistsoftheFacilityandofEuropeanandnon-Europeanhospitalsindevelopingnewprotocolsandparticipatinginmulticentreprospectivecomparativeclinicaltrials.TheScientificNetworkofUniversities,ResearchCentresandHospitalswillconnectallthegroupseitherdoingorplanningexperimentsintheexperimentalhallsoftheFacility.

***

InWesternEuropeabout50%ofalltumourpatients,correspondingeveryyeartoabout2500patientspermillioninhabitants),areirradiatedwithX-raybeamsproducedwhenelectrons,acceleratedtoabout10millionelectronvolts(10MeV)byalinearaccelerator,bombardaheavytarget.Withmanycross-firingX-raybeamslargeradiation“doses”aredeposited inthesolidtumourtargettopreferentiallykill thecancerouscells, inspiteofthe fact that theelectrically neutral X-rays traverse thepatient body and irradiate alsohealthytissues.

In the last twenty years a novel radiation therapy has been introduced: “hadrontherapy” (also called “charged particle therapy”, “particle therapy” or “ion beamtherapy”). It uses, instead of X-rays, beams of either protons or carbon ionsmovingbetween30%and60%of the speedof light. The reason is that a beamof electricallychargedprotonsorionsproducesa“Braggpeak”ofhighdosejustbeforestoppinginthetissues.Downstream (upstream) of theBragg peak no (little) dose is deposited so thatprotons and carbon ions can deliver higher doses to the tumour, sparingmuch betterthanX-raysnormaltissueslocatedinfrontandbehindit.

The targetsof radiation therapyare theDNAdoublehelix of the traversed cells. Thedistance between two successive “ionizations” – i.e. between the events in which anatomoramolecule loosesoneelectron –determinethebiologicalandclinicaleffects.Theradiationis“sparsely”(“densely”)ionizingifthisdistanceislarger(smaller)thanthe2-nanometerdiameterofthedoublehelix.

ProtonshavepracticallythesamebiologicalandclinicaleffectsasX-raysbecausetheyarebothsparsely ionizing radiations.But, since thedose ismuchmoreconcentrated inthe tumour, for the same probability of cure they cause less secondary effects in theclose-by“organsatrisk”thatcannotbeirradiatedbecauseofunacceptableconsequencesforthepatientqualityoflife.InparticularitisgenerallyacceptedthatallchildrenshouldbetreatedwithprotonsandnotX-rays.

Instead carbon ions –which are carbonatomsdeprivedof their six electrons – are adifferent typeof radiationbecause ina traverseddoublehelixan ionproduces twentytimesmoreionizationsthanaprotonreachingthesamedepthinthepatientbody.Whenenteringthetissuescarbonionsbehaveassparsely ionizingradiations, i.easX-raysandprotons,but,byslowingdown, in the last3-4centimetresof theirpath in thepatient’sbody become “densely ionizing” andproducemultiple clusteredDNAdamages,which

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cannotberepairedbytheusualmechanismsthatprotectallcells.ThusthecarbondoseisnotonlymoreconcentratedinthetumourbutisalsomuchmoreeffectivethanX-raysandprotonsincontrolling“radioresistant”tumours,whichare3-5%ofallsolidtumours.

X-raysareproducedbyelectronlinearaccelerators–calledalso“linacs”thatare1-metrelongcoppertubeshavingadiameterofabout10centimetres.Ifprotonandcarbonionscouldbesoeasilyaccelerated,X-rayswouldnotbeusedanymoreinradiationtherapy.However a therapy accelerator for proton and ion therapy ismuch larger, as shown inFigure1,andcostlierthananelectronlinac.

Figure1–LayoutofHITCentreinHeidelberg.

TheconfigurationsofalltherunningprotonandcarbonionssynchrotronsareverysimilartotheoneshowninFigure1.

The schematic drawing of the SEE Facility of Figure 2 is based on the synchrotrondesigned at CERN in the 90s by a CERN-TERA-MedAustron collaboration. Two centresderivedfromthisdesignareatpresenttreatingpatients inPavia(CNAO)and inWienerNeustadt (MedAustron). This design has been used to estimate the construction andrunningcostsoftheFacility.

Figure 2 –As discussed in the text, the Facility, which features four treatment rooms and twoexperimentalareas,willberealizedinthreestages.Thetotallengthisabout150metres.

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Afteraninitialstart-upperiod,theproposedFacilitywill

A. treatwithcarbon ionsandprotons, forabout50%of thedaytimeand in2(and – at a later stage – in 4) treatment rooms, 250 (and later 500)patients/year, to cover a large fraction of the yearly number of SoutheastEuropepatientshavingtumoursof thehighestpriority forcarbonandprotonirradiations;

B. work,fortheremainingfractionofthedaytime–plusnightsandweekends,on

1. invitro radiobiologyexperiments, tobetterunderstand the fundamentalmechanismsofradiosensitivityandradioresistance,

2. animal studies for in vivo determination of the efficacy of carbon andotherionsinthetreatmentofhumanradioresistanttumours,

3. medical physics measurements and development of novel radiationdetectorsandoptimizedtreatmentplanningsystems.

WiththeaboveprogramstheFacilitywillbeuniqueintheworldbecauseoftheampletimedevotedtoclinical,radiobiologicalandmedicalresearch.Infact,mostoftheotherfacilitiesconcentrateonpatienttreatmentandthetimeleftfortheresearchprogramsisinsufficient.

AsfarasprogramAisconcerned,tumourseligibleforhadrontherapyareaccountingforabout10%ofallradiotherapypatients,1%ofwhichareintheveryfirstlevelofpriority.This corresponds to about 280 tumours per year (80 for protons and 200 for carbonions)onapopulationof tenmillionpeople, so that theFacilityof Figure2, irradiatingabout 500 patients per year,will offer a state of the art treatment for often hopelesstumours toabout two thirdsof the regionalpopulation.Recruiting themwillbeoneofthemainchallengesofthisinitiative.

Forprotonsthemaintargetswillbesolidtumoursofchildren.Carbonionbeamswillbeusedforthehighestpriority,mostlyradioresistant,tumours:adenoidcysticcarcinomasofsalivaryglands,adenocarcinomasofheadneckandthorax,mucinousmelanomasofheadand neck, chordomas and chondrosarcomas, non-small cell lung carcinomas,hepatocarcinomas of large size and pelvic relapses of adenocarcinomas. For protontherapytheaimisasignificantreductionoftoxicityand,forcarboniontherapy,theaimis a gain of progression free survival, for mainly radioresitant tumours, from 50%,achievedwithX-rays,tomorethan75%.

Thetimeplanforeseesatleast1yearfortheorganizationoftheConstructionTeamandthe discussion with the potential vendors of the different components. This will befollowedby4yearsfortheconstructionand1yearforthecommissioning.Itissupposedthattheconstructionsitewillbea“greenfield”andthat itscostwillnotbechargedtotheproject.

For program B2 an animal facility will be built for the permanent housing of smallrodents. Larger animals will be treated in collaboration with an external VeterinaryDepartment,whichcanbelocatedinadifferentcountryoftheRegion.

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Theconstructionofthetreatmentroomsandtheexperimentalhallswillbestagedsothat a lower initial investment will allow from the beginning significant clinical andresearchactivities.Accordingtoapossiblescenario,initiallytheresearchprogramswillbecarriedoutinthefirstexperimentalhall(EH1ofFigure2)devotedtoRadiobiology(RB),Animalstudies(AS)andMedicalPhysics(MP),whilebeamsofmanydifferentionspecieswillbeavailableintwotreatmentrooms(TR1andTR2)wheretwohorizontalbeamsandaverticalbeamwillbeavailable(Figure2).

Theinvestmentneededforthisfirststagehasbeenestimatedtobe120M€that,addedtotheabout45M€forbuildings(atWesternEuropeancosts),givesatotalofabout165M€.

The second stage, inwhichaprotongantrywill be installed,will require about20M€.With further 35 M€ the Facility will be completed with an ion gantry and a secondexperimentalhall(EH2).

Ithasbeenestimatedthat fortherunningofthefacility37expertswillbeneeded.Atthe same time 46 people will take care of the clinical, radiobiological and physicsprograms. Moreover many hundreds of visiting scientists, coming from inside andoutsidetheRegion,willparticipateinthevariousscientificprograms.

Therunningcostwillbeabout11M€/year,whichwillbereducedto6M€/yearwhentakingintoaccountthe5M€/yearcoming,afterfewyearsoftreatingpatients,fromtheincomesduetotheabout500patientsirradiatedeveryyear.

***TrainingoftheyounggenerationisanessentialandintegralpartoftheInitiative.Therealisationof theprojectwill take several yearswhichgives sufficient time to trainnotonlythefutureteamthatwillhelptobuildandlateroperatetheinstallationsbutalsotoformausercommunity.

Asanticipated,toreachtheclinicalandscientificgoalstwoNetworkswillbeset-upfromthe beginning of the project and continuously extended: the ClinicalNetwork and theScientificNetwork,thatwillbelocatedindifferentInstitutions.

Afteran initialperiod, the twoNetworksdescribedwillbeused to recruit the teacherswhowillformnewexperts,comingmainlyfromSEE,innumbersthatexceedtheneedsofthe Facility, so that other Hospitals and Institutions will eventually employ them, thusraisingthescientificlevelandthequalityoftheworkdoneintheRegion.

WiththebuildingofthisFacilitytherewillbemanyopportunitiesfortechnologytransfertotheSEE-countries.Firsttheprocurementofthedifferentcomponentsforthemachineand beam lines (magnets, vacuum system, girders, beam lines, power supplies, controlsystem, etc.) can be preferentially assigned to local industries.Moreover the Initiativewillgiverisetospin-offsnotdirectlylinkedtothefacilitiesbutprovidinganinitialsparkfornewactivitiesintheRegionandwillpromotethedevelopmentofregionalbroadband-digitalnetworks.

UgoAmaldi

Geneva,20thMay2018

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INDEX

EXECUTIVESUMMARY...................................................................................................31.

PART1-MOTIVATIONS,GOALSANDPROGRAMS1.1. MOTIVATIONSANDGOALSOFTHESOUTH-EASTEUROPECENTREFORHADRONTHERAPY

ANDBIOMEDICALRESEARCH........................................................................................14

1.2. PHYSICALANDRADIOBIOLOGICALBASESOFX-RAYANDPROTONTHERAPY...............................15X-raytherapy........................................................................................................15DosedistributionsandtreatmentschemesinX-raytherapy................................16Physicalbasesofhadrontherapy.........................................................................18Radiobiologicalbasesofprotontherapy..............................................................20

1.3. RADIOBIOLOGICALBASESOFCARBONIONTHERAPY............................................................21RelativeBiologicalEffectivenessandLinearEnergyTransferofcarbonions.......21CarbonionsareradiobiologicallydifferentfromX-raysandprotons...................23RBE-weighteddose...............................................................................................24

1.4. THERAPYWITHOTHERIONS..........................................................................................26RBEversusLETforvariousionspecies..................................................................26Choosingtheoptimaliontherapy.........................................................................27

1.5. TECHNIQUESOFHADRONTHERAPY.................................................................................28EuropeanCentresforcarbonionandprotontherapy..........................................28Activedosedelivery..............................................................................................29Rotatinggantries..................................................................................................30Beammonitoringandmovingorgans..................................................................31Measurementsofthedosedistributions:in-beamPETandpromptgammas......32

1.6. PATIENTSTREATEDWITHPROTONSANDCARBONIONBEAMS...............................................32

1.7. CLINICALPROGRAMANDITSEQUIPMENT.........................................................................34Generalframework...............................................................................................34Typesoftumourstotreatandtheirepidemiology...............................................35Typesoftumoureligiblewith................................................................................35Practicalorganizationoftreatments:logisticsandrecruitment,follow-up.........37Multi-centreclinicalresearchandlocalclinicalresearch......................................38Equipmentfortheclinicalprogram......................................................................38

1.8. RADIOBIOLOGYPROGRAMANDITSEQUIPMENT.................................................................39Generalframework...............................................................................................39Invitroandinvivoradiobiology:openproblems..................................................39Referenceradiationsource...................................................................................41Equipmentfortheradiobiologyprogram:low-energyline...................................41Materialscience....................................................................................................42Equipmentfortheradiobiologyprogram:high-energylineandtargethandling.43

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1.9. ANIMALPROGRAMANDITSEQUIPMENT..........................................................................44Generalframework...............................................................................................44Problemstobefaced............................................................................................45Programoftheanimalexperiments.....................................................................47Equipmentforanimalexperiments.......................................................................47

1.10. MEDICALPHYSICSPROGRAMANDITSEQUIPMENT...........................................................49Generalframework...............................................................................................49Medicalphysicsprogram......................................................................................49Equipmentforthemedicalphysicsprograms.......................................................49

1.11. TWOEXTENDEDNETWORKS........................................................................................50

1.12. EDUCATIONANDTRAINING.........................................................................................51

1.13. KNOWLEDGETRANSFERANDSPIN-OFFSTOTHEREGION....................................................52

PART 2 - CONCEPTUAL DESIGN OF A MULTIPLE-ION THERAPY ANDRESEARCHFACILITY2.1 CHOICEOFTHESTUDYCASE..........................................................................................54

2.2 OVERVIEWOFTHEACCELERATORSYSTEM........................................................................54

2.3 FROMTHEIONSOURCETOTHESYNCHROTRONEXTRACTIONSYSTEM.....................................57Injectionline..........................................................................................................57Synchrotron...........................................................................................................57

2.4 BEAMTRANSFERTOTHETREATMENTANDEXPERIMENTALROOMS........................................59

2.5 SOFTWARES..............................................................................................................60ControlSystem......................................................................................................60DoseDeliverySystem............................................................................................61MedicalsoftwareandQualityAssurancetools.....................................................62TreatmentPlanningSystemforions.....................................................................62

2.6 STAGINGOFTHEPROJECT............................................................................................62

2.7 SITEREQUIREMENTS...................................................................................................64

2.8 TIMELINEANDORGANIZATION......................................................................................65Timeline................................................................................................................65Organizationalmodel...........................................................................................65

2.9 INVESTMENTSANDMANPOWERFORTHECONSTRUCTIONANDTHEUPGRADING......................67ConstructionoftheCentre....................................................................................67UpgradingoftheCentre.......................................................................................69

2.10 COSTSOFPERSONNELANDMAINTENANCEDURINGTHEEXPLOITATION..................................69PersonnelneededforrunningtheFacility............................................................69Personnelandinvestmentsfortheexploitationyears..........................................70

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APPENDIXAWORLDCARBONCENTRESANDTHEIRCONSTRUCTORS.................................................................73

APPENDIXBSTATUSOFTHECOMPARISONSWITHX-RAYTHERAPYANDABLATIVEPROCEDURES.............................77

Protontherapy......................................................................................................77Carbonionsandotherlightions...........................................................................79

APPENDIXCRADIOTHERAPYDEPARTMENTSINTHESEECOUNTRIES................................................................83

APPENDIXDMATERIALSSCIENCEWITHTHELOW/MEDIUMENERGYBEAMLINE..................................................87

IonBeamAnalysis.................................................................................................87MaterialModification...........................................................................................87RadiationHardnessstudies...................................................................................87

MOTIVATIONS, GOALS AND PROGRAMS

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1. MOTIVATIONS,GOALSANDPROGRAMS

PART1

MOTIVATIONS,GOALSANDPROGRAMS

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1.1. MOTIVATIONSANDGOALSOFTHESOUTH-EASTEUROPECENTREFORHADRONTHERAPYANDBIOMEDICALRESEARCH

Hadron radiation therapy (HT), with beams of protons and carbon ions, is in rapiddevelopment so thatworldwide about 70 centres are treatingpatients and another 70areunderconstruction(AppendixA).Protons have biological effects that are similar to the ones of X-rays, the standardmodalitywithwhichmore than5millionpeopleare treatedeveryyearworldwide,butdelivertheirenergyalmostexclusivelytothetumourtargetthussparingthesurroundinghealthytissuesandreducingthenegativesecondaryeffects,asthelong-terminductionofnewtumours.

Carbon ionsareadifferent typeof radiation,because theyproducedifferentandmoreseveredamagesthanX-raysandprotonsattheendoftheirrangeinthepatient’sbody.Thisincreasedefficacyallowsthecontroloftheso-called“radioresistanttumours”,whichareabout5%ofallsolidtumoursandarepoorlycontrolledbyeitherX-raysorprotons.

Inspiteofthefactthat,bytheendof2017,morethan160,000patientshadbeentreatedwithprotonsand25,000withcarbonions,clinicalresearchisstillneeded,inparticularinthequantitativedeterminationoftheaugmentedefficacyfortumoursandnormaltissuesand inthechoiceof the ionspecieswhichproducethebestclinicaloutcomeforall theverydifferenttypesofradioresistanttumours.Ithastobeaddedthat• carbonionsmaynotbeanoptimalchoiceforalltypesoftumoursandthatthe

explorationofotherpossibilities(e.g.lighterasheliumorheavierasoxygenions)requireslong-rangeplanningandyearsofstudy;

• anyclinicalresearchprogramhastobebasedonsoliddataandmodels,inparticularontheaccuratesimulationoftheradiationfield(insilicon)andonexperimentsperformedwithcellcultures(invitro)andwithanimals(invivo).

Veryfewtwo-armstudieshavebeencompletedtocomparetheclinicalresultsofX-rays,hadron beams and other modalities (Appendix B). This is due to the way thesemodalities have been historically implemented and, more recently, to the lack offacilitiesreallydevotedtoexperimentalandclinicalsciences

Onthebasisofthesearguments,theFacilitydescribedinthisReportisintendedtobeaCentreopentomedicaldoctorsandscientistscomingfromEuropeanandnon-Europeancountries.Itsstaffmemberswillworkinclosecollaborationwithexternalexperts(i) totreat,whencompleted,during50%ofthedaytime,withcarbonandotherions,

about500patients/year,whowillparticipateinmulticentreclinicalstudies;(ii) towork,fortheremaining50%ofthedaytime-plusnightsandweekends,on• radiobiologyexperiments,• animalstudies;• medicalphysicsmeasurementsandmodelsdevelopment.

(iii) tocontributetotheinventionandimplementationofnewtechniquesandmethodsintheclinicalandscientificfieldslistedunderA.andB.

For program B.2 an animal facility for rodents will be available in the Centre. LargeranimalswillbeirradiatedincollaborationwithaVeterinaryDepartment.

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Medicalimaginginstrumentation,i.eCT,PETandMRI,willbeneededinthefacility,whichwillnothavepatientbeds.However,theCentrewillbebuiltclosetoahospitalthatwillprovidebeds,intherarecasesinwhichtheyareneeded,andofcoursegeneralmedicalcares.Ifpossible,theavailabilityofaRadiationOncologyDepartmentwithlinacsforX-raytherapyand thecorrespondingmedical imaging tools, in thatnearbyhospitalwouldbeveryuseful. Thiswill reduce thevarietyofdiagnostic instruments tobe installed in theFacility.(TheRadiationDepartmentsoftheSEEcountriesarelistedinAppendixC.)

ForradiobiologyexperimentstheCentrewillfeaturealow-energybeam(7-8MeV/u)andahigh-energybeam(upto430MeV/u).Thislow-energybeamcanbealsoemployedforMaterial Science and, in particular, for Ion BeamAnalysis (IBA),MaterialModificationsandRadiationHardnessstudies(AppendixD).

1.2. PHYSICALANDRADIOBIOLOGICALBASESOFX-RAYANDPROTONTHERAPY

X-raytherapyIn Europe about 50% of all tumour patients (i.e. about 2500 patients per 1 millioninhabitants every year) are irradiated with X-ray beams produced when electrons,acceleratedbyalinearacceleratortoabout10millionelectronvolts(10MeV),bombardaheavymetaltarget(Figure1.1).TheX-raybeamisshapedasatransversesectionofthetumour target by a “multileaf collimator”madeof computer controlledmovablemetalfingers.

Figure1.1Thelinac(a),themagnetsthatdeflecttheelectronbeamby270°,thetargetandthecollimatorsaremountedona“gantry”thatrotatesaroundthepatient(b).

Radiation oncologists useworldwide about 30,000 electron linear accelerators (linacs),more than half of all the running acceleratorswith energies larger than 1MeV. TodayRadiationTherapy(RT)withX-raysisbyfarthemostcost-effectivecancertreatment.Theaimofaradiationtreatmentistodepositinthetumourtargetlargeenoughenergyperunitofmass–aquantityspecifiedbythe“radiationdose”thatistheenergyabsorbedbyaunitofmass;the radiation dose is measured in “grays”: 1 Gy = 1 joule / 1 kg. Thisenergyisnottransferreddirectlybythe1-10MeVphotons,constitutingtheX-raybeam,butindirectlybytheelectronsthatareputinmotionbythephotonsand,beforestoppingwithatortuouspaththatisabouttenmillimetreslong,loseenergyintwoways:

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1. by promoting the electrons of the traversed atoms and molecules to a state ofhigherenergyinaphenomenoncalledmolecular“excitation”,

2. by“ejecting”atomicelectrons,mostofwhich,inturn,exciteatomsandejectotherelectronsinaphenomenoncalledmolecular“ionization”.

Immediatelyafterwardstheexcitedmoleculesgobacktotheirnormalstatesothatitcanbe said that the main result of a radiation beam crossing a piece of matter is thedeposition of energy in the form of ionizations of its atoms and molecules. The localradiation“dose”canbeconvenientlythoughtastheenergyleftbythebeam,intheformofionizations,inamilligramoftissue.

About70%ofthisenergyisabsorbedbywatermoleculesandproducesReactiveOxygenSpecies (ROS), i.e. simple molecules containing oxygen, which are chemically veryaggressiveandareusually called “free radicals”or “oxidants”.Bywandering in the celltheseradicalscanarriveontheDNAmoleculeandbreak iteitherononestrand(singlestrand break, SSB) or on both strands (double strand break, DSB). Because of itsimportance theDNAmolecule isprotectedbyanelaborate repair system that restoreswithhighfidelity the SSBsandmostof theDSBs. Theunrepairedbreaks can cause thedeathof thecell;onaverageonlyoneoutofabout50DSBs is lethal to thecell.TheseindirecteffectsoftheX-raybeamonDNAare,obviously,chemicalphenomena.

ROSareactivatedinoxygenatedtissuesanddeactivatedinhypoxicones.Forthisreasonhypoxictumourcellstendtobe“radioresistant”, i.e.torequire largerX-raydosestobeseverelydamaged.Hypoxiccellsarefoundatthecentreofsomelargetumoursbuttherearealsotumoursthatareradioresistantwithoutbeinghypoxic.Globallyabout5%ofthetumours treated by radiations are very radioresistant. They are the major problem ofconventionalradiotherapysincethecurerateislowbecauseoftentheX-raydosecannotbe increased, as necessary for their control,without irradiating close-by critical organsthatcannotbeirradiatedwithoutcompromisingthepatientqualityoflife.

About70%ofthedepositedenergyproduces indirecteffectsmediatedbyfreeradicals.Fortheotherabout30%directeffectsareatwork:oneoftheelectrons,putinmotionbytheX-rayphotons,crossesthedoublehelixand,byejectingelectrons,producesdirectlyeitheraSSBor,morerarely,aDSB.Thisisaphysicalphenomenon.

In reality thesituation ismorecomplex,but thedistinctionbetween indirectanddirecteffectsremainsbroadlyvalidandcanbeusefullyusedincomparingtheeffectsontissuesofX-raysandhadronbeam.

DosedistributionsandtreatmentschemesinX-raytherapy

AsshownbythebluecurveofFigure1.2,thedepth-dosedistributionofaconventionalX-raybeam, after reachingamaximumat a fewcmdepth, is characterisedbyanalmostexponential attenuation and absorption of the dose, and consequently delivers themaximum of the dose near the beam entrance, but continues to deposit significantamounts of energy at distances beyond the cancer target until it exits. The X-ray dosedetermines the clinical effects of the treatment, which are well understood for both

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normalandcanceroustissuesthankstomorethan100yearsofstudies1.

Figure1.2–Comparisonof depthdoseprofiles of high-energyphoton (X-rays, in blue), protons(green)andcarbonions(red)beams.Theabscissaisthedepthinwaterorinasofttissue.

Since,asshowninthefigure,after10-20millimetrestherelativedosedecreaseswiththedepthalsotheclinicaleffectsdecrease.Toconcentratethedoseandproducethelargercurative effects in the tumour target, the X-ray dose is given frommany directions byrotatingtheelectronlinacaroundthepatientandmodulatingtheshapeandintensityofeachbeamusingcomputer-controlled“multileaf”collimators(Figure1.1).

TheexamplegiveninFigure2.2,whichreferstoalargeskullbasetumour,showsthat–tominimize thedosegiven tonormal tissues–X-raysare crossed-fired from9directions;still,thecolourscaleindicatesthatsurroundingnormaltissuesreceivedosesthatareaslargeas50%ofthedosegiventothetumour.

Figure 1.3 –With 9 non-coplanar X-ray beams the dose to this large skull base tumour is veryuniformandthebrainstem(ingreen)canbespared,butlargedosesaregiventothewholebrain(left figure). In thecaseof4proton (orcarbon ions)beamthesituation ismuchmore favorable(rightfigure).

With these techniques of cross-firing, called Intensity Modulated Radiation Therapy(IMRT),a“conformal”X-raytreatmentcanbegivenattheexpenseofagreater integraldose, which is unavoidably deposited in the normal tissues surrounding the targetbecause,asshown inFigure1.2, theX-raysdose isdistributedallalong thepath in thepatientbody.

1Recentlyneweffectsof theautoimmunesystemandcharacteristicsof thecancer stemcellshavebeendiscoveredanditisnotexcludedthatthesenewunderstandingswillbringbeneficestofuturepatients.

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In a typical treatmentwithX-rays a total doseof 60-70 grays is deposited in a tumourtarget in25-35daily fractionsover5-7weekssotogivetimeforunavoidably irradiatedhealthycellsandtissuestorepairtheradiationdamages.Interestingly,thisfractionationprinciplemakespossiblesomere-oxygenationofhypoxic–andthereforeradioresistant–tumour cells and the transitionof tumour cells from radio-resistant cell cycle stages tomoresensitivestages.

Physicalbasesofhadrontherapy

Theheartofanelectronlinearaccelerator–calledalso“linac”–issmallandlight:averyspecial 1-metre long copper tube thathasadiameterof about10 cm (Figure1.1). Thelinacismountedonagantrythatrotatesaroundthecouchwherethepatientislaying,sothat thebeamofX-rays –producedwhen theacceleratedelectronshit aheavymetaltarget–canbedirectedtowardsthesolidtumourfromanydirection.Converselyhadronaccelerators are larger, weightier and costlier than X-rays electron linacs because aproton(carbonion)is2000(24,000)timesheavierthanprotonsandhastobeacceleratedto about 200 MeV (5000 MeV), instead than 10 MeV, to treat a 30-centimetre deeptumour.Insteadoflinearaccelerators,circularonesareneeded–called“cyclotrons”and“synchrotrons”–inwhichbunchesofparticlesarebentbypowerfulmagnetsonacircularpathandateveryturngetasmallenergyincrease.

Proton therapy cyclotrons are nowadays superconducting with a diameter of about1.5metres,butalsosynchrotronsareused.For treating300mmdeepsolid tumours,atypical230MeVtherapysynchrotronforprotonshasadiameterof6-8metresandthemagnets,whichbendthebeamonacircularpath,weightensoftons.Sinceacarbonionismadeof6protonsand6neutronsandhastobeacceleratedto5000MeV,totreatthesametumourtarget,thediameterofanionsynchrotronhastobeabout3timeslarger,i.e.18-25metres.Inthesesynchrotronsthegroupsofparticles,areinjectedatenergiesofabout100MeVbyaspecial“injector”linacandcirculateduringonesecondforaboutonemillionturns.

ThelayoutoftheHeidelbergIonTherapyCentre(HIT)isshowninFigure1.4.

Figure 1.4 – Layout of HIT Centre in Heidelberg. By the end of 2017 HIT, which was the firstEuropeancarbonionandprotoncentre,hadtreatedwithcarbonions4700patients.

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The configurations of all the running ions synchrotrons are very similar. Typically theyfeature:o two(ormore)ionsources,o aninjectorlinac,o asynchrotron,o aHighEnergyBeamTransportline,madeofmagnetsthatfocusthebeam,o one or more horizontal beamlines, equipped with instruments that “paint” the

tumourandproducedosedistributionssimilartotheoneofFigure1.3b,o sometimesacarboniongantrythatrotatesaroundthepatientcouch.

AsshowninFigure1.3b(right),withaprotonoracarbonionbeamauniformdosecanbedeposited inatumourtarget,ofanyshapeand location inthebody,sparingnormalhealthy tissuesmuchbetter thanX-rays. This is due to the fact that inmatterhadronsmovepracticallyinstraightlinessothattheBraggpeaksofFigure1.2givesorigintothe“spot”showninFigure1.5.

Figure1.5–Inwater(andalsoinsofttissues)theBraggpeakgivesorigintoathree-dimensionalspotthatisatadepthof200mmwhentheenergiesoftheprotonsandcarbonionsare170MeVand4000MeVrespectively.

The transverse dimensions of 200-300mmdeep spot are about 10mm in the case ofprotons and about 4mm in the caseof carbon ions. Another difference, not shown inFigure 1.5, is that in the carbon case downstream of the spots there is a small “tail”(showninredinFigure1.2)duetothefragmentationofafractionofthecarbonionsintosmallernuclei.

DuetotheBraggspotitispossibletoconcentratetheprotonandcarboniondosesonthetumourtarget,sparingmuchbetterthanwithX-raysnormaltissueslocatedinfrontandbehindit.Sincethedosesaremore“conformal”tothetarget,radiationoncologistscanincreasethehadrondosetothetumourwhiledepositingthesamedoseaswithX-raysinthe healthy tissues, thus increasing the cure rate with the same secondary effects.Alternatively,bygivingwithhadronsthesamedosetothetumouraswithX-rays–andthushavingthesamecurerate–onecanreducesecondaryeffectsinnormaltissuesas,forinstance,thelong-termprobabilityofsecondarytumours.

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Radiobiologicalbasesofprotontherapy

Alongmostoftheirpathinthepatientbody,energeticprotonsbreaktheDNAindirectly,throughthemediationofthesameReactiveOxygenSpeciesproducedbyX-rays.AsforX-rays,onlyabout30%of thedepositeddosecausesdirect damages to thedoublehelix.Becauseofthis,forthesamedosetothetumourtarget,thebiologicalandclinicaleffectsofprotonsaresimilartotheonesofX-rays.However,thereisanon-goingdebateinhowfara substantially increasedeffectiveness that is alsoobserved in-vitro at lowerprotonenergies isofclinicalrelevance,as itmightshowupatthedistaledgeofthetreatmentfield. Systematic experimental in-vivo data are lacking here,which could help to clarifyboththeprotoneffects inthe lastmillimetreoftheirrangeinbiologicaltissuesandtheclinicalconsequencesofthenuclearinteractionsofprotonsandotherions2.

SinceprotonsbehavebiologicallyandclinicallysimilarlytoX-rays,mostclinicalprotocolsforprotontherapytakeadvantageoftheknowledgeaccumulatedinmorethanhundredyears of conventional radiotherapy and adapt them with only slight modifications forprotontherapy.Inparticular,thedoseistypicallysubdividedin20-30fractionsover4-6weeks.

Given the more conformal dose distributions of protons with respect to X-rays, theindications for proton therapy are clear: they are to be preferredwhen a high enoughdosecannotbedepositedinthetumourtargetbecauseaclose-bycriticalorganlimitsthemaximum allowable dose. As said above, the higher conformity can be used either toincrease thedose to the tumouror todecrease thedamages tonormal tissues.Protontherapyiswellsuitedtothecaseswherethetumourisradiosensitive(about95%ofthecases)andthefastfall-offofthedoseallowsdepositingalargerdoseinthetargetforthesamedoseasX-raysinthesurroundingnormaltissues.

Ithastoberemarkedthata largerdose isbeneficialbecausedose-responsecurvesaretypicallyverysteep,andevenamodest10%increaseofthedosedepositedinatumourgivestypicallyanincreasedprobabilityoflocalcontrolofthetumouritselfbyabout20%.This implies, theoretically, that passing from 60 Gy to 66 Gy, the control probabilityincreasesfrom50%to70%,anotnegligiblegain.

Treatment protocols are well defined and – by the end of 2017 –more than 160,000patients had been treatedwith proton beams. Todaymany radiation oncologists thinkprotons shouldbeused for thoseabout10%of theadult cases inwhich the tumour isclosetoorgansatrisk,whichareorgansthat,ifheavilyirradiated,wouldcauseaseriousdeteriorationofthepatientqualityoflife.

About1%oftheseadultcases(correspondingtoabout25patientsonapopulationof1million people) arehigh priority cases.Moreover, it is now generally agreed that solidtumoursinchildren(6-7childrenpatientsonapopulationof1millionpeople)shouldbetreatedwithcurativeintentwithprotonsandnotwithX-rays.

2 At present the differences between protons and X-rays are a topical argument. See, for instance, Tommasino F, and Durante M, Proton Radiobiology, Cancers 2015;7:353-381. doi:10. 3390/cancers7010353

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1.3. RADIOBIOLOGICALBASESOFCARBONIONTHERAPYAlthoughprotonsandcarbonionsshowsimilardepthdoseprofiles,thelateralscatteringis reduced forheavier ionsand theBragg spotofa carbonpencil beam is transversallyandlongitudinallysmaller.Ontheotherhand,assaidabove,carbonandotherionsshowasmalldosecontributionbeyondtheBraggpeak,whichistheresultofthefragmentationoftheionsleadingtolighternucleiwithalongerrangeinmatter.

RelativeBiologicalEffectivenessandLinearEnergyTransferofcarbonions

Because of the smaller spots in both the lateral and the longitudinal direction, carbonbeams exhibit dose gradients about three times steeper than protons. But the mainadvantageof carbon ionsascompared toprotons is the significantly increasedRelativeBiologicalEffectiveness (RBE) in the lastcentimetresof thecarbonrange intissues.ThemeaningofRBEcanbeunderstoodfromFigure1.6.

Figure1.6–ExampleofcalculationoftwoRBEvaluesfromthesurvivalcurvesofcultivatedcellsirradiatedwithaphotonbeamandacarbonionbeamhavingLET=200eV/nm=200keV/μm.

RBE isdefinedas theratioof thereferencedoseDX (usuallyduetoX-raysproducedby200-250keVelectrons)tothedoseDionnecessarytoproducethesamebiologicaleffect–e.g.survivalof10%ofthecells–withionirradiation:

RBE=[DX/Dion]sameeffect (1.1)

The figureshows thatat the10%survival levelRBE=2.4whileat the1%survival levelRBE= 2.0, demonstrating in a simple example that the RBE value depends on theconsideredbiologicalorclinicaleffect.

Thequantity“dose”isamacroscopicparameterthatdoesnotdescribesthemicroscopicstructureoftheenergydepositionevents. It isthespatialdistributionofthe ionizationsalongandaroundtheparticletrajectory–calledthe“trackstructure”–thatdeterminesthebiologicaleffects.

Oneimportantscalefortheunderstandingofthespecifichigh-LETeffectsisthediameteroftheDNAmolecule,about2nanometres,astheDNArepresentsthemaintargetoftheradiationattackinsidethecell.However,alsootherscalese.g.onthelevelofchromatinorganization(socalled“giantloops”withasizeintheorderof1µm)andthecellnuclearsize(about10µm)areknowntobeofparticularrelevance.

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Therelevanceof thenmscale is illustrated inFigure1.7, indicatingthedecreaseof theaveragedistancebetweentwosuccessiveionizations(indicatedbytheletter“d”inFigure1.7a)whenacarbonionpenetratesinthepatientbody,loosingenergytillitstops.

Figure1.7–(a)Aparameterdefiningthebiologicaleffectistheaveragedistancedbetweentwoionizations.(b)ddecreaseswhentheenergyoftheiondecreasesduringtheslowingdownprocessandisequalto2nmforaresidualrangeR=40mm.

This can be understood quantitatively by introducing the energy lost by the chargedhadron in a unit track length called “Linear Energy Transfer” (LET), which can beexpressedasafunctionoftheeffectivechargeZeff,themassnumberA(whichisthetotalnumberofprotonsandneutrons)andthespeedβ=v/coftheprojectile:

LET=constZ2eff/(Aβ2) (1.2)

Eq.(1.2)highlightsthemostrelevantdependenciesoftheso-calledBethe-Bloch-formula,whichdeterminetheshapeoftheBragg-peak:

2. the rise of the energy deposition with depth as a consequence of thedecreasingenergy,andthusspeedβ,and

3. thedrop,afterreachingthemaximum,asaconsequenceoftheparticlechargeZ,whichcapturesatomicelectronsandbecomesZeff<Z.

Point(i)canbemademoreexplicitbywritingEq.(1)asanapproximatefunctionofthe“residualrange”Rinwater(orinsofttissues):

LET≈5.0Z1.13A0.435/R0.435(Rinmmofwater;LETineV/nm=keV/μm).(1.3)

TheformulaexpressesthefactthattheBraggpeak–showninFigure1.2andexploitedinallhadrontherapytreatments–hastheform1/R0.435,i.e.itisroughlyproportionaltotheinverseofthesquarerootofR3.Moreover,atequaldistancesRfromthestoppingpoint,acarbonion(Z=6,A=12)ischaracterizedbyaLET,andhencebyanionizationdensity,thatis22timeslargerthantheonesofaproton(Z=1,A=1)4.Thislargeratioisattherootofthedifferentradiobiologicalandclinicaleffectsofcarbonionsandprotons.

3 In the lastmillimetres thedivergenceof Eq. (1.2)whenR goes to zero iswashedoutby the fact thatparticles penetrating in matter have different ranges, when the paths aremeasured from the entrancepoint.Thisphenomenonisduetothestatistical fluctuationsoftheevents inwhichhigh-energyelectronsareputinmotion(“straggling”). 4 For helium the ratio is 4.

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CarbonionsareradiobiologicallydifferentfromX-raysandprotons

Foragiven ionspecies, theLET-value is themaindeterminantof the ionRBE.A typicalbehaviourisshowninFigure1.8foracelltypeoftenusedinradiobiologicalstudies.

Figure1.8–RBEversusLETfora10%cellsurvival.BydefinitionX-rayshaveRBE=1.

The figure shows thatwhen,during the slowingdownprocess, the LETbecomes largerthan about 30 eV/nm (equivalently, larger than 30 keV/μm or 300 MeV/cm) the RBEincreases sharply attaining values larger than 3 for LET ≈ 200 eV/nm, and then dropstowardshigherLETvaluesasaconsequenceofsaturationeffectsthat isequivalenttoawasteofenergy(socalled“overkill”).

The value 30 eV/nm can be qualitatively understood because a particle with LET = 30eV/nmleavesinthe2nmdoublehelix60eV,andabout30eVareneededtoproduceoneionization.ForLETlargerthanabout30eV/nmtheionizationsaresoclosealongtheiontrack(withdlessthan1nm,onaverage)thatonespeaksof“denselyionizing”radiation.

Fordifferentcellsandendpoints,theexactshapeandpositionoftheLET-dependenceofRBEmayvary.However,asdiscussedindetailinSection1.4,thecurvessignificantlyrisefor LET-values above few tens of eV/nm. Converting this into distances betweenindividualionizations,thiscorrespondstoafewionizationspernm,whichisoftheorderof magnitude to induce by independent ionizations either a DSB or a more severedamage.

Duetothefrequentejection(duetostatisticalfluctuations)ofmorethanoneelectronathigh LET when crossing the DNA molecule, severe DNA lesions called “clustered not-reparabledamages”.Thesedamageshinderthecellcycle,stopthetumourgrowth,andalsomay induce thecell internalprogram for itsowndestruction (apoptosis) yieldingafasttumourregression.TheseeffectsareduetothedirectinteractionoftheionswithaDNAmolecule.

Mostcellsandtissuesshowthisgeneralbehaviour,butthenumericalvaluesaredifferentaccordingtotheirtypeandtotheend-pointconsidered.Ingeneralonecanstate

1≤RBE≤5forcarbonions, (1.4)

Although the rangeofRBEvalues isvery similar forprotons, theyexhibit the increasedeffectivenessonlyattheverydistalendoftheirpenetrationdepth,whereasforcarbon

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ionstheelevatedRBEisspreadoveralargerdepth;thesedifferentialcharacteristicsarediscussedinmoredetailinSection1.4.

Summing up, the electrons put in motion by X-rays are sparsely ionizing because theaverage distances between ionization are much larger than 1 nm. Also protons aresparsely ionizing, a part the last millimetre before stopping. Through the chemicalmediationofReactiveOxygenSpecies(ROS),about70%ofthedose,depositedbythesetwo sparsely ionizing radiations, produces spatially well separated indirect effects, inparticular theDouble StrandBreaks that are not repaired and induce the death of thecell.

In the clinical practice the similarity of the phenomena induced by proton and X-raysbeamstranslatesinthegeneralizeduseofasinglevaluefortheRBE:

RBE=1.1forprotons. (1.5)

The radiobiological and clinical effects of carbon ions are different because they aredenselyionizing. Inparticularinthelastcoupleofcentimetresoftheirrange,wherethetumourtissuesarelocated,dissmallerthan1nmandtheybehaveasadifferenttypeofradiationwithrespecttoX-raysandprotons:about70%ofthedepositeddoseproducesdirectlycloselyspaceddamagesthat,notbeingmediatedbyROS,are insensitivetotheoxygencontentofthetissueandproducenot-reparableclustereddamagestotheDNA.Because of this behaviour the tumours – which are radioresistant to both X-rays andprotons,i.e.about5%ofallsolidtumours–aretheelectivetargetsofcarbonandotherlightions..

SinceinX-rayandprotontreatmentsthetotaldoseisdepositedinmanysessions,toletnormal cells repair during the intervening days, and with carbon ions the repairmechanism are not effective, when using carbon ion beams it is possible to cut thenumber of sessions from 25-30 to 10-15 thus sparing physiological stresses to thepatientsandreducingthetreatmentcost.

RBE-weighteddose

Intreatingpatientswithcarbonandotherlightionstheknowledgeoftheradiobiologicaleffectiveness,toapplytobothtumourandnormaltissues,iscrucialbecausetheradiationfieldmustbequantifiedbygivingthe“RBE-weighted”dose

DRBE=RBExD, (1.6)

which is reportedasGy(RBE)and isobtainedbymultiplying thephysicaldoseDby theRBEvalueofthatparticulartissue.

Although conceptually simple, Eq. (1.5) needs tobe appliedwith caution in the clinicalenvironment because RBE of a tissue is not just characterized by a single value, butdependsonseveralfactors,firstofalltheLETandtheconsideredeffectlevel.ThusRBEvarieswithintheirradiatedvolume,whereasforphotonradiationtheeffectivenessisthesamethroughouttheirradiatedvolume.

TwotypicaldoseresponsecurvesareshowninFigure1.6.TheblueonereferstoX-raysandfeaturesa“shoulder”thatisduetotherepairmechanismoftheDSBsinducedbyasparsely ionizing radiation. Instead, for carbon ions (red curve) at LET values around200 eV/nm (and thus at theirmaximumeffectiveness) the shapeof thedose response

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curveisalmostlinear(inalogarithmicscale)becausetheclustereddamagesproducedbyadensely ionizingradiationarenotrepaired.Thesedifferentshapesareattheoriginofthe fact that the RBE value depends on the chosen survival rate, i.e. of the dose persession.

WhenapplyingEq.(1.5)thepercentageerrorontheRBE-weighteddoseDRBEequalsthepercentage error on RBE and thus the precise characterization of RBE and itsdependencies on the relevant physical and biological factors is of utmost importance.Dataforcellscultivated invitroareavailable,astheonesshown inFigure1.6,butcellsand tissues in vivo may behave differently and only detailed animal studies andcumulatedhumantreatmentdatacangivetheinformationneededfortheirradiationofhumanpatients.

A reduction of uncertainties is highly desirable and thus many well-conceivedexperimentswillbeneededtogatherenoughinformationandreducetheerroronDRBEtolessthan±5%.Notethat inX-raytreatmentstheerroronthedoseD,which istheonlyrelevantquantity,isrequiredtobesmallerthan±2.5%.

Inatreatmentplanningprogramtheincreasedradiobiologicaleffectivenessisintegratedinamodelthatdescribestheradiosensitivityofnormalandcanceroustissues.Themostused one in Europe is the Local Effect Model (LEM) developed at GSI, the researchLaboratoryclosetoDarmstadt5.Thismodel isbasedonthecompletethree-dimensionaldistributionof the ionizationsanddamagesaround the trackand theknowledgeaboutthe photon dose response curve for the endpoint of interest; it allows the accuratedescriptionsofbiologicaleffectsin-vitroandin-vivo.

Insummary,carbonionbeamsofabout5000MeVareindicatedfortreatmentofdeep-seatedtumours,whichareradio-resistantbothtoX-raysandtoprotons.Thesetypesoftumoursarethustheelectivetargetsinacarbonionfacility.

Ingeneralthemajordeterminantsthatneedtobeconsideredare:1. theenhancementofRBEisparticularlypronouncedintheBraggpeak,andvarieswiththeresidualrangeoftheparticle;2. theRBEof ionsdecreaseswith increasingdosepersession(Figure1.6); thusthesubdivisionofthetotaldose infractions isan importantparameterthataffectstheRBE;3. theRBEof ionsishigherforcellsthatmanifestahigherrepaircapacityandthusareresistanttophotonradiationascomparedtocellsshowingahighersensitivitytophotonradiation;4. the biological effects of ions are less sensitive to oxygen concentration ascomparedtoconventionalradiation.

The relevanceof these factorshasbeenclearlydemonstrated innumerous in-vitroandin-vivoexperimentalapproachesbutmanyexperimentshavestill tobeperformedbothforcellmonolayers in-vitroorsmallanimals invivo.TheCentredescribedinthepresentReportwillgreatlycontributetothisprogramsincethepresentlyrunningfacilitiesarenotsufficient.

5ElsässerT,KrämerM,ScholzM.,AccuracyoftheLocalEffectModelforthepredictionofbiologicaleffectsofcarbonionbeamsinvitroandinvivo,Radiother.Oncol.2008;71:866-872,

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1.4. THERAPYWITHOTHERIONS

RBEversusLETforvariousionspecies

TheCentrewill featuremany ion sources andnumerous in vitro– in vitro experimentsand clinical studies will be performed, in collaboration with other ion Centres, tounderstandwhichionsarebestsuitedtotreatthemanydifferenttumourtypes.Thebiologicalandclinicalphenomenaarecomplexanddeterminedbymanyparameters,butthemainaspectscanbeillustratedbymeansofthecompilationshowninFig.1.9.Itcompares RBE(LET) curves, as predicted by the Local Effect Model for a variety ofdifferentionspeciesfromprotonstoNeions.

Figure1.9–TheLocalEffectModel,inagreementwithexperiments,predictsthattheRBEcurvespeakatlargerLETswhentheionchargeincreases.

ThesegmentsshownasthicklinesindicatetherangeofLETvaluesforwhichtheresidualrange–computedfromEq.(1.3)–isintheintervalfrom20mm(lowerendofthethickline)and1mm(upperend).Themostprominent featuresof thiscomparison is theshiftof thecurvestohigherLETvalueswhenincreasingtheatomicnumberoftheionspecies.

Obviously,LETisnotagoodparametertocharacterizetheRBEfordifferentparticles,asingeneralthelighterparticlesshowahigherRBEascomparedtotheheavierparticlesatagivenLET.ThiscanbeexplainedbythedependenciesinEq.(1.2):lighterparticleswithsmaller charge require a lower velocity, and thus energy, as compared to the heavierparticles to have the same LET. At lower energy, however, the lateral spread of theenergydepositionwithin individualparticle tracks is smaller, leading toahigherenergydensityandconsequentiallyalsohigherbiologicaldamagedensity,finallyresultinginthehigherRBE.

However,despitethefactthattheexpectedmaximalRBEvaluesareverysimilarforthedifferent ion species, this does not directly translate into similar clinically relevant RBEvalues.Inordertoassessthose,oneneedstoconsidertherangeofLETvaluesreflecting

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similar geometrical conditions with respect to penetration depth and to estimate thevariationofRBEacrossthetumour.

For example, if a tumour of 20mm diameter is considered, this variation can becharacterized by the spread of RBE values between ions with 1mm remaining range,representative for the distal edge, andwith 20mm remaining range, representative fortheproximaledgeofthetumour.ThisspreadofRBEvaluesisshowninFig.1.9bythefulllinesegments.Fromthis itbecomesobvious that in thecaseofprotonsonly the lowerpartoftheRBE(LET)curvecanbeexploitedintherapy,whereasincarboniontherapythecompleterisingbranchofthecurveisexploited.

Whengoing toevenheavier ions likee.g. neon,however, at thedistal edge saturationeffects dominate, whereas the RBE is already substantially elevated upstream of theproximaledge, i.e. in thenormal tissue. Thishasbeen,unfortunately,demonstrated inthe80”sattheBevalacoftheLawrenceRadiationLaboratory,manypatientshavebeentreated with neon ions with unexpected side effects, since – even for deep-seatedtumours–thepatientswereirradiatedwithdenselyionizingradiationwithelevatedRBEallalongtheparticlerange.

Essentially forthisreason,whileattheendof80”sthepreferred ionwasoxygen-16, in1994 at NIRS Hirohito Tsujii and his collaborators, worried by the possible effects ofoxygenionsonnormaltissues,initiatedtheirradiationswithcarbonions.Apartsome400patientstreatedinBerkeleywithheliumandothersmalltrials,tilltodaycarbonionsarethepreferredchoice,butitiscertainlynotoptimalforallradioresistanttumours.

Choosingtheoptimaliontherapy

Manyadditionalfactorsneedtobeconsideredforthechoiceoftheoptimalionspeciesforagiventreatmentscenario,andrealistictreatmentplanningcomparisonsarerequiredforthedecisionabouttheoptimalionspecies.

Theseplanningstudiesshouldbebasede.g.onthecomparisonoftheRBEweighteddosein the target region as compared to theRBEweighteddose in the surroundingnormaltissue. Here, the essentially different radiobiological characteristic of the tumour andnormaltissueareofparticularrelevance,asingeneraltheyareconnectedwithdifferentRBEvalues.

Inaddition,sinceRBEalsodependsonthedoselevel,thefieldconfiguration(1-fieldvs.2-field)andfractionationschemewillplayakeyroleintheassessmentoftheoptimalion.Finally, within the target hypoxia can substantially alter the radiosensitivity of thecorrespondingtumourregionandwiththatalsotheexpectedRBE,andinthiscasesevenheavierionsthancarbon,asforexampleoxygenionbeams,mayhaveadditionalbenefits,astheyshowamorereducedsensitivitytohypoxia.

Itisobviousfromthisdiscussionthatalargenumberofwellplannedandcomplementaryin vitro and in vivo studies have to be performed to clarify which ion has the largestcontrolprobability forwhat typeof tumourwithminimal sideeffects.Given theampletime dedicated to experimental studies, the SEE Facility has the potential of greatlycontributing to this ambitious program, which will cover many years because theradiobiological results will have to be validated bymulti-centre phase II and III clinicaltrials.

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1.5. TECHNIQUESOFHADRONTHERAPY

EuropeanCentresforcarbonionandprotontherapy

Thecarbonionandproton“dual”centrerepresentedinFigure1.4wasdesignedbyGSIandbuiltwith the technical supportof SiemensMedical. Itwas the first inEuropeandfollowed theGSI “PilotProject” that treatedwithcarbon ions440patients in theyearsacrossthenewmillennium.ThecentresinMarburgandShanghai,establishedbySiemensCompany,arefurtherdirectdescendantsofthepilotproject.Bytheendof2017HIT,hastreatedwithcarbonions4700patients.

Two European proton and carbon ion centres have their roots at CERN, which wasinvolvedintheirdesign.Infactin1996CERN,theTERAFoundationandtheMedAustrongroupinitiated,undertheleadershipofPhilBryant,theProtonandIonMedicalMachineStudy(PIMMS)withtheaimofdesigningasynchrotronanditsbeamlinesthatwouldbeoptimizedforlightiontherapy.ThetwolightionCentresareCNAOinPavia(firstprotonpatientin2011)andMedAustroninWienerNeustadt(firstprotonpatientin2016).TheyareshowninFigure1.10and1.11.

Figure 1.10 – Perspective view of the CNAO centre, which features 3 treatment rooms with 4therapeuticbeams(3horizontaland1vertical),and1experimentalroom.

Figure1.11– TheMedAustroncentre features1proton treatment roomwith rotatinggantry,2lightionstreatmentroomswith3beams(2horizontaland1vertical)and1experimentalroom.

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By the end of 2017 CNAO had treated 1600 patients (75% with carbon ions) andMedAustron had treated about 100 patients (with protons); carbon ion treatment isplannedforthemiddleof2018.

Activedosedelivery

In all hadron therapy centres until 1997 relatively simple “passive spreading systems”havebeenusedtoproduceaSpreadOutBraggPeaksimilartotheoneofFigure1.12.Inthisapproach,afirst“scatterer”widensthepencilbeamwhiletheirenergyisadaptedtothedistalformofthetumourbyusingappropriateabsorbers.Downstreamofthesingle(andsometimesdouble)scatterer,thetransverseformoftheirradiationfieldisdefinedbycollimators.

Figure1.12–(a)Penetratingintoabiologicaltissueanarrowmono-energeticproton(carbonion)beamproducesaBraggspotthathasadiameternotsmaller than10mm(4mm)diameter. (b)NumeroussuperimposedBraggpeaksgiveauniformdosetoatumourof10cmlength.

Onlyin1997GSI6andPSI7havedevelopednovel“activespreadingsystems”wherethechargedhadronsforma“pencilbeam”,havingtransverseFullWidthsatHalfMaximuminthe 4-10 mm range, which is magnetically deflected over the treatment area andmodulatedinintensity(IntensityModulatedParticleTherapy=IMPT).

In theGSI “active spreading” techniqueusedwith synchrotrons,which is called “rasterscanning”, the target volume isdivided into slicesofequal ionenergyandeach slice isdividedintosmallvolumes.These“plannedspots”or“voxels”(i.e.3-dimensionalpixels)aretreatedseparatelybymovingtheBraggpeakinthetransverseplane,bymeansoftwoorthogonal bendingmagnetsplaced fewmetresupstreamof thepatient, and then thebeam of constant current is kept fixed for the time needed to deposited the dosedeterminedbytheTreatmentPlan.Whenoneslicehasbeentreated,theenergyofthebeam is reduced for thenext slice. In practice, the complete target volume consists of5,000–15,000voxels,whicharetreatedin2-6minutes.

6 Haberer T, et al., Magnetic scanning system for heavy ion therapy, Nucl.Instrum.Methods Phys.Res. A 1993;330 :296-314. 7 Pedroni E, et al,, The 200 MeV proton therapy project at the PaulScherrer Institute: conceptual design and practical realisation, Medic. Phys. 1995;22:37-53.

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Formono-energeticionstheBraggpeakisverynarrow,sothattheenergyoftheparticleshas to be changed during the irradiation to cover the tumour depth. In cyclotrons thebeamenergycannotbevaried,sothatmovableenergyabsorbersandmagneticselectionsystemshavetobeusedtoadapttherangeoftheparticlestothedepthofthetargettobeirradiated.Insynchrotronsitiseasytovarytheenergyoftheextractedbeam.

In1994thefirstpatientwastreatedwithacarbonionbeamattheNationalInstituteofRadiologicalSciences(NIRS,Chiba,Japan),whichsincethenhasbeenthepioneercentreforthistypeofradiotherapy.ForabouttwentyyearsHIMACpatientshavebeentreatedwithpassive dose spreading techniques, inwhich the beam energywas changed everysynchrotron beam spill. At present themore effective active spreading techniques areusedinalmostallthecentres.Figure1.13showsthemainelementsinstalledonabeamline(andonagantry)inordertoperformirradiationswithsuchamodality.

Figure 1.13 – Disposition of the elements of active delivery system and beam monitors withrespecttothepatienttreatmenttable.

The delivery system includes: two scanningmagnets, themonitoring system, the high-accuracy robotic patient positioning, a six degrees of freedom couch and the in-roomimagingdevicesforpositionverification.

Attheisocentrethescanningmagnetsmovethebeamtransversallywithaspeedthatistypically20m/s.Thebeampositionischeckedinrealtimethankstoaredundantsystemofmonitorchambers.Toapply4Dirradiationstrategiesthison-linemonitoringsystemisintegratedwithinstrumentsforthedetectionofthepatientrespiratorymotion.

Rotatinggantries

SystemssimilartotheoneofFigure1.13arealsomountedonlargemechanicalstructuresthat rotatearound thepatient. The IBAprotongantryof Figure1.14hasadiameterof3.7m.

Figure1.14–The230MeVIBA“compact”protongantryweights110tons.

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Sincethe“rigidity”ofcarbonionshavingthesamerangeas230MeVprotons isalmostthree times larger, the gantries are larger and/or reach highermagnetic field. The HitgantryofFigure1.4weightsabout600tonsandatmaximumfieldconsumesabout400kW.Superconductingmagnetsallowhighermagnetic fieldsandthus lowerweightsandmuchlowerpower.SincefewyearspatientsaretreatedattheCHIBAcentreofNIRSwiththesuperconductinggantryofFigure1.15.

Figure1.15–The430MeV/usuperconductinggantrybuildfortheCHIBAcentreis15mlongandhasadiameterofabout6m.Itweightsabout300tons.

In Japan the advanced superconducting gantry of Figure 1.16 is under development.Many laboratories and companies are pursuing the same goal so that, when the SEEFacilityiongantrywillhavetobechosentherewillbevariousvaluablealternatives.

Figure 1.16 – The future “compact” superconducting carbon ion gantry is compared with thegantrythatispresentlytreatingpatientsatCHIBA:

Beammonitoringandmovingorgans

Thebeammonitoringsystemconsistsofasetofpositionsensitivedetectorsandbeamintensity detectors. In the existing facilities, beam position is measured using eithermultiwire proportional chambers (MWPC) or multistrip ionization chambers, having asub-millimetrespatial resolutiononthepositionofapencilbeam.Asaconsequenceofthehighscanningspeedandinordertoallowformultiplemeasurementsperbeamspot,ahighrepetitionrateofabout10kHzforthesepositionmeasurements isrequired.Forbeamintensitymeasurementsionizationchambersareused,alsowithacorrespondinglyhigh repetition rate. Two independent detectors for position and intensity

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measurements,respectively,areusedtoachieveredundancy,which isrequired,aspartof the safety system: only when both detectors give consistent results, the irradiationcontinues,otherwisethetreatmentisinterrupted.

The treatment of moving tumours, e.g. lung tumours, is particularly challenging withactive beam delivery systems, as the combination of beam movement and targetmovementcanleadtoundesiredinterferencepatternsandconsequentlytodistortionsofthedosedistribution.Thedevelopmentofadequatemotionmitigation techniques is inthe focus of intensive research and development activities, and different concepts likegating, rescanning and tumour tracking are discussed. Although tracking, which is thefollowingofthetargetmovementsbyappropriatecontinuousadjustmentsofthebeamdeflection(withthescanningmagnets)andofthebeamenergy,seemsthemostelegantway,theparticularchallengehereistheaccuratedetectionoftheactualtargetposition.Therefore, gating (i.e. the treatment only during well defined motion phases) and re-scanning (i.e. multiple irradiations with consequential wash-out of the potentialdistortions)arethealternativesusedatpresent.

Measurementsofthedosedistributions:in-beamPETandpromptgammas

In order to fully exploit the advantage of the steep distal dose fall-off that can beachieved with ion beams, the accurate knowledge of the beam range is of greatimportance.RangecalculationsarebasedonCT-imageinformationthatallowstakingintoaccount the differential, tissue dependent stopping power. As the correspondingcalibration, as well as patient positioning and organ movement, contribute touncertainties in the range, in-beam determination of the actual beam range duringtreatmentishighlydesirableforverificationpurposes.WithinthepilotprojectperformedatGSI,thesemeasurementsweredonebasedonthepositronemissiontomography(PET)technique,exploitingthefactthatasmallfractionoftheprimaryionsareconvertedintopositronemitting isotopesdue tonuclear reactionswhen thebeampenetrates tissue8.Thedetectionofpromptgammas,whichalsoareemittedinthesenuclearreactions,hasbeendiscussedformanyyearsasapotentialalternative;thefirstclinicalinstrumentsarenowenteringtheclinic9

1.6. PATIENTSTREATEDWITHPROTONSANDCARBONIONBEAMSOverthelasttwodecadesparticlebeamcancertherapyhasgainedahugemomentum.Manynewcentreshavebeenbuilt,andmanymoreareunderconstruction(Figure1.17).Attheendof2016therewereworldwide67centresinoperationandanother63areinconstruction or in the planning stage. Most of these are proton centres, 25 in USA

8EnghartW,Fromm WD, GeisselH, et al.,Thespatialdistributionofpositron-emittingnucleigeneratedbyrelativisticlightionbeamsinorganicmatter,Phys.Med.Biol.1991;37:2127-2131.FiedlerF,PriegnitzM,JülichR,etal.,In-beamPETmeasurementsofbiologicalhalf-livesof12Cirradiationinducedbeta+-activity.ActaOncol.2008;47:1077-1086.

9 Pinto M, De Rydt M, Dauvergne, et al., Technical Note: Experimental carbon ion range verification ininhomogeneousphantomsusingpromptgammas.MedPhys.2015;42:2342-2346Richter C., PauschG, Barczyk, et al., First clinical application of a prompt gammabased in vivo protonrangeverificationsystem,Radiother.Oncol.2016;118:232–237.

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(protonsonly),19inEurope(ofwhich3dualcentres),15inJapan(ofwhich4carbonand1dual)and2(1carbonand1dual)inChina,4(protonsonly)inotherpartsoftheworld.Thedetailedcharacteristicsofthe10carbon(andsometimesproton)facilitiesaregiveninAppendixA.

Figure1.17– Hadrontherapyfacilitiesinoperationworldwide,underconstructionandintheplanningstageattheendof2016.(www.ptcog.com)

From1994,whenatHIMAC(NIRS)thefirstpatientwastreatedwithcarbonions,NIRShasbeen leadingthedevelopmentofcarbon iontherapy. Asdiscussedabove,HITwas thefirsthospitalbaseddualcentreinEurope(Figure1.4).ThiswasfollowedbyCNAOinPavia(Figure1.10)andMedAustroninWienerNeustadt(Figure1.11).

Atpresentsixty-threenewcentresareunderconstruction-sothatby2021,therewillbehadron therapy in130 centresoperating in30different countries. The locationsof theEuropeancentresareshowninFigure1.18.

Figure1.18–Europeanhadrontherapyfacilitiesinoperationorunderconstructionin2016.

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AsshowninFigure1.19,thenumberoftreatedpatientsgrowthsalmostexponentially.Attheendof2007thepatientswere61.855,ofwhich53.818withprotonsand4.450withcarbonions.Attheendof2016thenumberhadgrownto168.000(145.000withprotons,23,000 with carbon ions). This is due primarily to the greater availability of centres,although till recently very few randomized studies had been initiated to compare theresults of hadron therapywith conventional X-ray therapy. Fortunately the situation ischanging,asshowninAppendixBwheretheon-goingphasethreestudiesarelisted,andinafewyearsanevenfasterincreaseofthenumberoftreatedpatientsisexpected.

Figure1.19–Patientstreatedwithprotonsandcarbonworldwidebytheend2016.

1.7. CLINICALPROGRAMANDITSEQUIPMENT

Generalframework

Given the evolution of treatment techniques in particle therapy as in X-ray photontherapy, it is necessary that the equipment of the Centre, or of the close-by Hospital,makeitpossibletoachieveatleastthefollowingperformancesandoperations:

- intheclose-byHospital(s)supportivecaresandtheassociatedtreatments;- volumeimagingcapability intheCentre:X-rayscanner,mandatory,MRIandPET

scanifpossible;- customizedpersonalpositioningdevices; - IGRT3Drepositioninginthetreatmentroom;- treatment by several beams in the sameposition of the patient, thus having at

leasttwodifferentincidences(H+VorH+OorH+V+Oorgantry);- dose rates which allow the rapid treatment of mobile tumours in pencil beam

scanningwithrepainting, i.e rates intherange3-10Gy/ (for500mL)sothatatreatment session takes less than 30-45 minutes, including installation andrepositioningofthepatient;

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- availabilityofseveralparticles:protons,helium ions ,carbon ionsandothers,asdiscussedinSection1.4;

- proximityofoneor severalhousing facilitieswitha capacityof receptionof thepatientswithlightmedicalcapabilities;

- locallysignificantcapabilitiestomanagecontrolledclinicalstudies- local facilities for scientific visitors and groups of students or professionals for

trainingsessions.

Treatmentcapacitymustbedefinedaccordingtothehealthobjectivesthatwillbegiventothecentre.Ifitisanofferofcareintendedtosatisfyalltheparticletherapyneedsofagivenpopulation,itispossibletocountthatasingletreatmentroomcancovertheneedsofapopulationof5to10millioninhabitants.

Typesoftumourstotreatandtheirepidemiology

The following table is based on European epidemiological studies preliminary to theItalian,AustrianandFrenchcarbontherapyprojectshavemadeitpossibletoestablishacensusofprioritycasesforthistypeoftherapy10.Infuturetheepidemiologywillhavetobe corrected for the age distribution of the regional population, which is described inAppendixE.

Thecaseseligibleforhadrontherapyaccountforabout10%ofallradiotherapypatients,whichareabout25000patientsper10millioninhabitants.About1%outofthis10%areintheveryfirstlevelofpriority,asindicatedinTable1.1.

Table1.1-Protontherapyandiontherapyindicationsofthehighestpriority.

Typesoftumoureligiblewith

highestpriorityforprotontherapy

Typesoftumoureligiblewith

highestpriorityforiontherapy(carbon)

Adults’skullbasetumours

Adults’unresectableorrelapsingmeningioma

Otherrareadults’centralnervoussystemtumours

Childs’centralnervoussystemtumours

Anyotherchilds’solidtumours

Adenoidcysticcarcinomasofsalivaryglands,includinghead&neckandthorax,sinusadenocarcinomas.

Mucinousmelanomasofheadandneckchordomasandchondrosarcomasofskullbaseandspine.

Softtissuessarcomasoflowandmediumgrade,unresectableorpartiallyunresectablewithoutthreatening

metastasis.

Nonsmallcelllungcarcinomas,ofsmallandmediumsize(N0,M0)unsuitableforsurgery.

Pelviclocalrelapsesofadenocarcinomas,M0andpreviouslyirradiatedbyX-rays.

Hepatocarcinomasuniqueandoflargesize.

Total:about80cases/yearfor10millioninhabitants

Total:about200cases/yearfor10millioninhabitants

10 Baron MH, Pommier P, Favrel V, Truc G, Balosso J, Rochat J., A “one-day survey”: as a reliable estimation of the potential recruitment for proton- and carbon- ion therapy in France. Radiother. Oncol. 2004;73 Suppl 2:S15-7.

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Theycorrespondstoabout280tumoursperyear(80forprotonsand200forcarbonions)on a population of tenmillion people, so that the Facility, treating (when completed)about500patientsperyear,willofferacuttingedgestateofthearttreatmentforoftenhopelesstumourstoabouttwothirdsoftheregionalpopulation.Recruitingthemwillbeoneofthemainchallengesofthisinitiative.

InTable1.1forprotontherapythehypothesisisasignificantreductionoftoxicityand,forion therapy, thehypothesis is a gainof 20 to 25%of tumourprogression free survival,increasingthesuccessratefrom≈50%to>75%.

ThesecondpriorityindicationsarecollectedinTable1.2.

Table1.2–Indicationsofsecondarypriorityforlightionstherapy.

SarcomasafterdefinitiveR1resection(+children)

Lungcarcinomasofmediumsizeunsuitableforsurgery

Prostateadenocarcinomaslocallyaggressive

HeadandNecklocallyadvancedsquamouscellcarcinoma

Highgradegliomas(+children)

Gastro-intestinal tumours highly radioresistant or anatomically difficult (somepancreatictumours,pelvictumours….)

Skullbasemeningiomas,unresectable

etc.

Total:>500/ycasesfor10millioninhabitants

For the carbon ion cases listed in Table 1.2 the approach is essentially based on theidentification of tumours anatomically either difficult to treat with X-ray and/orradioresistant.

Concerningproton therapy, the scopeof the application is lesswell definedbecause itdependson three things: the levelofqualityof thecompetingX-rayoffer (for tumourswith difficult anatomical localization), the existence or not of an offer of light iontreatments,whichisalsocompeting(forradioresistanttumours)andfinallytheeconomicresources that can be allocated to a therapeutic optimization, which fundamentally isproton therapy. Taking theseparameters into account, thedemand forproton therapycanrange fromone- to threeoreven four-foldcomparedto thedemandfor light ions.Thusonecancounton200to800casesoffirstandsecondpriorityprotontherapyfor10millioninhabitantsperyear,takingintoaccountalmostallthechildrentobetreatedforcurativepurposes11.

Asawhole,itcanbeemphasizedthatformostofthecasesitisquestionofraretumours,the recruitmentofwhich, inorder toobtainaparticle-therapydecision,presupposesahealthcaresystemthat isefficientandabletohandleall typesofcancersandtocovertheentirepopulationinanequitablemanner.

11 Institut Curie-Paris, private communication.

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Practicalorganizationoftreatments:logisticsandrecruitment,follow-up

AClinicalNetworkofoncologydepartmentsofhospitals, located insideandoutsidetheRegion,willhavetobeorganizedtocoverthegeographicalareadrainedbytheparticle-therapy centre of SEE. The hub of the Network is better placed in an already wellequipped conventional Radiotherapy Department located in a different country, so toinvolve,evenbeforethebeginningoftheFacility,asmanyCentresaspossible.

This Network should organize the identification of eligible cases, the systematic andtraceablediscussionofthesecasesinacollegialandmultidisciplinarycentralizedtumourboard,ifpossibleintheformofasingleweeklyteleconferencemeetingtoapplythesameselectioncriteriainallparticipatingcentres.Thisworkwillhavetobedonedownstreamofthelocalmultidisciplinarytumourboardmeetingswhichwillhavetheroleofproposinga radiotherapyorientation for theeligible cases.Definitiveeligibilitywill bedevoted tothe special network centralized tumour board. Of course, the Network will be alsoresponsibleofthemulticentreclinicalstudiesdiscussedinthenextSubsection.

All eligible patientswhowill accept the possibility of being treatedby hadron therapy,andpossiblebepartofastudy,willhavetobeseeninfullconsultationwiththeirentiremedical filebyaradiationoncologistspecialized inparticle-therapyeither inoneof theRegional Centres of the Network or in the central Facility. After this consultation, thepatient,whowillgenerallycomefromadistance,shouldbeabletohavethefirsttimeofhis/her care at the Centre, in particular the realization of a personalized positioningdevicefollowedbyanimagingsessioninthetreatmentposition.Thiscantakecantakeadayandthereforejustifiestheneedforahousingcapacitynearby.

Thepatientthenreturnshomeforthetreatmentpreparationperiod,approximatelytwoweeks,thenreturnsandstaysonsiteforthedurationofthetreatment.Thisdurationcanbeveryvariable:fromaweek,foraveryhypo-fractionatedtreatment,upto7or8weeksforcurrentlyfractionatedprotontherapy.Asareminder,thereferencetimeforacarboniontreatmentiscurrently4weeksfor16successivefractions,atarateofonefractionperday,4 to5daysperweek.Protontherapyrequiresmore fractions.Anywaythepatientand,often,arelativehavetobelodgedinahotelnotfarfromtheFacility.

At the end of the treatment, like any oncology patient, patients will have to follow asurveillanceprogram(follow-up)byoneoftheCentresoftheNetworkthatcanlastfrom5to10years,orevenmoreforcertainendpointsrelatedtoverylatetoxicity.Infactitisimpossible,forreasonsofmedicalavailabilityandoftravellingcosts,tocentralizeallthefollow-upactivityintheFacility.Oncologistsorspecialistsinthevicinityofpatientsshouldthereforecarryoutmostofthefollow-up.Neverthelessit isusefulforthedevelopmentofthemedicalexpertiseofradiationoncologistsofthehadrontherapycentretobeabletofollowsomeofthesepatientsforacertaintime.Soitwillhastobefindawaytodoso.It can depend on various criteria: patient’s will, place of residence, possibility ofdisplacement,particularityofthecase,etc.

Since today virtually no hadron therapy is part of an irrefutable standard of care, it isimportant,andevennecessary,foranypatienttoparticipateinonewayoranotherinthescientificevaluationofparticletherapy.

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Multi-centreclinicalresearchandlocalclinicalresearch

ThecurrentdevelopmentofparticletherapyinEuropewithabouttwentyprotontherapycentres and four carbon therapy centres makes possible the establishment of multi-centreprospectiveclinicalstudies.ESTROandENLIGHTworktogethertoachievethis.AllmulticentrestudiesshouldbeabletobeactivatedinthisfuturehadrontherapyCentre.

Itcouldthenbeassumedthattheacceptanceofapatienttobedefinitivelyeligibleforahadrontherapy,paidbyahealthinsurance,shouldbeconditionalonhis/herinclusioninatrialthatwouldcorrespondtohis/hertypeoftumour,or,at least,his/herinclusioninafollow-up cohort. This principle includes, of course, randomized comparative studiescomparing hadron therapy versus X-ray, which create the situation of having nohadrontherapyforhalfoftherecruitedpopulation.

Thisprinciplebeinglaiddown,itmustberecognizedthat,inparticularinpaediatrics,nocomparative clinical studies have been carried out and many indications of protontherapyinpaediatricsareconsideredbymanytobeacceptedstandards.

In adult situations, even for indications considered validated in proton therapy, thequestionofthecomparisonofcarbontherapyversusprotontherapyarises.Asaresult,anyadultshouldbeabletoparticipateinaclinicalresearchprotocol.

In the absence of protocol adapted to the condition of truly eligible patients, patientsshould participate in at least a cohort follow-up protocolwith a long-term prospectivecollectionofmonitoringdata:tumourresponse,toleranceandqualityof life intheverylongterm,secondcancers,etc.Thiscanbedonethroughinternetapplicationsspecificallydevelopedforpatients.Thecollectionofthesedatamust imperativelybecarriedout inallcases.Thisismandatoryinanyprotocolofclinicaltrialandthisshouldbeorganizedinpersonalized or cohort follow-up for all patients who would not be included in aprospectiveclinicaltrial.Sovirtuallyweshouldlearnsomethingfrom100%ofpatients.

Equipmentfortheclinicalprogram

AsstatedinSection1.1,thegoalistotreat500patientsin50%ofthedaytime.Sinceinatreatmentroomworkingfulltimeonecantreat250patients/year,thecompletedFacilitywillfeaturefourtreatmentrooms:

1) oneroomwithahorizontalbeam,2) oneroomwithahorizontalandaverticalbeam,3) aprotongantry,4) alightiongantry.

Todevote50%ofthedaytimetotheclinics,patients’treatmentswillbegin intheearlymorningsandendinthelatemorningorearlyafternoon,andthisfor5daysperweek.

To reduce the initial financial needs it is foreseen to equip initially only the first tworooms and to add in subsequent phases the proton gantry and the ion gantry. Mostprobablythebunkerswillhavetobeconstructedfromthebeginning.

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1.8. RADIOBIOLOGYPROGRAMANDITSEQUIPMENT

Generalframework

Tofullyutilizethebeneficialradiobiologicalpropertiesofionbeams,aconcertedresearcheffortiscalledforprovidingenhancedknowledgeonthetumourresistancemechanismsandonthemethodstoidentifythem,atthetimeofthediagnosis,sotohelpcliniciansintheirdecisionmaking fortreatment. Systematic radiobiologicaldatatogiveguidance tothe biologists and physicists on how to properly apply and improve the potentialcapabilitiesofparticletherapyarealsoneeded.

This need is widely recognized in the community but existing centres do not havesufficient beam timeavailable for the requiredbasic research efforts. Their focus is onclinicaluse,andresearchtimeisoftenlimitedtoafewhoursatatime,notadequateforsystematic researchstudies.Thus the internationalhadrontherapycommunityurgentlyneeds a dedicated centre for radiobiology research and physics research, offeringextendedblocksofbeamtime,withbeamsofavarietyofionsandenergiessuitableformultidisciplinaryclinicallyorientedresearch.TheSEEIISTFacilitywillrespondtothisneedbyprovidingarangeofdifferentionspecies(fromprotonstoargonions)forsystematicradiobiologyexperimentstobettercharacterizetheRelativeBiologicalEffectiveness(RBE)and its complex dependencies, allowing also improvements of the biophysical modelsthat are required to implement these dependencies in the treatment planningprocedures.

Invitroandinvivoradiobiology:openproblems

TheradiobiologicalbackgroundforhadrontherapyhasbeendescribedinSection1.2-1.4.Whilethephysicalpropertiesoftheseradiationshavebeentheaimofintenseresearch,less focus has been put on the actual biological responses to cell irradiation. Theradiobiological response to hadron radiations is on many levels different from that ofphoton radiation12. Data for determining clinical relevant RBE values are of greatimportance, but it should also be emphasized that the biological effects of particleradiationisnotforallendpointsaquestionofadoseeffectthatcanbecorrectedwithaRBEfactor,but isratherseenasadifferentbiology13.Tofullyexploittheadvantagesofparticle therapy, there is a range of unresolved radiobiological questions thatmust beanswered,andthereisaneedformoreexperimental invitroand invivoradiobiologicaldatatosupportandelaborateontheexistingknowledge.

As the time frame for theproposedproject isnotyetdefined, it isdifficult toenvisagewhich research topics will be of highest interest at the time when the beams will beavailable in the experimental halls. At present it is sufficient to list some of themostimportanttopicswhicharecurrentlyunderinvestigation,demonstratingthatresearchinthisfieldisstillofutmostimportancedespitethefactthatclinicalfacilitiesarealreadyinoperation:• AnincreasedprotonRBEattheendoftheparticlerangeisclearlyvisibleinin-vitro

studies, but in clinical settings this seems to play a less pronounced role.

12 DuranteM,Newchallengesinhigh-energyparticleradiobiology,Br.J.Radiol.2014;87:20130626.13 Durante M, Orecchia R, Loeffler JS, Charged-particle therapy in cancer: clinical uses and futureperspectives,Nat.Rev.Clin.Oncol.2017;14:483–495.

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Therefore, the debate is still on going, whether the increased RBE at the distaledgeofatreatmentfieldneedstobeconsideredintreatmentplanningforprotontherapy.Toclosethegapbetweenin-vitroandclinicalstudies,in-vivostudiesareindispensableforabetterunderstandingoftheabove-mentioneddiscrepancies.

• Due to thebetter conformationof thedose,partial volumeeffectsmightplayamoreimportantroleinionbeamtherapy;astypicallysmallvolumesareinvolved,thesemightcounteractthelocallyincreasedeffectiveness.Thisinterplaybetweenpartial volume and RBE effects also requires in-vivo studies, as partial volumeeffectscannotbemimickedbyin-vitrosystems.

• There is increasing evidence that radiation treatment in combination with astimulationoftheimmunesystemmightfurtherincreasetheeffectivenessofthetreatment. Also modulation of the repair capacity in combination withradiotherapy might be beneficial. Systematic studies on all such types ofcombinationtreatmentsarerequired.

• Stemcellsareattheoriginofnormaltissueregenerationandalsorepresentthemajor players for the regrowth of tumours after radiotherapy. A betterunderstanding of the peculiar properties of stem cells with respect toradiosensitivity, repair and regeneration capacity is of high importance for theimprovementofanyradiationtreatmentmodality.

• Drugs,nanoparticlesandotheragentscanmodifytheradiationresponseandthusthebio-effectivenessofradiotherapy.Therearemanyopenavenuessinceonlyasmallfractionofthepossiblechoiceshasbeenexperimentallystudied.

• Cell migration represents one of the key processes leading to metastases. Theproblems tobe tackledare:how far radiationcaneitherenhanceor reduce theability of cells tomigrate and affect the occurrence ofmetastases andwhetherthere are differences in that respect between sparsely and densely ionizingradiations.

• Treatmentplanningforionbeamtherapyrequirestheuseofbiophysicalmodels.Althoughalotofexperimentaldataisalreadyavailable,discriminationofdifferentmodels should be optimized using experimental conditions that are particularlysensitivetomodeldifferencesandthusfrequentlyrequireadditionalexperimentaldata.

• Asconformityof the treatment ismuchbetterwith ionbeam irradiation,at thesametimereducingthevolumeand/ordosetothenormalsurroundingtissueandthusnormal tissue complications, other factors like theprobabilityof secondarycancer inductionwill become an important factor for the choice of the optimaltreatmentmodality.

Systematicstudiesonall levels from in-vitrocell transformationuptosecondarycancerinduction in animal models are thus desirable to better characterize the essentialdifferencesbetweenconventionalandionbeamtreatments.

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Taking into account also other research directions like radiation protection or morefundamental studies to elucidate the mechanisms of radiation action, a plethora offurthertopicscanbeenvisagedwhichwouldfitintoaresearchprogramofsuchafacility.

Referenceradiationsource

ForRBEstudiestherewillbeaneedforareferenceradiationsource.Traditionally,60Cohasbeenusedasreference,butmostfacilitieshaveout-phased60Coirradiation,andmostradiobiological studies are now using X-rays as reference. For X-irradiation of smallanimalstherearespecificadvancedX-rayunitsavailable,asaPXIcabinetX-Rayirradiator(220-250kV). However, it has to be kept in mind that using orthovoltage X-ray asreference radiation, rather than the more clinical relevant megavoltage, is alreadyintroducingaslightlydifferentialbiologicaleffect.

Equipmentfortheradiobiologyprogram:low-energyline

In vivo biological experiments at the low energy beam line require energies of 7-10MeV/u,dependingontheionspecies.Thisminimumenergyisdefinedbytheenergylossin the exit window (thin, about 20 micron hostaphan/kapton), the thickness of theionizationchamberrequiredfordosimetryandsmallairgapsthataretechnicallyrequiredtoallowirradiationofstandardcellculturevesselslikee.g.Petridishes.Thesamplesareplacedinmagazinesaapproximately20samplesbelowthebeamlineandaretakenbyavacuumgrabtomoveitinthebeamforirradiation(seeFigure1.20and1.21).

Figura1.20–Schematicviewofthelowenergybeamlinesamplechanger,asitisusedattheUNILACbeamlineatGSI,Darmstadt.

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No scanning system is required here, as radiobiological experiments at low energiestypically usebroadbeam irradiationwith no specific requirements concerning complexfield geometries. The typical field sizes can be kept comparably small (about 5cmdiameter).Wideningof thebeambyusing ionbeamoptical elements likequadrupoleswillbesufficient;thishelpstokeepthecostforthisadditionalbeamlinetoaminimum.

Dosimetryisperformedusingathinionizationchamber,whichiscalibratedbymeansofCR39trackdetectorsthatareirradiatedexactlyatthepositionofthebiologicalsamples.Homogeneitycheckscanbevisuallyqualitativelyperformedusinga scintillationscreen.By analysing the spatial distribution of particle tracks on the CR39 detectors one canobtainaquantitativevalidation.

Samples are irradiatedon air, i.e. themedium flowsoutof thePetri dishes as soonasthey are lifted from themagazine to the irradiation position.Only a very thinmediumlayerremains,coveringthecellsandpreventingcellsfromdryingforseveralminutes.

Acontrolsystemcanberealizedusingoff-the-shelf industrialcomponentsandsoftwaredevelopmentenvironmentslikee.g.LabView,etc.

AnexampleforthelayoutofsuchanirradiationfacilityisshowninthepictureofFigure1.21. As the setup is contained in a closed box (this is required for biological safetyreasons), it can be easily removed and replaced by other devices like e.g. onlinemicroscope,setupformaterialsresearchetc.

Figure 1.21–Photographof thenew sample changer setup, as it is use