AFacilityforTumourHadronTherapy

andBiomedicalResearchinSouth-EasternEuropeintheframeworkofSEEIIST

(SouthEastEuropeInternationalInstituteforSustainableTechnologies)

U.Amaldia,J.Balossob,M.Dosanjhc,J.Overgaardd,S.Rossie,M.ScholzfandB.SingersSørenseng

UgoAmaldiEditor

a TERA Foundation, Novara, Italy b Department of Radiotherapy and ARCHADE, François Baclesse Center, Caen, France c CERN, Geneva, Switzerland d Department of Experimental Clinical Oncology, Aarhus, Denmark e CNAO Foundation, Pavia, Italy f GSI, Darmstadt, Germany g Department of Experimental Clinical Oncology, Aarhus, Denmark

THISDOCUMENTHASBEENPRODUCEDUNDERTHEAUSPICESOFTHEMINISTRYOFSCIENCE,MONTENEGRO

(*)ReferencestoKosovointhisdocumentshallbeunderstoodinthecontextoftheUNSecurityCouncilresolution1244(1999).

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EXECUTIVESUMMARYIn 2016 at a Workshop 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 convincingthem to participate in its launching. Given the positive reactions, in Spring 2017 Iwasasked to organize and chair an Editorial Committee aiming at the preparation of theconceptual design report of a “Facility for Tumour Hadron Therapy and BiomedicalResearch”(HTR).Dr.DieterEinfeldwasputinchargeofthesametaskinconnectionwitha“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”.Followingthis,anIntergovernmentalSteeringCommitteewascreated,andSanjaDamjanovicwaselectedasthechairperson.InthisframeworkonJanuary25-26aForumon“NewInternationalResearchFacilitiesforSouthEastEurope”wasorganizedatICTP(Trieste),whereafirstdocumentpreparedbythetwoEditorialCommitteesandentitled“Basic Concepts for the South East Europe International Institute for SustainableTechnologies”was distributed, presented anddiscussed. The Forumwaswell attendedandthediscussionswerelivelyandproductive.

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

Meanwhile the two Editorial Committees have continued producing more detaileddocuments. This Report describes the conceptual design of the Hadron Therapy andResearchFacility. Ihopethatthiswillbeuseful,asastartingpoint,fortheexpertswhowill be put in charge, for the next two to three years, of writing the Technical DesignReportthatwillcoveralltechnical,scientific,financialandlegalaspectsoftheInitiative.

IthasbeenwiselydecidedbytheSteeringCommitteethatthesiteoftheFacilitywillbechosenat a later stageof theproject.Here Iwant to emphasise thatother importantdecisionswillhavetobetakenatthesametimebecausetwoNetworkswillhavetobeorganizedandtheirhubsarebetterplacedelsewheresoasto involveintheInitiativemore Institutions,belongingtodifferentcountrieshenceenhancingandenlargingthecollaborationintheregion.

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TheNetworksareessentialforthesuccessoftheInitiative.IndeedTheClinicalNetworkwill allow the radiationoncologists and relatedexpertsof theRegion towork togetherwith the oncologists of the Facility and of European and non-European hospitals indeveloping new protocols and participating in multicentre prospective comparativeclinicaltrials.TheScientificNetworkofUniversities,ResearchCentresandHospitalswillconnect all the groups either currently carrying out or planning experiments in theexperimentalhallsoftheFacility.

***

InWesternEuropeabout50%ofalltumourpatients,correspondingeveryyeartoabout2500patientspermillioninhabitants),areirradiatedwithcurativeintentwithionisingradiationsasX-raybeamsproducedbymedical linearacceleratorsmarketedworldwidebyseveral internationalcompanies.X-raybeams,whicharemadeof fewMeVphotons,areproducedwhenelectrons,acceleratedtoabout10millionelectronvolts(10MeV)byalinear accelerator, bombard aheavymetal target. X-rayshave theproperty to traversethe body, thus, many cross-firing X-ray beams are necessary to deposit much largerradiation “doses” in the tumour target than in the surrounding healthy tissues topreferentiallykill thecancerouscellsandsimultaneously minimisingthedamagetothesurroundingtissues.

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%-60%ofthespeedoflight.Thereasonisthatabeamofelectricallychargedionsproducesa“Braggpeak”ofhighdosejustbeforestoppinginthetissuesatitstargetdepth. Downstream (upstream) of the Bragg peak no (little) dose is deposited so thatprotons and carbon ions can deliver higher doses to the tumour, sparingmuch betterthanX-raysnormaltissueslocatedinfrontandbehindit.

ThesensitivetargetofradiationtherapyistheDNAofthetraversedcells.Thedistancebetween two successive ionizations – i.e. between the events in which an atom or amoleculelosesoneelectron–determinethebiologicalandclinicaleffects.Theradiationis“sparsely”(“densely”)ionizingifthisdistanceislarger(smaller)thanthe2-nanometerdiameteroftheDNAmolecule.

ProtonshavepracticallythesamebiologicalandclinicaleffectsasX-raysbecausetheyare both sparsely ionizing radiations. But, since the dose of protons is much moreconcentrated inthetumour, for thesameprobabilityofcuretheycause lesssecondaryeffects in theclose-by“organsat risk” thatcannotsustainsignificant dosesbecauseofunacceptable consequences for the patient’s quality of life. In particular it is generallyacceptedthatchildrenshouldbetreatedwithprotonsinsteadofX-rays.

Carbonions–whicharecarbonatomsdeprivedoftheirsixelectrons–areadifferenttypeofradiationbecauseinatraverseddoublehelixacarbonionproducestwentytimesmore ionizations than a proton reaching the same depth in the patient body. Whenenteringthetissuescarbonionsbehaveassparselyionizingradiations,i.e.asX-raysandprotons,but,byslowingdown, in the last3-4centimetresof theirpath in thepatient’sbody, they become “densely ionizing” and produce multiple clustered DNA damages,whichcannotberepairedbytheusualmechanismsthatprotectallcells.Thus,thecarbondoseisnotonlymoreconcentratedinthetumourbutisalsomuchmoreeffectivethan

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X-raysandprotons in controlling“radioresistant” tumours,whichare3-5%ofall solidtumours.

X-rays are produced by electron linear accelerators – also called “linacs” – that are 1-metrelongcoppertubeshavingadiameterofabout10centimetres.Ifprotonandcarbonionscouldbesoeasilyaccelerated,X-rayswouldhaveaminorpartinradiationtherapy.However, a therapyaccelerator forprotonand ion therapy ismuch larger, complex, asshowninFigure1,andcostlierthanalinacforX-rays.

Figure1–LayoutofHITCentreinHeidelberg.

TheconfigurationsofalltherunningprotonandcarbonionssynchrotronsareverysimilartotheoneshowninFigure1.

Accordingly, the schematic drawing of the SEE Facility of Figure 2 is based on thesynchrotron designed at CERN in the 90s by a CERN-TERA-MedAustron collaboration.TwocentresderivedfromthisdesignareatpresenttreatingpatientsinPavia(CNAO)andin Wiener Neustadt (MedAustron). This design has been used to estimate theconstructionandrunningcostsoftheFacility.

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

Afteraninitialstart-upperiod,theproposedFacilitywill

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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. researchwork, for the remaining fractionof theday time–plusnightsandweekends,on

1. in vitro radiobiologyexperiments, tobetterunderstand the fundamentalmechanismsofradiosensitivityandradioresistance,

2. animalstudiesforinvivodeterminationoftheefficacyofcarbonandotherions in the treatment of human radioresistant and radiosensitivetumours,andnormaltissues’effects,

3. medical physics measurements and development of novel radiationdetectorsandoptimizedtreatmentplanningsystems.

WiththeaboveprogramstheFacilitywillbeuniqueintheworldbecauseoftheampletimedevotedtopre-clinical,radiobiologicalandmedicalphysicsresearch.Infact,mostoftheotherfacilitiesconcentrateonpatienttreatmentandthetimeleftfortheresearchprogramsisinsufficient.

AsfarasprogramAisconcerned,tumourseligibleforhadrontherapyaccountforabout10%ofall radiotherapypatients,1%ofwhichare intheveryfirst levelofpriority.Thiscorrespondstoabout280tumoursperyear(80forprotonsand200forcarbonions)forapopulationoftenmillionpeople,sothattheFacilityofFigure2,irradiatingabout500patientsper year,will offer a stateof theart treatment foroftenhopeless tumours toabout two thirds of the regional population. Recruiting them will be one of the mainchallengesofthisinitiative.

Forprotonsthemaintargetswillbesolidtumoursinchildren.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,theaimisagain in cure rateand survival, formainly radioresistant tumours, fromabout50%,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.

Theconstructionofthetreatmentroomsandtheexperimentalhallswillbestagedsothat a lower initial investment will allow from the beginning significant clinical andresearchactivities.Accordingtoapossiblescenario,initiallytheresearchprogramswillbe

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carriedoutinthefirstexperimentalhall(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,afterafewyearsoftreatingpatients,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,whichwillbelocatedindifferentInstitutions.

Afteran initialperiod, the twoNetworksdescribedwillbeused to recruit the teacherswho will train the new experts, comingmainly from SEE, in numbers that exceed theneedsoftheFacility,sothatotherHospitalsandInstitutionswilleventuallyemploythem,thusraisingboththescientificlevelandthequalityoftheworkdoneintheRegion.

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

UgoAmaldi

Geneva,30thJuly2018

TheauthorsoftheReportgratefullyacknowledgethecontributionofA.Celebic(ClinicofOncology and Radiotherapy, Podgorica, Montenegro) who produced Appendix C“RadiotherapyDepartmentintheSEEcountries”.

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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...............................................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..........................................................................................53

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,GOALSANDPROGRAMS

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1. MOTIVATIONS,GOALSANDPROGRAMS

PART1

MOTIVATIONS,GOALSANDPROGRAMS

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1.1. MOTIVATIONSANDGOALSOFTHESOUTH-EASTEUROPECENTREFORHADRON

THERAPYANDBIOMEDICALRESEARCHHadron 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 not very different to the ones of X-rays, thestandard modality with which more than 5 million people are treated every yearworldwide.Protons,howeverdelivertheirenergyalmostexclusivelytothetumourtargetthussparingthesurroundinghealthytissuesandreducingthenegativesecondaryeffects,aswellasthelong-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• carbon ionsmay not be an optimal choice for all types of tumours and that the

explorationofotherpossibilities (e.g. lighter ions suchas asheliumorheavier asoxygenions)requireslong-rangeplanningandyearsofstudy;

• any clinical research program has to be based on solid data and models, inparticular on the accurate simulation of the radiation field (in silico) and onexperimentsperformedwithcellcultures(invitro)andwithanimals(invivo).

Veryfewtwo-armstudieshavebeencompletedtocomparetheclinicalresultsofX-rays,hadron beams and other modalities (Appendix B). This is due both to the way thesemodalitieshavebeenhistoricallyimplementedand,morerecently,tothelackoffacilitiesreallydevotedtoexperimentalandclinicalresearches.

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

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

(iii) to contribute to the establishment and implementation of new techniques andmethodsintheclinicalandscientificfieldslistedunderA.andB.

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

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Medical imaging instrumentation, i.e. CT, PET and MRI, will be needed in the facility,whichwillnothavepatientbeds.However,theCentrewillbebuiltclosetoahospitalthatwill provide beds, in the rare cases in which they are needed, and of course generalmedicalcare.Ifpossible,theavailabilityofaRadiationOncologyDepartmentwithlinacsfor X-ray therapy and the correspondingmedical imaging tools, in that nearbyhospitalwouldbeveryuseful.ThiswillreducethevarietyofdiagnosticinstrumentstobeinstalledintheFacility.(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;theradiationdoseismeasuredin“grays”:1Gy=1 joule /1kg.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”.

Immediatelyafterwardstheexcitedmoleculesgobacktotheirnormalstatesothatthemainresultofaradiationbeamcrossingapieceofmatteristhedepositionofenergyinthe form of ionizations of its atoms andmolecules. The local radiation “dose” can beconvenientlythoughtastheenergyleftbythebeam,intheformofionizations,inaunitmassof tissue.About70%of thisenergy isabsorbedbywatermoleculesandproducesReactive Oxygen Species (ROS), i.e. simple molecules containing oxygen, which arechemicallyveryaggressiveandareusuallycalled“freeradicals”or“oxidants”.BydiffusinginthecelltheseradicalscanarriveontheDNAmoleculeandbreakiteitherononestrand(single strand break, SSB) or on both strands (double strand break, DSB) producing,sometimes,clustereddamages.BecauseofitsimportancetheDNAmoleculeisprotectedbyanelaborate repair systemthat restoreswithhighfidelity theSSBsandmostof theDSBs.Theunrepairedbreakscancausethedeathofthecell;onaverageonlyoneoutofabout50DSBsis lethaltothecell.These indirecteffectsoftheX-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 organsthatcannotbeirradiatedwithoutcompromisingthepatient‘squalityoflife.

About70%ofthedepositedenergyproduces indirecteffectsmediatedbyfreeradicals.For the other approximate 30%direct effects are atwork: one of the electrons, put inmotion by the X-ray photons, crosses the double helix and, by ejecting electrons,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 documented for bothnormalandcanceroustissuesthankstomorethan100yearsofstudies1.

1Recentlyneweffectsof theautoimmunesystemandcharacteristicsof thecancer stemcellshavebeendiscoveredanditisnotexcludedthatthesenewunderstandingswillbringbeneficestofuturepatients.

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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(leftfigure).Inthecaseof4proton(orcarbonions)beamsthesituationismuchmorefavorable(rightfigure).

With these techniques of cross-firing, called Intensity Modulated Radiation Therapy(IMRT), a very “conformal” X-ray treatment can be given at the expense of a greaterintegraldose,whichisunavoidablydepositedinthenormaltissuessurroundingthetargetbecause,asshown inFigure1.2, theX-raysdose isdistributedallalong thepath in thepatientbody.

In a typical treatmentwithX-rays a total doseof 60-70 grays is deposited in a tumourtarget in25-35daily fractionsover5-7weekssotogivetimeforunavoidably irradiatedhealthycellsandtissues torepair theradiationdamage. Interestingly, this fractionation

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principlemakespossiblesomere-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 (carbon ion) is 2000 (24,000) times heavier than an electron and has to beacceleratedtoabout200MeV(5000MeV), insteadof10MeV,totreata30-centimetredeep tumour. Instead of linear accelerators, circular ones are needed – called“cyclotrons” and “synchrotrons” – in which bunches of particles are bent by powerfulmagnetsonacircularpathandateveryturngetasmallenergyincrease.

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,hadtreated4700patientswithcarbonions.

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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 in a tumour target, of any shape and location in the body, sparing normalhealthy tissuesmuchbetter thanX-rays.This isdue to the fact that inmatter,hadronsmovepracticallyinstraightlinessothattheBraggpeaksofFigure1.2givesorigintothe“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)duetothefragmentationofafractionofthecarbonionsintosmallernucleiendingtheircoursealittlefurtherthantheBraggpeak.

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, there isanon-goingdebate inhowfarasubstantially increasedeffectivenessthatisalsoobserved in-vitroatlowerprotonenergiesisofclinicalrelevance,asitmightshowupat thedistaledgeof the treatment field.Systematicexperimental in-vivodataarelackinghere,whichcouldhelptoclarifyboththeprotoneffectsinthelastmillimetresof their range in biological tissues and the clinical consequences of the nuclearinteractionsofprotonsandotherions2.

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 carbonpencilbeam 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”withasizeintheorderof1mm)andthecellnuclearsize(about10mm)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)andthespeedb=v/coftheprojectile:

LET=constZ2eff/(Ab2) (1.2)

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

1. the riseof theenergydepositionwithdepthasaconsequenceof thedecreasingenergy,andthusspeedb,and

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

Point1.canbemademoreexplicitbywritingEq.(1.2)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/nmleavesonaverageinthe2nmdoublehelix60eV,andabout30eVareneededtoproduceoneionization.ForLETlargerthanabout30eV/nmtheionizationsaresoclosealong the ion track (with d less than 1 nm, on average) that one speaks of “denselyionizing”radiation.Thiscorrespondstoafewionizationspernm,whichisoftheorderofmagnitudetoinduce,byindependentionizations,eitheraDSBoramoresevereclustereddamage.

Duetothefrequentejection(duetostatisticalfluctuations)ofmorethanoneelectronathigh LET when crossing the DNA molecule, severe DNA lesions called “clustered not-reparabledamages”areproduced.Thesedamageshinderthecellcycle,stopthetumourgrowth,andalsomayinducethecellinternalprogramforitsowndestruction(apoptosis)yieldingafasttumourregression.

Mostcellsandtissuesshowthisgeneralbehaviour,butfordifferentcellsandendpoints,the exact shape and position of the LET-dependence of RBEmay vary, as discussed inSection1.4.

Ingeneralonecanstate

1≤RBE≤5forcarbonions, (1.4)

Although the rangeofRBEvalues isvery similar forprotons, theyexhibit the increasedeffectivenessonlyat theverydistalendoftheirpenetrationdepth,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 the Double Strand Breaks that induce the cell death when they are notrepaired.

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 repairmechanisms are not effective, when using carbon ion beams it is possible to cut thenumber of sessions from 25-30 to 10-15 thus reducing the stress to the patients andloweringthetreatmentcost.

RBE-weighteddose

Intreatingpatientswithcarbonandotherlightionstheknowledgeoftheradiobiologicaleffectiveness,toapplytobothtumourandnormaltissues,iscrucialbecausetheradiationfieldmustbequantifiedbygivingthe“RBE-weighted”dose

DRBE=RBExD, (1.6)

which is reportedasGyRBE)and isobtainedbymultiplying thephysicaldoseDby theRBEvalueofthatparticulartissue.

Although conceptually simple, Eq. (1.6) needs tobe appliedwith caution in the clinicalenvironment because RBE of a tissue is not just characterized by a single value, butdependsonseveralfactors,firstofalltheLETandtheconsideredeffectlevel.Thus,RBEvarieswithintheirradiatedvolume,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.(1.6)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 systematic animal studies andaccumulatedhumantreatmentdatacanprovidetheinformationneededforplanningtheirradiationofhumanpatients.

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

Inatreatmentplanningsoftwaretheincreasedradiobiologicaleffectivenessisintegratedinamodelthatdescribestheradiosensitivityofnormalandcanceroustissues.Themostused one in Europe is the Local Effect Model (LEM) developed at GSI, the researchLaboratoryclosetoDarmstadt5.Thismodel isbasedonthecompletethree-dimensionaldistributionof the ionizationsanddamagesaround the trackand theknowledgeaboutthephotondoseresponsecurvefortheendpointofinterest;itallowsthedescriptionsofbiologicaleffectsin-vitroandin-vivo.

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

Ingeneral,themajordeterminantsthatneedtobeconsideredare:1. theenhancementofRBE,particularlypronounced in theBraggpeak, andwhichvarieswiththeresidualrangeoftheparticle;2. thedecreaseof ions’RBEwith increasingdosepersession (Figure1.6); thus thesubdivisionofthetotaldose infractions isan importantparameterthataffectstheRBE;3. thehigherRBEofionsforcellsthatmanifestahigherrepaircapacityandthusareresistant to photon radiation as compared to cells showing a higher sensitivity tophotonradiation;4. thebiologicaleffectsof ions, lesssensitivetooxygenconcentrationascomparedtoconventionalradiation.

The relevanceof these factorshasbeenclearlydemonstrated innumerous in-vitroandin-vivoexperimentalapproachesbutmanyexperimentshavestill tobeperformedbothforcellmonolayersin-vitroorsmallanimalsinvivo.TheCentredescribedinthepresentReportwillgreatlycontributetothisprogramsincethepresentlyrunningfacilitiesarenotsufficient.

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

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1.4. THERAPYWITHOTHERIONS

RBEversusLETforvariousionspecies

TheCentrewill featureseveral ionsourcesandnumerous invitro– invivoexperimentsand 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, suchasneon,however,at thedistaledge saturationeffects dominate, whereas the RBE is already substantially elevated upstream of theproximaledge, i.e. in thenormal tissue. Thishasbeen,unfortunately,demonstrated inthe80”sattheBevalacoftheLawrenceRadiationLaboratory,wheremanypatientsweretreated with neon ions with unexpected side effects, since – even for deep-seatedtumours–thepatientswereirradiatedwithdenselyionizingradiationwithelevatedRBEallalongtheparticlerange.

Essentially forthisreason,whileattheendof80”sthepreferred ionwasoxygen-16, in1994 atNIRSHirohito Tsujii andhis collaborators, concernedby thepossible effects ofoxygen ions on normal tissues, initiated the irradiations with carbon ions. Apart fromsome400patientstreatedinBerkeleywithheliumandothersmalltrials,tilltodaycarbonions are the preferred choice, but it is certainly not necessarily optimal for allradioresistanttumours.

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 thecorresponding tumour region andwith that also the expected RBE, and in these casesevenheavier ions than carbon, as for exampleoxygen ionbeams,mayhave additionalbenefits,astheyshowamorereducedsensitivitytohypoxia.

Itisobviousfromthisdiscussionthatalargenumberofwellplannedandcomplementaryinvitroand invivostudieshavetobeperformedtoclarifyanddefinewhichion(s)havethelargestcontrolprobabilityforwhichtypesoftumourwithminimalsideeffects.Giventheample timededicated toexperimental studies, the SEE Facilityhas thepotential ofgreatly contributing to this ambitious program, which will last decades 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 treated440patientswithcarbon ions 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(notrepresented).

Figure1.11–TheMedAustronsynchrotronfeeds1protontreatmentroomwithrotatinggantry,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 therapy 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)Numerous superimposed Bragg peaks at progressively reduced depth give a uniform dose to atumourof10cmlength.

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 deposit 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.

Figure1.13–Placementoftheelementsofactivedeliverysystemandbeammonitorswithrespecttothepatienttreatmenttable.

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 lowerweightsandmuch lowerpower. Sincea fewyearspatientsare treatedat theCHIBAcentreofNIRSwiththesuperconductinggantryofFigure1.15.

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.

Figure1.16–ThefutureJapanese“compact”superconductingcarboniongantryiscomparedwiththegantrythatispresentlytreatingpatientsatCHIBA:

Beammonitoringandmovingorgans

Thebeammonitoringsystemconsistsofasetofpositionsensitivedetectorsandbeamintensity detectors. In the existing facilities, beam position is measured using eithermultiwire proportional chambers (MWPC) or multistrip ionization chambers, having asub-millimetre spatial resolutionof thepositionofapencilbeam.Asa consequenceofthehighscanningspeedandinordertoallowformultiplemeasurementsperbeamspot,ahighrepetitionrateofabout10kHzforthesepositionmeasurements isrequired.Forbeamintensitymeasurementsionizationchambersareused,alsowithacorrespondinglyhigh repetition rate. Two independent detectors for position and intensitymeasurements,respectively,areusedtoachieveredundancy,which isrequired,aspartof the safety system: only when both detectors give consistent results, the irradiationcontinues,otherwisethetreatmentisinterrupted.

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The treatmentofmoving tumours,e.g. liveror lung tumours, isparticularly challengingwith active beam delivery systems, as the combination of beammovement and targetmovementcanleadtoundesiredinterferencepatternsandconsequentlytodistortionsofthedosedistribution.Thedevelopmentofadequatemotionmitigation techniques is inthefocusofintensiveresearchanddevelopmentactivities,anddifferentconceptssuchasgating, rescanningandtumourtrackingarebeingdiscussed.Althoughtracking,which isthe following of the target movements by appropriate continuous adjustments of thebeamdeflection (with thescanningmagnets)andof thebeamenergy, seems themostelegantway,theparticularchallengehere is theaccuratedetectionoftheactualtargetposition. Therefore, gating (i.e. the treatment only duringwell definedmotion phases)and re-scanning (i.e.multiple irradiationswith consequentialwash-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. Range calculations are based on CT-images information that allows takinginto account 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,whicharealsoemittedinthesenuclearreactions,hasbeendiscussedformanyyearsasapotentialalternative;thefirstclinicalinstrumentsarenowenteringtheclinic.9

1.6. PATIENTSTREATEDWITHPROTONSANDCARBONIONBEAMSOverthelasttwodecades,particlebeamcancertherapyhasgainedahugemomentum.Manynewcentreshavebeenbuilt,andmanymoreareunderconstruction(Figure1.17).Attheendof2016therewereworldwide67centresinoperationandanother63areinconstruction or in the planning stage. Most of these are proton centres, 25 in USA(protonsonly), 19 in Europe (ofwhich3 aredual centres), 15 in Japan (ofwhich4 arecarbonand1dual)and2(1carbonand1dual)inChina,4(protonsonly)inotherpartsof

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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theworld.Thedetailedcharacteristicsofthe10carbon(andsometimesproton)facilitiesaregiveninAppendixA.

Figure 1.17 – Hadron therapy facilities in operation worldwide, under construction and in theplanningstageattheendof2016.(www.ptcog.com)

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

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

Figure1.18–Europeanhadrontherapyfacilitiesinoperationorunderconstructionin2016.

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AsshowninFigure1.19,thenumberoftreatedpatientsgrowthisalmostexponential.Attheendof2007thenumberofpatientswere61.855,ofwhich53.818withprotonsand4.450withcarbonions.Attheendof2016thenumberhadgrownto168.000(145.000withprotons,23,000withcarbonions).Thisisdueprimarilytothegreateravailabilityofcentres,althoughtillrecentlyveryfewrandomizedstudieshadbeeninitiatedtocomparetheresultsofhadrontherapywithconventionalX-raytherapy.Fortunately,thesituationischanging,asshown inAppendixBwheretheon-goingphasethreestudiesare listed,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; - IGRT3Drepositioninginthetreatmentrooms;- 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 ofmoving tumours in pencil beam

scanningwithrepainting,i.eratesintherange3-10Gy/min(for500mL)sothatatreatment session takes less than 30-45 minutes, including installation andrepositioningofthepatient;

- availability of several particles: protons, helium ions, carbon ions andothers, asdiscussedinSection1.4;

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- proximityofoneor severalhousing facilitieswitha capacityof receptionof thepatientswithlightmedicalcapabilities;

- localsignificantcapabilitiestomanagecontrolledclinicalstudies- 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, Austrian and French carbon therapy projects. Itmade it possible to establish acensusofprioritycasesforthistypeoftherapy10.Infuturetheepidemiologywillhavetobecorrectedfortheagedistributionoftheregionalpopulation(seeAppendixE).

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

Table1.1-Protontherapyandiontherapyindicationsofthehighestpriority.

Typesoftumoureligiblewith

highestpriorityforprotontherapy

Typesoftumoureligiblewith

highestpriorityforiontherapy(carbon)

Adults’skullbasetumours.

Adults’unresectableorrelapsingmeningioma.

Otherrareadults’centralnervoussystemtumours.

Childs’centralnervoussystemtumours.

Anyotherchild’ssolidtumours.

Adenoidcysticcarcinomasofsalivaryglands,includinghead&neckandthorax,sinusadenocarcinomas.

Mucinousmelanomasofheadandneck,chordomasandchondrosarcomasofskullbaseandspine.

Softtissuessarcomasoflowandmediumgrade,unresectableorpartiallyresectablewithoutthreatening

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;Mayer R(1),Mock U, Jäger R, Pötter R, et al. Epidemiological aspects of hadrontherapy: a prospective nationwide study of the Austrian projectMedAustron and the Austrian Society ofRadiooncology (OEGRO). Radiother Oncol. 2004 Dec;73 Suppl 2:S24-8; Krengli M, Orecchia R.Medicalaspects of the National Centre For Oncological Hadrontherapy (CNAO-Centro Nazionale AdroterapiaOncologica)inItaly.RadiotherOncol.2004Dec;73Suppl2:S21-3.

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Theycorrespondtoabout280tumoursperyear(80forprotonsand200forcarbonions)on a population of ten million people, so that the Facility, treating (when completed)about500patientsperyear,willofferacuttingedgestateofthearttreatmentforoftenhopelesstumourstoabouttwothirdsoftheregionalpopulation.Recruitingthemwillbeoneofthemainchallengesofthisinitiative.

InTable1.1forprotontherapythehypothesisisasignificantreductionoftoxicityand,forion therapy, thehypothesis is a gainof 20 to25%of tumourprogression free survival,increasingthesuccessratefrom≈50%to>75%.

ThesecondpriorityindicationsareshowninTable1.2.

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/or areradioresistant.

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, which is also competing (for radioresistant tumours), and, finally, theeconomicresourcesthatcanbeallocatedtoamorecostlytherapeuticmodalityasprotontherapy is. Taking these parameters into account, the demand for proton therapy canrangefromone-tothreeorevenfour-foldcomparedtothedemandforlightions.Thus,one can count on 200 to 800 cases of first and second priority proton therapy for 10millioninhabitantsperyear,takingintoaccountalmostallthechildrentobetreatedforcurativepurpose11.

As a whole, it can be emphasized that for most of the cases it is a question of raretumours, the recruitment of which, in order to obtain a particle-therapy decision,presupposesahealthcaresystemthatisefficientandabletohandlealltypesofcancersandtocovertheentirepopulationinanequitablemanner.

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 wellequippedconventionalRadiotherapyDepartment located inadifferentcountry,soastoinvolve,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 alsoresponsibleforthemulticentreclinicalstudiesdiscussedinthenextsubsection.

All eligible patientswhowill accept the possibility of being treatedby hadron therapy,andpossiblebepartofastudy,willhavetobeseeninfullconsultationwiththeirentiremedical filebyaradiationoncologistspecialized inparticle-therapyeither inoneof theRegionalCentresoftheNetworkorinthecentralFacility.Justafterthisconsultation,thepatient,whowillgenerallycomefromadistance,shouldbeabletohavethefirsttimeofhis/her care at the Centre, in particular the realization of a personalized positioningdevicefollowedbyanimagingsessioninthetreatmentposition.Thiscantakeadayandthereforejustifiestheneedforahousingcapacitynearby.

Thepatientthenreturnshomeforthetreatmentpreparationperiod,approximatelytwoweeks,thencomesandstaysonsiteforthedurationofthetreatment.Thisdurationcanbeveryvariable:fromaweek,foraveryhypo-fractionatedtreatment,upto7or8weeksforcurrentlyfractionatedprotontherapy.Asareminder,thereferencetimeforacarboniontreatmentiscurrently4weeksfor16successivefractions,atarateofonefractionperday,4to5daysperweek.Protontherapyrequiresmorefractions.Anyway,thepatientand,often,arelativehavetobelodgedinahousingnotfarfromtheFacility.

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.Nevertheless,itisusefulforthedevelopmentofthemedicalexpertiseofradiationoncologistsofthehadrontherapycentretobeabletofollowsomeofthesepatientsforacertainlengthoftime.Soitwillbenecessarytofinda way to do so. It can depend on various criteria: patient’s will, place of residence,possibilityofdisplacement,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 studiescomparinghadrontherapyversusX-ray,whichcreatesthesituationofhavingnohadrontherapyforhalfoftherecruitedpopulation.

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.

The collection of these data must imperatively be carried out in all cases. This ismandatoryinanyprotocolofclinicaltrialandthisshouldbeorganizedinpersonalizedorcohortfollow-upforallpatientswhowouldnotbeincludedinaprospectiveclinicaltrial.Sopracticallyoneshouldlearnsomethingfrom100%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 commitment it is foreseen toequip initially only the firsttworoomsandtoaddinsubsequentphasestheprotongantryandtheiongantry.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,notadequateforsystematicresearchstudies.Thus,theinternationalhadrontherapycommunityurgentlyneeds 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,lessfocushasbeenputontheactualbiologicalresponsestocellirradiation.

Theradiobiologicalresponsetohadronradiationsisonmanylevelsdifferentfromthatofphoton 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 toenvisagewhichresearchtopicswillbeofhighestinterestatthetimewhenthebeamswillbecomeavailable in the experimental halls. At present it is sufficient to list some of themostimportanttopicswhicharecurrentlyunderinvestigation,demonstratingthatresearchinthisfieldisstilloftheutmostimportancedespitethefactthatclinicalfacilitiesarealreadyinoperation:

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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• AnincreasedprotonRBEattheendoftheparticlerangeisclearlyvisibleinin-vitrostudies, but in clinical settings this seems to play a less pronounced role.Therefore,thedebateisongoing,whethertheincreasedRBEatthedistaledgeofa treatment field needs to be considered in treatment planning for protontherapy.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.

Systematic studiesatall levels from in-vitro cell transformationup to secondarycancerinduction 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,butmostfacilitieshavephased-out60Coirradiation,andmostradiobiological studies are now using X-rays as a reference. For X-irradiation of smallanimals there are specific advanced X-ray units available, such as a PXI cabinet X-Rayirradiator(220-250kV).However, ithastobekeptinmindthatusingorthovoltageX-rayas reference radiation, rather than the more clinical relevant megavoltage, is alreadyintroducingaslightlydifferentialbiologicaleffect.IndeedorthovoltageX-rayshaveaLETslightlyhigherthantheoneofmegavoltageX-rays.

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 theionizationchamberrequiredfordosimetryandsmallairgapsthataretechnicallyrequiredto allow irradiation of standard cell culture vessels e.g. Petri dishes, flasks etc. Thesamplesareplaced inmagazinesofapproximately20samplesbelowthebeamlineandaretakenbyavacuumgrabtomove it inthebeamfor irradiation(seeFigure1.20and1.21).

Figure1.20–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.

Samplesareirradiatedinair,i.e.themediumflowsoutofthePetridishesassoonastheyare lifted from themagazine to the irradiationposition.Onlya very thinmedium layerremains,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 usedat theUNILACbeamlineatGSI,Darmstadt.

Materialscience

AsmentionedinSection1.1anddetailedinAppendixD,thelow-energybeamcanalsobeusedforexperimentsonmaterials.Themainfieldsofresearchare:

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1. IonBeamAnalysis(IBA),whichincludesaseriesofanalyticaltechniqueswithMeVionsinordertoprobethecomposition,elementaldepthprofile,localchemistryandstructureofsolids.

2. MaterialModification,inwhichMeVionsinducepronouncedmodificationofthestructural,physicalandchemicalpropertiesofagivenmaterial.

3. RadiationHardnessstudies,inwhichIonbeamsareusedfortestingtheradiationhardnessofmaterialsusedfornuclearwastestorageorofelectroniccomponents,inparticularinspaceapplications.

Equipmentfortheradiobiologyprogram:high-energylineandtargethandling

Thebeamdeliveryfortheexperimentalcaveforradiobiologyexperimentsmusthavethesameflexibilityasthepatienttreatmentrooms,i.e.itmustbeequippedwithafullyactive3Drasterscansystemandthecorrespondingmonitorsystem.Theminimumfieldsizeforradiationbiologyexperimentsisabout10x10cm2.

Reducing the redundant system layout, i.e. using only one position sensitive and oneintensity sensitive monitor chamber, could minimize costs. In addition, the interlocksystem could be designed in a simpler way, depending on the type of validationexperimentsthatshouldbeperformedintheexperimentalcave.

To reduce the needed investment, initially one could also envisage performing criticalexperimentsdirectly in thepatient treatmentroomandreservetheexperimental roomonly for less demanding experiments. Attractive solutions could consist of a hybridsystem,combiningofanactivelateral2Dscanningsystemwitharangeshifterthatallowsscanning the beam in depth. This solution requires only a few pre-setmono-energeticbeamstobepreparedfortheexperimentalroom.Aspassivedepthscanningproducesaslightly higher contribution of fragments in the beam, it should be carefully discussedwhichlevelofaccuracyandcomparabilitytothefullyactive3Dbeamdeliveryisrequired.Comparisons between the passive system at HIMAC with the active system at GSI,however,revealedthatdifferencesaremarginalifotherconditions(widthofSOBP,depthofSOBP)areidentical14.

For standard irradiations with comparably small SOBP even simpler solutions can beimplemented, using 3D-ridge filters (see paper by U. Weber et al.), allowing tosubstantiallyreduceirradiationtimesandthusincreasingsamplethroughput.

Applicationofsimplerectangularfieldswithmono-energeticbeamsdoesnotrequiretheuseofacomplextreatmentplanningsystem;thecontrolsystemthusshouldallowusinga“bypass” of the typical patient-like delivery procedures based on a separate simple,robust, and fast software module for this task. For the more patient-like biologicalexperiments, however, the full chain should also be available starting with the plangenerationusinganexperimentallyorientedTPSprocedure.

14UzsawaA.,AndoK,FurusawaY,etal.,BiologicalIntercomparisonusinggutcryptsurvivalsforprotonandcarbon-ionbeams,J.Radiat.Res.2007;48:A75-A80.

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As a consequence of the higher beam energy and more sophisticated beam deliverysystem much higher flexibility is given with respect to sample types and targetgeometries.Mostexperimentscanbeperformedusingstandardcultureflasks (12.5,25or75cm2),butalsoe.g.phantoms, inwhichbiologicalsamplesarespatiallydistributed,can be usedor any othermore complex geometry by exploiting the capabilities of thescanningbeamdeliverysystem.

For standard experiments, a robust sample handling system is needed that allows forhigh-throughput experiments which optimally utilize the available beam time and arethenmostly limitedby the irradiation timeper sample. Simplemovingbeltshavebeenhelpfule.g.at theGSI facilities,whereupto10-15samplescanbeplaced ina rowandirradiatedsequentiallywithouttheneedforaccesstothetreatmentroom(seeFig.1.22).Totaltimesperirradiationsetaregivenbythetoleranceofthebiologicalsamplesagainstcooling down to room temperature and other factors. Also, robotic systems could beused, showing a higher flexibility concerning positioning, but for the price of highercomplexityandprobablylessrobustness.

Positioningofsamplesinthebeamrequireacombinationofremotecontrolledlaserandcamerasystems.Camerasystemsshouldoptimallybemoveabletocoverthefullroom.

Figure1.22–ConveyerbeltsystemusedatGSI.

1.9. ANIMALPROGRAMANDITSEQUIPMENT

Generalframework

AsmentionedinthelastSection,inhadrontherapythereisasurprisinglackofdatafromin vivo experiments, which in other treatment modalities have been regarded as anecessary link between the hypotheses generated by in vitro experiments and patienttreatments.Cellexperimentsgivegoodindicationsofthevariouseffects,butinreality,invivo, there are many biological functions interacting together, which is impossible tomimicinvitro.

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To be able to comply with the issues of a different radiobiology and a varying RBE inhadron therapy, it is crucial to have experimental biological studies to determine theextentandmagnitudeoftheseeffects.Asanecessarynext-step,frominvitrostudies,invivostudiesenablesimulationofclinicaltreatmentsinanimalmodelsandgiveessentialinformationtodeterminetheoptimalradiationmodalitytoprotectnormaltissuesandtooptimizetheanti-tumoureffects.Thepossibilityofdevotingampletimestothesestudies,onvariousinvivomodels,makestheCentreuniqueintheworldlandscape.

Problemstobefaced

At present, one of the crucial points in particle radiobiology is to establish the RBE ofdifferentnormaltissuesinasystematic,large-scaleinvivosetup,usingrelevantparticles.Thisshouldincludesimulationofclinicaltreatmentwithfractionationaswellasdifferentpositionsinthebeam.Relevantnormaltissuemodelsshouldincludefunctionalandtissueendpoints,representingbothearlyandlateradiationinducedreactions.

Figure1.23–Examplesofinvivodataonearlyandlateradiationinducedreactions.Herefromacuteskinreaction(moistdesquamationofirradiatedareasoftheskin)(toppanel)and radiation induced fibrosis, a late reaction of tissue to radiation (lower panel), incarbonionirradiatedmice15.

15 SørensenBS,HorsmanMR,AlsnerJ,etal,Relativebiologicaleffectivenessofcarbonionsfortumourcontrol, acute skin damage and late radiation-induced fibrosis in amousemodel, Acta Oncol. (Madr).2015;54:1623–1630.

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The list is long, however a number of examples can be given with some relevantbibliography:

1) assaysforacuteskinreactions16andradiationinducedfibrosis17(Figure1.23)2) modelsofneurologicaldamageofthespinalcord,centralnervoussystem,

peripheralnerves,opticnerve,etc.183) lunginjury194) urinarybladderfunction205) cartilagetolerance,6) differenttissuetypesandpositionoftheirradiatedorganalongthebeampath

andthespread-outBraggpeak7) cognitiveassays,suchasNovelobjectrecognition(NOR)andnovelobjectlocation

(NOL)218) dosefractionation.

Thenormaltissuestudiesshouldbeaccompaniedby invivostudiesofRBEofapaneloftumours’modelswithdifferent radio sensitivities toenlighten the therapeuticeffectatdifferentLETs.

InadditiontothesecompulsoryRBEstudies,questionaswhatimpacthighLETradiationhasonfactorsascytokineexpression, inflammationandangiogenesishavebeenraised,andsuggestivedatafrombothinvitrostudies222324andclinicalstudies25havesuggestedadifferential effect from photon radiation. However, to elucidate whether these effectscouldpossiblyhaveaclinicaleffect,invivostudiesareneeded.

Asanimalmodelsarenottrivialtosetupinafacility,ananimalstudyprogramcouldbepartlybasedonresearchersfromotherinstitutions,whereanimalsmodelshavealreadybeenimplemented,refinedandoptimized.

16 Horsman MR, Siemann DW, Chaplin DJ, et al.,Nicotinamide as a radiosensitizer in tumours andnormaltissues:theimportanceofdrugdoseandtiming,Radiother.Oncol.1997;45:167–174. 17 StoneHB,Leg contracture inmice: anassayofnormal tissue response. Int.J.Radiat.Oncol.Biol.Phys.1984;10:1053–1061. 18 VanDerKogelAJ,Chroniceffectsofneutronsandchargedparticlesonspinalcord,lung,andrectum,Radiat.Res.1985;104:208–2016. 19 vonderMaaseH,OvergaardJ,VaethM,Effectofcancerchemotherapeuticdrugsonradiation-inducedlungdamageinmice,Radiother.Oncol.1986;5:245–257. 20 LundbeckF,Anexperimentalinvivomodelinmicetoevaluatethechangeinreservoirfunctionoftheurinary bladder due to irradiation alone or combinedwith chemotherapy, Recent results cancer Res.FortschrittederKrebsforsch.ProgrèsdanslesRech.surlecancer.1993;130:89–102. 21 ForbesME,PaitselM,BourlandJD,etal,Early-delayed,radiation-inducedcognitivedeficits inadultratsareheterogeneousandage-dependent,Radiat.Res.2014;182:60–71. 22 GirdhaniS,LamontC,HahnfeldtP,etal,Protonirradiationsuppressesangiogenicgenesandimpairscellinvasionandtumourgrowth,Radiat.Res.2012;178:33–45. 23 GirdhaniS,SachsR,HlatkyL,Biologicaleffectsofprotonradiation:whatweknowanddon’tknow,Radiat.Res.2013;179:257–272. 24 NielsenS,BasslerN,GrzankaL,etal,Differentialgeneexpression inprimaryfibroblasts inducedbyprotonandcobalt-60beamirradiation,ActaOncol.(Madr).2017;56:1406-1412. 25 GridleyDS,BonnetRB,BushDA,etal,Timecourseofserumcytokinesinpatientsreceivingprotonorcombined photon/proton beam radiation for resectable but medically inoperable non-small-cell lungcancer,Int.J.Radiat.Oncol.Biol.Phys.2004;60:759–766.

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Projectscoulduseanimalsthatstaytemporarilyatthefacilityforirradiation,andarethenbroughttothehomeinstitutionsforfollowup,asthiscanbeaverylongprocess;forlatereactions,thetimeforobservingtheanimalscanbeuptoseveralmonthsoryears.

ProgramoftheanimalexperimentsAsdiscussedabove,thevariationofRBEandthepossibleclinical impactthereofwillbeinvestigated inasystematic, large-scalesetupusingapanelofclinically relevant invivomodels.

Toconducttheexperimentsanin-houseanimalfacilitywillbeestablishedforpermanenthousingofsmallrodents.LargeranimalswillbetreatedincollaborationwithanexternalacademicVeterinaryDepartment.

This long-termactivitywill providedata for thedevelopment, in collaborationwith theother European institutions, of biological models and their implementation in humanTreatmentPlanningSystems.Finally,suchahighqualitypreclinicalresearchisnecessarytosecuresolidfoundationsforclinicalresearch.

Equipmentforanimalexperiments

An example of a small-scale, yet complete and self-sufficient, animal facility for smallrodentsisshowninFigure1.24.TheCentrewillfeatureasmallanimalfacilitysimilartotheoneshowninthisfigure.Besidesthis,acleaningroomforwashingequipment,aswellasalaboratorywillbeavailable.

Ithas tobeconsidered that thereare legal requirements for thebuildingspecificationsforananimalfacility,e.g.ofthenoiselevel,onventilationandtemperature.Ithastobeapprovedforhousingofexperimentalanimalsbytheauthorities.AllfacilitiesforhousingandtreatmentofanimalswillcomplywithEUregulation.

For a part-time facility, based on visiting scientist bringing their own equipment, theanimal facility should containoneormoreconditionedcabinets for small rodents (asaScantainer or similar). The animal facility should, as a minimum, be equipped with alaminarflowforanimalhandling.Thereshouldbeaccesstoarangeofgenerallaboratoryequipment,butthiscouldbedoneinconnectionwithapossibleinvitrofacility.

Theanimalfacilityshouldbeincloseproximitytotheexperimentalbeamroomtoavoidtoolongtransportbetweenanimalpreparationandanimaltreatment.Apossibilitywouldbe to place the animal facility in the basement, with direct connection to theexperimentalbeamroom,toavoidpatientareastobeexposedtoallergens.

Largeranimals couldbebrought to the siteonlywhenneeded,and then the follow-upcouldbedoneinanexternalfacility.

Ifasetupwithvisitingscientistwithvisitinganimalsisconsidered,itisnecessarytohaveanisolatedsectionthatcanserveasquarantineroomfortemporaryhousingofanimals,toensurenoriskofcontaminationbetweenvisitingandin-houseanimals.

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Figure1.24–SchematicofthenewlydesignedanimalfacilityforsmallrodentsattheDepartmentofExperimentalClinicalOncology,AarhusUniversityHospital.

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1.10. MEDICALPHYSICSPROGRAMANDITSEQUIPMENT

GeneralframeworkFromthemedicalphysicspointofview,thesuccessofatumourtreatmentdependsbothontheaccuracyofthetreatmentplanandonthequality,precisionandreproducibilityofthe detectors, which control and ensure that the distribution of the delivered dose isequal – within an accuracy of about 2% – to the optimized output of the TreatmentPlanningSystem(TPS).

Withabout25,000patientstreatedworldwidewithcarbonions,eventhoughtheamountof accumulated knowledge is impressive; many areas are still almost uncharted, inparticularsincethemedicalcommunityisnowmovingtowardstheuseofionsdifferentfromcarbon.Many ionspecieswillbeavailableattheCentre,whichwillhaveboththeinstrumentationandthebeamtimetostudythem.

Medicalphysicsprogram

Tofullyexpandthetherapeuticapplicationofparticlebeams,thereisarangeofphysicsquestionstosolve,inclosecollaborationwiththeotherEuropeanandJapanesecentres,soto:

1. measure very accurately the stopping power of living tissues by new imagingmodalitiesasforexample“proton-radiography”(tomography).

2. measurethefragmentationofthedifferent ionspecies, inbiologicalmatter.TheresultswillbeimplementedinMonteCarlo-basedTPSs,toenhancetheaccuracyoftherangecalculationandfragmentationrelateddose.

3. developnewbeammonitorsdetecting,duringandafterthetreatment,andwithmillimetreaccuracy,thepositionwheretheionbeamstopsinthepatientbodytoassess,inrealtime,theaccuracyofthedosedeposition.ThisisatpresentcentredonthedetectioneitherbyPETofisotopesproducedintheinteractionsoftheionswith the body nuclei, or of “prompt gammas”,which are also emitted in thesenuclear reactions secondary to fragmentation, but other techniques are beingdeveloped as proton radiography and ultrasounds emitted by the beamletinteractingwithtissues.

4. to trackmoving organs andprovide a 3D localization in spaceof a tumour thatmovesduringthetreatment.Manytechniquesarebeingdevelopedbutnonearecurrently fully satisfactory; this will be certainly one of the focus of theexperimentalactivity.

Asawhole,manytechnologicalachievementswillcomeoutandbetterdetectorswillbedevelopedandbroughtfromthelaboratorytotheclinicandindustry.

Equipmentforthemedicalphysicsprograms

ThephysicsexperimentswillbeperformedintheFacilityexperimentalhall(s)attheendofdedicatedtransportlines.Atleastoneofthesehorizontallineswillhavethepossibilityoftransversallyscanningthebeamonanareaofatleast15cmx15cm.

In principle it would be possible to share the beam(s) with the in vivo and in vitroprograms,butthepreferredsolution is tohavefromthebeginningdifferentbeam(s) in

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thesameexperimentalhall.Asa laterstage,asecondexperimentalhallwillbebuilt towidenthepotentialitiesoftheFacilityandofitsexperimentalprograms.

Todevelopandqualifysomedetectors,measurementswillhavetobeconductedalsointhe treatment rooms on either phantoms or patients. These experiments will greatlyprofitfromtheveryspecialfeatureofthisFacility,i.e.ofthefactthatonlyabout50%ofthedailydaytimewillbedevotedtopatienttreatments.

1.11. TWOEXTENDEDNETWORKSTo reach the clinical and scientific goals twoNetworkswill have to be set-up from thebeginningoftheprojectandcontinuouslyextended.Itwouldbeconvenienttolocatethehubs of these twoNetwork, aswell as theVeterinaryDepartment for large animals, incountriesthataredifferentfromtheoneinwhichtheFacilitywillbebuilt.Thiswillmakethebestuseofall theexpertise in theRegionand facilitate theapprovalof theoverallproject.

The Clinical Network, discussed in Section 1.7, should be the first one. It will give theopportunity to theHospitalsandOncological Institutesof theRegion towork together,even before the construction of the Facility, and, afterwards, to refer patients to theFacilityand share clinicalprospective investigationsandpatients’ follow-up. Secondly itwillallowtheradiationoncologistsoftheRegionstoworktogetherwiththeirEuropeancolleagues(inparticularatHIT,CNAOandMedaustron)andnon-Europeancolleaguesinmulticentreprospectivecomparativestudiesto improve, theknowledgeboth inhadrontherapyandinclassicalradiationoncologythroughclinicalresearchpractice.

ThisNetworkwill needawidebandwidth connection toexchangemedical recordsandimagessothatallinvolvedexpertswillparticipateinregularteleconferencesgatheringtoreview and discuss patients’ cases for medical decision; this is a powerful tool forprofessional development and training, data sharing and referral to the Facility of thepatientswhoneedhadrontherapytreatment.

The second network is a Scientific Network of Universities, Research Centres andHospitals, which will connect all the groups either doing or planning to performexperiments in the experimental halls of the Facility. Also, in this case the hub of theNetworkshouldbelocatedinanInstituteofadifferentcountrythantheoneinwhichtheFacilitywillbebuiltandthemaincollaboratorswillbeatHIT,CNAOandMedAustron.TheensemblewillworkasoneofthelargeInternationalCollaborationsthatbuildinstrumentsandperformexperimentsattheCERNaccelerators.Indeed,allthescientistsandmedicaldoctorswillhavethesamepurpose:performingtheirexperimentsinoptimalconditionsand,at thesametime,utilizingatbest thebeamtimemadeavailableat theFacility. IntheframeworkofthisNetworkaProgramCommittee,composedofexpertsbothinternalandexternaltotheFacility,willallocatethebeamtime.

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1.12. EDUCATIONANDTRAININGTheprimaryobjectiveofthisinitiativeisnotonlytoextendexistingresearchactivitiesandtreatpatientsbutalsotocreatecompletelynewopportunitiesforcutting-edgeresearchandtechnologyforthewelfareoftheRegion.

Secondly, it is thehopethatbystrugglingandworkingtogether foracommontaskthehumanrelationsbetweenscientistsandengineersaswellasbetweenadministratorsandpoliticiansfromcountrieswithdifferentandsometimesproblematichistoriescanbeanessentialelementinbuildingmutualtrustashasbeensuccessfullydemonstratedbythecaseofCERNandSESAME.

Training of the young generation is an essential and integral part of the initiative. Therealisationoftheprojectswilltakeseveralyears,whichgivessufficienttimetotrainnotonlytheteam,thatwillhelptobuildandlateroperatetheinstallations,butalsotoformauser community. In both cases, specialised users in the important fields that will beservedbythefacilitiesdonotyetexistintheRegionandhavetobecreated.Thiswillbeanessentialpartofcapacitybuilding.

Thetrainingwillmainlyconsistoftwoparts.

ThefirstistograntfellowshipsforyoungpeopletobesenttoEuropeanlaboratoriesforoneortwoyearstogeteducationandtrainingasscientistsorengineersinvariousspecialfields.Themanagementofsuchaprogrammewouldbethetaskoftheprojectleadersbyselecting promising candidates from the Region and finding host laboratories to hostthem.

Thesecondcomponentof trainingwouldbetheorganisationofworkshopsandschoolsfor futureusers.TheseshouldbeorganisedbyaTrainingProgrammeCommittee tobesetupfromthebeginning.

Morespecifically,beforetimezeroatleastoneyear,probablytwoyears,willbedevotedto educating and training the people, coming from the Region, who – under theleadership of a few world-known experts – will constitute the core group of theConstruction Team that will design, build and commission the Centre. These youngengineers and scientistswill be trained by the European Institutes,whichwill take theresponsibilitytohelpandsupport,inthelong-term,theproject.

Afterthisinitialperiod,thetwoNetworksdescribedinSection1.11willbeusedtogatherthenecessaryexpertiseandtrainingthenewexpertscomingmainlyfromtheRegion.ThistrainingwillbedonebyhavingthepersonneloftheFacilitybothvisitingforeigncentresforlongstaysandfollowingcoursesthatwillbegiven,byinternalandexternalteachers,onsite.Indeed,oneofthemaingoalsoftheFacilityistotrainhighlycompetentexpertsin numbers, which exceed the needs of the Facility, so that other Hospitals andInstitutionswilleventuallyemploythem,thusraisingtheculturallevelandthequalityoftheworkdoneintheRegion.

TheFacilitywillbeverynaturally linkedtotheUniversitiesoftheRegionandwillbeanexcellentpartnerforMasterandPhDcoursesandtheses.

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1.13. KNOWLEDGETRANSFERANDSPIN-OFFSTOTHEREGIONTechnologyandknow-howtransfersarevitalpartsoftheinitiative.Inordertoattainthegoals the accelerator and the high-tech hardware and software components of thecomplexwillnotbeorderedasaunitfromindustrybut,rather,willbedesigned,withthehelpofexpertsandlaboratoriesinEurope,andwillbebuilt,mountedandcommissionedbytheConstructionTeam.Thisistheusualwayinwhichmostscientificlaboratorieshavebeen created in Europe.Only conventional equipmentwouldbebought from the shelffrom industries whereas for new developments, prototypes will be ordered and laterproductioncontractswillbeawardedtoindustry.Thisallowsalargeflexibilitytousethemostmodern technologies for the projects and, as experience has shown, provides anextremelyefficient technology transfer to industry. It also reduces the total costof theprojects since the global risk is not put on the shoulder of industry. To facilitate thecollaboration with industry it is envisaged to also establish a kind of “trainingprogramme”forandwithindustrywiththetasktoexplaintofirmsnotyetincontactwithresearchinstitutionshowtocooperateandhowtopresentproposalsforadjudicationofcontracts.

With the construction of this Facility there will be many opportunities for technologytransfertotheSEE-countries.Firsttheprocurementofthedifferentcomponentsforthemachineandbeamlines(magnets,vacuumsystem,girders,beamlines,powersupplies,control system, etc.) can be preferentially assigned to local industries. Wherever thecapabilities of local industries are lacking it will be conceivable to establish joint R&Dprograms for pre-series prototypes thus promoting these industries. These prototypesshould be manufactured in the member countries by giving their industry a specialeducation/training from other facilities and from the staff of the Centre. With theproductionof theprototypes, thehome industrieswill be formed tobe successful in alatercallforthetenderingprocess.Likewise,itwillbenecessarytoeducatetheindustriestobidsuccessfullyfollowingtheprocurementruleofmostadvancedEUcountries.

Like the training program, we believe that the technology knowhow transfer programoutlinedcouldhelpincreatingasetofskilledscientistswhowillbeattractedtoworkatthe Facility and no longer seek employment elsewhere in Europe, thus reversing oralleviatingthebraindrainsufferedbytheRegion.

The initiative will give rise to spin-off activities not directly linked to the facilities butproviding an initial spark for new activities in the Region. Two examples may bementioned.TheFacilitywillneedelectricpowerthatwillbeanon-negligiblepartoftheoperatingcost.Toreducethis,onecouldconsiderinstallingsolarpanels.ThiscannotbeconsideredonlyfortheCentre,sincepowerisneededalsowhenthesunisnotshining;ontheotherhand,powercanbesuppliedtothegeneralnetworkwhentheacceleratorisnotworking.Hencesuchanoptionmustbeintegratedintheregionalpowernetwork.

A second spin-off development concerns the creation of regional broadband-digitalnetworks.ThetwoNetworksdescribedinSection1.11willservealargeusercommunitythatisspreadintheRegionandEurope.TheinfrastructuresneededtotransmitdatafromtheCentretotheusers,andviceversa,mightbecomeamodel forawidernetworkfortheRegion,astheWorldWideWebcreatedfortheusersofCERNhasattainedworldwideimportance.

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PART2

CONCEPTUALDESIGNOFAMULTIPLE-IONSTHERAPYAND

RESEARCHCENTRE

2.1 CHOICEOFTHESTUDYCASE

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The Second Part of this Report is devoted to the description of the facility - which isneededtopursuethegoals,describedintheFirstPart,intumourtherapy,radiobiology,animal studies and medical physics – and to its cost estimates. Since for costing thesynchrotronandthetransportbeamlinesitisnecessarytochooseaspecificdesign,ithasbeen decided to use as case study theProton-IonMedicalMachine Study described inSection1.5,whichhasgivenbirthtoCNAOandMedAustron(Figures1.10and1.11).Thestrikingly different layouts of these two European centres, shown in Figure 2.1,demonstratetheflexibilityofthebasicdesignanditsadaptabilitytodifferentconditionsandneeds.

Figure 2.1. Comparison of the layout of the two facilities built on the basis of Proton and IonMedicalMachineStudyheldatCERNbetween1995and2000.

IthastobeunderlinedthatthedecisiontostudythiscasedoesnotimplythatthisdesignwillbechosenfortheconstructionoftheSouthEasterEuropeFacility.

2.2 OVERVIEWOFTHEACCELERATORSYSTEMThe layout of the accelerator system is based on the 25-metre diameter PIMMSsynchrotronofFigure2.2,whichcanacceleratedifferenttypesofhadronbeams,suchasHelium,Carbon,Oxygen,NeonorArgon, and is suited formany researchprograms, asthosediscussedintheFirstPart,andfortreatingtumours.Itfeaturesthreesources,butmorecanbeadded,andthreehigh-energybeams,whichareonlyindicativeofwhatcanbedonetodistributethebeamstothevariousareasdiscussedinSection2.6.

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Figure 2.2 – In the basic layout of the accelerator system there are three sources and threebeamlines,oneofwhichisstraightandguidestheparticlestoabeamdump.

ThehadronbeamsaregeneratedinanElectronCyclotronResonance(ECR)ionsource.ALow-Energy Beam Transportmagnetic line (LEBT), with spectrometer magnets for ionseparation, isconnectedtothe ionsource.TheLEBTbeamismatchedtothe inputofaRadio Frequency Quadrupole (RFQ) which accelerates the beams from 8 keV/u to 400keV/u.Subsequentaccelerationisperformedwithasequenceoftwodrift-tubeLinacsuptoabeamenergyof7MeV/u.AMediumEnergyBeamTransport line(MEBT)strips,de-bunches and charge-state separates the beam and transports the selected ions to theinjectionpointofthesynchrotron.Amulti-turninjectionisperformedinthesynchrotrontoprovidetherequiredintensity.

The synchrotron accelerates the beam to the requested energy and stores it forsubsequent slow extraction. A High Energy Beam Transfer line (HEBT) transports thebeameither to theexperimentalareaor toa treatment room.The layoutofFigure2.2has three beamlines, the first to the right toward an experimental area for researchpurposes(EH1),thesecondandthethirdtothelefttowardtwopatienttreatmentrooms(TR1andTR2).Ofcourse,thereisthepossibilityofmodifyingthedistributionanduseofthelinesandofaddingnewones.TheproposedlayoutisdescribedinSection2.6.

ThedimensionsandnumbersofmagnetsaregiveninTable2.1.

Table2.1–DimensionsandnumbersofmagnetsforthebasicsystemofFigure2.2.

Approx.dimensionsofacceleratorwithonetreatmentroom

Circumferenceofthesynchrotron 77.6m

Lengthoftheinjector(LEBT,Linac,MEBT) ≈60m

Numberofmagnets(Linacnotincluded) 162

Numberofmagnetpowersupplies(Linacnotincluded) 130

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InthenextSectionsthedifferentcomponentsofthesystemaredescribed.ThetechnicalspecificationsofthedifferentpartsaregiveninTable2.2,followingthebeampathfromthesourcetothepatient.

Table2.2–Generalspecificationsoftheparticleacceleratorsystem.

Ionspecies

Beamparticlespecies

4He2+,12C6+,36Ar16+,withapropersetupallspeciesbetweenpandArcanbeaccelerated,inparticularp,O,Ne.

4He2+energyrange[MeV/u] (30-)75-220*4He2+range[mm] (9-)45-30012C6+energyrange[MeV/u] (50-)140-430*12C6+range[mm] (7-)47-31036Ar16+energyrange[MeV/u] 205-35236Ar16+range[mm] 30-7436Ar18+energyrange[MeV/u] 205-43036Ar18+range[mm] 30-102

MaximumnumberofHeionsperspill ≥1010

MaximumnumberofCionsperspill ≥109

Maximumnumberof36Ar16+ionsperspill ≥2108

Maximumnumberof36Ar18+ionsperspill** ≥2107

SetupChange

Timetochangebetweenionsources ≈1min

Timetoswitchbeamfromroomtoroom ≈1min

Timebetweenendandstartofextractionfornewaccelerationcycle. <2s

Rampingtimeofsynchrotrontohighestmagneticfield

<1s

Beamintensityvariationwrtmaximumnumber 0.01-1

Stabilityofextractedbeam

Beamintensityinstability(100msaveragingtimeandDynamicIntensityControlactivated;thefirst100msofspillarenotincluded).

<±5%

Extractedbeamintensityfluctuations(averagingon1ms) Max/Min<5

Beamwidthvariationsatisocentre <20%

IntegralintensityvariationwithoutDynamicIntensityControlactivated <±30%

Averageenergyvariationsfromsynchrotron <0.1%* Energy range within which beams are compliant with clinical specification. For beams with energies

betweenlowerclinicalenergylimitandenergyinparenthesis,clinicalbeamqualityisnotguaranteed.** For36Ar18+lowerintensitycanbeprovidedbecauseofthelowstrippingefficiency.

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2.3 FROMTHEIONSOURCETOTHESYNCHROTRONEXTRACTIONSYSTEM

Injectionline

TheECRionsourcescanbeoperatedeitherinDCorinpulsedmode.Thebeamcurrentisreproduciblewithin±5%frombeamcycletobeamcycle.SomeparametersofthesourcesarelistedinTable2.3.

Table2.3–Sourceparametersforsomeionsusedforhadrontherapy.

Iontype 1H+ 4He2+ 12C4+

Ioncurrent(µA) 700 1000 200

Energy(keV/u) 8 8 8

Ionsourcepotential(kV) 24 16 24

Each ion source branch of the LEBT is equipped with a solenoid, a quadrupole, twohorizontal and vertical correctors, a 90-degree spectrometer dipole magnet and aquadrupoletriplet.

Thepurposeof theLEBTbeamline is to select the ion typeof interest (withamass-to-chargeratio(A/Q)intherange1.0to3.0),totransportitandtomatchthebeamtotheacceptanceoftheRFQlocateddownstreamoftheLEBT.

Inordertocleanthedesiredionbeamfromatomic,molecularorisotopicimpurities,theionsarefilteredbyamagneticspectrometersystem,whichhasaresolvingpowerofmorethan 50. Moreover, to cut the needed portion of beam injected in the RFQ, anelectrostatic chopper system generates pulses with duration of a few hundredmicroseconds,asrequiredforthepulsedoperationoftheLinac.

AttheendoftheLEBTaLinacsystemacceleratestheionstotheinjectionenergyofthesynchrotron. The Linac system consists of three linear accelerators: a RFQ (up to 400keV/u)and two IHdrift tubeaccelerators (up to4.2MeV/uand7MeV/u respectively).TheLinacispulsedat5Hzwithapulselengthof0.3millisecondsandhasapeakpowerof250kW.Thetotalpeakpower isabout1.1MW.TheLinacsystemhasatransmissioninexcessof70%.

TheMEBTbeamlinetransportsthe7MeV/ubeamfromtheLinactotheinjectionpointofthesynchrotron.Itcontainsastripperfoil,whichstripsandpossiblydissociatesthebeamtofullystrippedatomicions(exceptforargonionsforwhichfullstrippingtobarenucleihas prohibitively low yield), separates the ion species depending on theirmass-chargeratioand,withanRFcavity,debunchesthebeamandhencereducesitsenergyspread.

Synchrotron

ThebeamfromMEBTismulti-turninjectedintothesynchrotrontoobtainanincreaseinthecurrent fromtheLinacbya factorof five.Thebeam is subsequentlyacceleratedtothe requested energy in less than one second. After acceleration, the beam is slowlyextractedduringupto10swithhighefficiency.Forgatingoperation,thedurationofthehigh-energy flattop can be increased up to 30 s. The main specifications of thesynchrotronarelistedinTable2.4.

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Table2.4–Mainspecificationsofthesynchrotron.

Injection unit

Particleafterstripping p 4He2+ 12C6+ 16O8+ 36Ar16+

Energy MeV/u 7 7 7 7 7

Magneticrigidityatinjection Tm 0.38 0.76 0.76 0.76 0.86

Acceleration

Accelerationrate Tm/s 10 10 10 10 10

Ramp-downtimeofmagnets s <1 <1 <1 <1 <1

Lowestextractionenergy* MeV/u 60 (30)75

(50)140 120 205

Highestextractionenergy MeV/u 220 220 430 430 352

Magneticrigidityatlowestextractionenergy* Tm 1.14 (1.59)

2.54(2.06)3.53 3.25 4.88

Magneticrigidityathighestextractionenergy Tm 2.42 4.52 6.62 6.62 6.62

Maximumnumberofparticlesperspill 2·1010 1·1010 1·109 5·108 2·108

Momentumspread % <0.1 <0.1 <0.1 <0.1 <0.1

Extractiontime s 1-10 1-10 1-10 1-10 1-10

Spillpauselength s 0.1-20 0.1-20 0.1-20 0.1-20 0.1-20Spillstructure,intensityratioImax/Imin(averagingtime≥1ms) <5 <5 <5 <5 <5

* Where twonumbers aregiven, theone in brackets canbeobtainedwithnon-clinical quality or lowerintensity.

The lattice is based on two symmetric, achromatic arcs (mx =mz = 360° with bendinganglesequalto180°)thathavebeende-tunedandjoinedbytwodispersion-freestraightsections(Figure2.3;).

Figure2.3–(a)Geometryofthesynchrotronwhichfeatures16bendingmagnets,24quadrupolesand4sextupoles.(b)Opticalfunctions:betatronfunctions(above)anddispersion(below)

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The24quadrupolesaregroupedin3familiesthatallowenoughflexibilitytomatchalltheneededtuneswhileconservingthedispersionfreeregions.The4chromaticitysextupolesare grouped in 2 logical families and are placed such that it is possible to changeindependently the horizontal and vertical chromaticity; these magnets are individuallypoweredtoallowsomeadditionalflexibilityinsettinguptheextraction.

ExtractionisperformedbyRF-knockoutatmultipleenergiesduringthesameacceleratorcycle,aprocedureabbreviatedasEVEthatstandsfor“EnergyVariableExtraction”.AfteranextractionEVEallowstheacceleration (ordeceleration) inabout100millisecondsofthe remaining particles to a different energy, so that the system is ready for anotherextractionwithoutlossofbeamquality.Thisprocedurereducestheirradiationtimewhenthedosetobedepositedatacertainenergyrequiressmallnumberofparticles.

2.4 BEAMTRANSFERTOTHETREATMENTANDEXPERIMENTALROOMSInthebasiclayoutofFigure2.2theHEBTlinetransportswithsmalllosses(<5%)thebeamfrom the synchrotron to2 therapy roomsand1experimental room.Theoptics systemallowsat the isocentreadjustable sizesof5-15mmFWHM,as shown inTable2.5.Theexperimentalbeamlinehasadouble isocentre:one fora conventional field size (20×20cm2),andtheother,afteralongerdrift,withanenlargedfieldsize(40×40cm2).

Table2.5–MainspecificationsoftheHEBTline.

Adjustablebeamwidth(FWHM)atisocentreforprotonsandheliumionsatmaxenergy(mm) 7-10-15

Adjustablebeamwidth(FWHM)atisocentreforcarbonionsatmaxenergy(mm) 5-8-10

Transversefieldforscanninginthetreatmentrooms(cm2) 20×20

Transversefieldsforscanningintheexperimentalarea(twopositions)(cm2)20×2040×40

TheHEBTstartswiththemagneticextractionseptaandcontainsacommonbeamlineandtwobeamlinebranchestothebeamportsof therooms.Eachbranchbeginswitha45°bendrealizedasapairof15°anda30°dipolemagnetspoweredbyonepowersupply.Theexperimentallineispointinginoppositedirectionwithrespecttothefirsttreatmentline.Thislayoutallowsthedesignofaflexibleexperimentalareawithmultipleroomsandconfigurationstoaccommodatedifferentresearchprojects.

Table2.6–MainspecificationsoftheHEBTline.

Maximumtransversescanningspeed(m/s) 20

Distancefromscannermagnetstoisocentreinthehorizontalandsemi-verticalbeamlines(m) 7.4

Momentumspread(95%),Δp/p(%) <0.1

Dispersionatisocentre,D(m) <0.1

Dispersiongradientatisocentre,dD/ds <0.1

The commonpart of theHEBT line contains a beamabort system,which prevents anybeam-particlesenteringthebeamlinewithin200µsafteraninterlocksignal.Itconsistsof

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twocorrectormagnetswithadeflectionangleof6mradonbothsidesofafastswitchingmagnetwithadeflectionangleof12mradatthecentre.ExtractioncanalsobestoppedbyswitchingofftheRFpowergoingtotheKO(knock-out)-exciter.ThebeamextractioncanberesumedusingtheKO-exciter.Thetimeneededtoabortandresumeextractionisabout1ms.

2.5 SOFTWARE

ControlSystem

ThemaintaskoftheControlSystemistoloadthemanyprocessors,whichareon-boardofthedifferentdevices,withtherelevantsettings,dependingontheplannedcyclestobeexecuted,andtomonitortheachievementoftheplannedresults.

TheareascoveredbytheControlSystemarethefollowing:• distributionoftheeventstosynchronizethebehaviourofallthedevices;• generationorchoiceofthesetpointstobeusedineachcyclebythedevices;• generationandvisualizationoftheinformationtomonitorthetreatment;• executionofthetaskstopreparetheplanttothetreatmentexecution;• executionofthetaskstoverifythecorrectbehaviouroftheplant;• implementationoftheplantsafetysystem;• executionofthetasksthatallowplacingthepatientintherightposition;• executionofthetaskstodeliverthebeamonthetargetwiththerightamountof

dose.

Figure2.4showstheconceptualarchitectureoftheControlSystem.

Figure2.4–SoftwarearchitectureoftheControlSystem.

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The concepts presented above are translated into a layered architecture based on anetworkofdispersedprocessors.Eachlayerhasasetofspecifictaskstobeaccomplishedtosupplyservicestotheimmediatelyupperlevelortotheoperators.

Figure2.5showsthemaincomponentsoftheconceptuallayeredarchitecture.

Presentation Layer

Medical Supervisory Procedures Virtual Equipment

Data Management Layer

asap

SeveralWS

Equipment Server Layer

Onceper cycle

or off line

1 SERVER

SeveralServers

Equipment Electronics Layer

Equip

men

tCo

ntro

ller

Tim

ing

Cycle

Deco

der

CPU

Several cPCI/PXIPLC

Front End Electronics (signal conditioning)

Ethernet or FieldBus

Many times

per cycle

Master Timing

Detectors and Actuators

Controls Domain

SubSystems Domain (e.g. Vacuum)

ManufacturerProtocols on

FieldBusor point to point

TCP/IP onGiga Ethernet

RT processes run once per cycle

RT processes can runmany times per cycle

Equip

men

tCo

mpo

nent

Equip

men

tCo

mpo

nent

Equip

men

tCo

mpo

nent

Equip

men

tCo

mpo

nent

Equip

men

tCo

mpo

nent

Equip

men

tCo

mpo

nent

Triggers

Level 1

Level 2

Level 3

Level 4

Equipment Electronics Domain

or off line

Prot

ocol

Adap

ter

Many times

per cycle

Triggers

Triggers

Sequence

Tim

ing

CPU

Cycle

Deco

der

Front End Electronics (Proprietary Protocols)

Proprietary Protocols

TCP/IP onGiga Ethernet

Operation Supervisory Procedures

Alarms & Security

Digit

iser

Repository

Once per cycle

Max XXXX elements

asap

Sequence

Equip

ment

Comp

onen

t

Equip

men

tCo

mpo

nent

Log

History

OPC-

UA S

erve

r

OPC-

UA /

S7

OPC-

UA

OPC-

UA S

erve

r

OPC-

UA C

lient

Once per Cycle per Station

asap

Equip

ment

Comp

onen

t

OPC-

UA

OPC-

UA

non

logge

d da

ta

Conf

igura

tion

data

Figure2.5–ControlSystemlayeredarchitecture.

DoseDeliverySystem

The DDS includes the acquisition data software, the interfaces with the treatmentplanning system, the communication interfaces with the control, timing and safetysystems.Bymeansofthecontrolsystem,theacceleratormachinecycle,setbytheDDS,isdistributedtotheacceleratorcomponents.

TheDDShasthetasktodrivethescanningmagnetscurrents,whichdefinetherequestedposition of the beam in the plan orthogonal to its propagation direction (X and Y co-ordinates),while the Z positionof theBraggpeaks is determinedby the energyof theparticles.

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Thetumourvolumetobetreatedissubdivided,bytheTreatmentPlanningSystem(TPS),into several slices, located at different depths inside the patient. The DDS is able torecognizethecompletionofthetreatmentofeachslicethankstoareal-timecheckofthebeamandthankstoamonitoringofthetreatmentevolution.

The end of a voxel, exactly like the end of a slice, is decided by the DDS through themeasurementofthenumberofparticles,bymeansoftwointegralionizationchambers.Attheendoftheirradiationofthevoxel,theDDScommunicatestothepowersuppliesofthescanningmagnetsthenewbeamposition.

MedicalsoftwareandQualityAssurancetools

The medical software includes the Oncology Information System (OIS). The custominterface standard called “DICOM Treatment Machine Interface” of the OIS gives theunique opportunity of achieving the “Record and Verify” full connectivity within theParticle Therapy environment, supporting pre-treatment checks including patientpositioning,treatmentaccessoryandsynchrotronsettingverification,treatmentdeliverydata and image recording in the patient database. It includes licences for ElectronicMedicalRecord forRadiationOncology,ResourceSchedulingSetup Intelligence,DICOMRT Ion Plan import and export, connections to third-party PACS, TPS and diagnosticscanners,sequencersfortransportbeamlinesandDTMIhadrondelivery.

TreatmentPlanningSystemforions

AsystemthatcanbeadoptedisRayStation®Version5,whichrepresentsthestate-of-the-art of amodern TPS in termsof advancedpatientmodelling, plandesign, optimizationandevaluation,biologicalmodellingforcarbonions,GPU-basedpencilbeamcarbondosecalculation engine, treatment adaptation, scripting and Quality Assurance (QA) planpreparation.

TheconfigurationofRayStation®V5includeslicensesforeachofthefollowingmodules:Carbon Planning, Deformable, Tracker and Adaptive. Advanced patient anatomicalmodelling, such as structure definition, image registration, propagation of structures,atlas-based and model-based segmentation, manual and semi-automatic organ andtarget delineation tools, is available. IMPT (Intensity Modulated Particle Therapy)optimizationandRelativeBiologicalEffectiveness(RBE)-weighteddosecomputationusingtheLocalEffectModel(LEM)forcarbonandheliumionsandprotontreatmentplansaresupported.

2.6 STAGINGOFTHEPROJECTTheconstructionofthetreatmentroomsandoftheexperimentalhallscanbestagedsothatarelativesmallinitialinvestmentwillallowfromthebeginningsignificantclinicalandresearchactivities;apossible layoutdevelopment is shown inFigure2.6.Note that theclinicalareasandtheexperimentalareasareonoppositesidesoftheHEBT linesothatthereisnomixingbetweentheflowofthepatientsandofthescientistsworkingintheexperimentalhalls.ThesequenceofFigure2.6isonlyoneofthemanypossiblescenarios.

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Thedesignthatwillberealizedwillbedeterminedbythegoalsofthepersonsinchargeatthetimetogetherwiththeinflowandthetime-profileofthenecessaryfunds.

Figure2.6–Threetopologiesthatcanbeusedforstagingtheprojectstartingfromthebaselinelayout(LayoutA).TheiongantryroomoflayoutCissolargetocontaintheGSIgantry(Figure1.4)butatthetimeofconstructionsmallersuperconductinggantrieswillbeavailable(Figure1.16).

AccordingtothescenarioofFigure2.6,theresearchprogramswillbecarriedoutintwoEHs halls devoted toRadiobiology (RB),Animal studies (AS) andMedical Physics (MP),wherebeamsofmanydifferentionspecieswillbeavailable,withthemaximumenergieslistedabove.ForradiobiologyexperimentstheCentrewillfeaturealsoalow-energybeam

64

(7-8MeV/nucleon),producedbythe injector. If thestagingapproach isadopted,atthebeginningoftheexploitationRBandMPexperimentswillbeperformedinthesamehall.

Theconstructionsequencedescribedinthefigureisasfollows:§ Thebaselinedesignforeseesthreeionssources,onetumourtreatmentroom(TT1)

withahorizontalbeam,onetumourtreatmentroom(TT2)withahorizontalandaverticalbeamand,giventheresearchpurposesofthefacility,alargeexperimentalhall (EH1) with 2-3 beams for in vivo radiobiology (RB), animal studies (AS) andmedical physics experiments (MP). The synchrotron accelerates hadrons at thehighestenergiesandalow-energybeamforradiobiologyisproducedbythelinac.

§ Inthesecondstageathirdtreatmentroom,withaprotongantry,canbeadded.Thethreetreatmentrooms(TT1,TT2andTT3)havethesamefootprintsothataprotongantry (Section 1.5) could also bemounted in TT1 and TT2. The addition of twohigh-performancesourcesisforeseentowidentheresearchpossibilities.

§ Theadditionof an iongantryandof a third experimental hall (EH3) (Section1.5)could complete the facility givingmore scope to the clinical research program. AsixthsourceincreasesthenumberofionspeciesroutinelyavailableattheFacility.

2.7 SITEREQUIREMENTSThelayoutofFigure2.6Ccoversanareaofabout170mx90m.Atpresentitcannotbesaid whether the bunker, containing the accelerator and the beam lines, will beconstructed in an underground bunker or at ground level. This will depend on thedimension of the site, the possible height limitations and the stability of the ground.Surfacebuildingswillhoststhreetypesofstaff,thosewhoareinvolvedintherunningoftheFacility,thosewhowillprovidetumourtreatmentsandthevisitingscientistscomingfromcollaboratingInstitutionsandHospitals.Atthisstageitcanbesaidthat,tocoveralltheneeds,anareanotsmallerthan300mx180mhastobeforeseen,correspondingtotwicetheareaofthelayoutofFigure2.6C.

Theelectriccabinservingthefacilityshouldhaveacapacitynotsmallerthan10MVAandthewaterfluxforcoolingtheequipmentshouldbeatleast1400cubicmeterperhour.

Inthe2-4roomsofthelayoutsoffigures2.6Aand2.6C,250-500patients,comingmainlyfromtheRegion,willbetreatedeveryyear.

Sinceonlyoutpatientswill be irradiated, the Facility shouldbebuilt not too far fromaHospital,whichcouldprovidetothepatientsthenecessarycareintegratingtheofferofthe Hadron Facility. The presence in the Hospital of a Radiotherapy Department -featuringmodern linacs forX-ray therapyand the correspondingmedical imaging tools(CT,PET,CT/PETandMRI)–wouldrepresentanimportantasset.Thiswouldalsoreducethe investments needed to install and maintain in the Facility some of the costlydiagnostic toolsmentioned above. In any case, the instruments installed in the Facilityshouldcomplementtheonesavailableintheclose-byHospitals.

Asdiscussedabove, forprogramB2 (Animal Studies) an in-houseanimal facilitywill beestablishedforpermanenthousingofsmallrodents.Theanimalfacilitywillbeplacedinthebasementandwillhaveadirectconnectiontotheexperimentalbeamroom,toavoid

65

patient areas to be exposed to allergens. The animal facility will include an isolatedsectionwhichcanserveastemporaryhousingforvisitinganimals,broughtinbyvisitingscientist,andwhichwillaftertreatmentbetakentothehomeinstitution.Thiswillenablethemostflexibleuseoftheexperimentalfacilities.

Larger animals will be brought to the site when needed, on the basis of a scientificcollaborationagreementwithaVeterinaryDepartment,whichwouldbebest located inoneof theSEEcountries thatdoesnothost theFacility. ThisDepartmentwillalso takecareofthefollow-up.

AllfacilitiesforhousingandtreatmentofanimalswillcomplywithEUregulation.

As for all the facilities of this type, the roads should be such that heavy pieces ofequipmentcanbetransportedandtheairportshouldnotbetoofar,sincemanyscientistswill visit the laboratories for performing experiments andpatients,with their relatives,willhavetospendonaverage4-5weeksintheCentre.

Sinceanaveragetreatmentlasts20-25sessions,atthebeginningmorethan20patientswillbeinthetreatmentareaseveryday;thisnumberwilldoublewhentheCentrewillbecompleted. A guesthouse and/or close-by hotels are needed to host them with theirrelatives.

2.8 TIMELINEANDORGANIZATION

Timeline

Overall6yearswillbeneeded:1year for thepreparation,4years for theconstructionandon-sitemountingand1yearforthecommissioning.Thetrainingofthelocalstaffwilltake1-2years.ConstructionandcommissioningtimesaregiveninFigure2.7.

OrganizationalmodelAcomplexmultipurposeresearchCentre,astheonedescribedinthisReport,cannotbeordered “turn-key” from a company because the team that will commission, run andimprove it over the yearshas to know in detail the innerworking of its parts and thereasonsforthechoicesmadeduringtheplanning,specification,construction,integrationand commissioning phases. A more effective approach foresees that the facility isdesigned,builtandcommissionedbyaGroupofexpertstogetherwitha“LocalTeam”oftalented young and enthusiastic people selected among graduate and post-graduatestudents – with some full-time senior scientists and engineers – which will becomeknowledgeableundertheguidanceoftheexperts.

Morespecifically,inthisSectionitissupposedthatthemanagementoftheOrganization–whichwill be funded for thedesign, construction, commissioning and runningof thefacility – will sign a Collaboration Agreement with European Institutions, which haveacquired direct knowledge in the many scientific and technical fields involved, byconstructing, commissioning and managing one or more similar centres. TheManagement of the Organization, with the help of the external experts, will have theresponsibilityoftrainingthemembersoftheLocalTeam.

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Figure2.7–Timeplanforthedesign,constructionandcommissioningofthefacility.

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DuringthefirstyeartheManagementoftheInstitutewillalsohavetheresponsibilitytodefinethespecificationsofallitsmanysubsystemsandlater,withthehelpoftheGroupofexpertsand theactivecontributionof theLocalTeam,will follow their construction,on-sitemountingandacceptancetests.

DuringtheinitialtraininganddesignphasetheInstitutewillalsoinvestigatetheexistenceand availability of local firms, possibly close to the site of the Centre, which could beinvolvedinthefacilityrealization.Thischoicehasmanyadvantages:firstly,itimpliestheinvestment of money in local firms and the creation of labour opportunities andrevenues;secondly,itwillallowthetechnologytransfertolocalindustriesthatwillthenbemorecompetitiveontheinternationalmarket;thirdly,itwillinducethecreation,closeto theCentre,of firms that could contribute to themaintenanceof the facilityonce inoperation.

After 1-2 preparation years, devoted to the education and training of the Local Teammembersandtothedefinitionof thedetailedspecificationsof thefacilitycomponents,theInstitutewillsigncontractswith2-3“MainContractors”,whichwillprovide–usingasmuchaspossibleRegionalsubcontractors–thehigh-techcomponentsofthefacilityandwilltakecareoftheirshipmentandonsitemountingandtesting.

One of theseMain Contractors will produce, install and test the control and safetysoftware, thepatientenvironmentandthe integrationof thetwoworlds, technicalandmedical.

At the end of the commissioning phase the Local Team – always supported by theexperts–willconstitutethecoreoftheRunningTeamthatwillmanagethefullcomplexand use it for both clinical treatments and research activities in radiobiology, animalstudiesandmedicalphysics.

2.9 INVESTMENTSANDMANPOWERFORTHECONSTRUCTIONANDTHEUPGRADING

ConstructionoftheCentre

Within the organizational framework described in the last Section, it is possible toestimate thecostof thedifferent subsystem (Table2.7). The last column includes boththecompanypersonneland thepersonnelof the LocalTeamduring the6yearsof theconstructionperiod.

TheaverageEuropeantotalcostoftheabout400specializedman-years–mostofthemworking in high-tech industries – is estimated to be 110 k€/man-year, so that the 400man-yearswouldneed44M€duringthesixconstructionyears.

Summing44M€tothe76M€,neededforthematerial investmentasreportedinTable2.7attheendofcolumn4,atotalof120M€isobtained.

It is worthwhile noting that this sum could be reduced if a sizeable fraction of thepersonnel working on the Facility construction would be paid with Regional salaries.Howeveritistooearlyintheprojecttobesurethatthiswillhappen.

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Table2.7– Investments ink€andman-years for thehardware layout (A)ofFigure2.6.AOTandMOTstayfor“AcceleratorandbeamsOrientedTechnologies”and“MedicalandresearchOrientedTechnologies”.

Item

Investmentsincomponents(k€)

Manyears

Fig.2.6A

AOT

3Sources 4,800 4Magnets 11,900 93Linac 10,700 16Powersupplies 8,600 68RadioFrequencysystem 600 2Beamdiagnostics 4,700 39Vacuumsystem 700 14Safetysystem 700 7Radiationsurveysystem 300 6HorizontalandverticalbeamlinesforTT2 6,300 5Low-energybeamlinetoEH1 4,700 3

Total 54,000 257MOT

ControlandSafetySystem(CSS) 4,300 99TreatmentPlanningSystem(TPS) 3,700 2OncologicalInformationSyst.(OIS) 4,100 42 Patient Positioning Systems (PPSs forTT1+TT2)

1,400 6

2 Patient Verification Systems (PVS forTT1+TT2)

3,000 2

Dosimetryandmonitoringdevices 600 44Nozzleassemblies(forTT1+TT2+EH1) 3,000 8Equipmentforinvitroradiobiology(RB) 300 6Equipmentforinvivoradiobiology(AT) 800 8EquipmentforexperimentalHallEH1 500 6

Total 21,700 145TOTAL 75,700 402

Thecostof thebuildingsandshieldingof thebaselinedesignhasbeenestimatedtobe45,000k€sothatthetotalinvestmentis120,000+45,000=165,000k€.

Ithastobeunderlinedthatthistotalinvestmentdoesnotinclude1. instrumentationformedicaldiagnostics(CT,PET,CT/PET,MRI…),2. acquisitionofIntellectualpropertyandlegalexpenses,3. insurances,4. marginfortheconstructor,5. contingency.

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UpgradingoftheCentreThenexttableconcernsthetwoupgrades:fromthelayoutofFigure2.6AtotheoneofFigure2.6BandfromthelayoutofFigure2.6BtotheoneofFigure2.6C.

Table2.8–Investmentsink€andman-yearsfortheupgradesofFigure2.6band2.6c.

Item

Investmentsincomponents(k€)

Manyears

Fig.2.6B

AOT

2ionsources(PKisis) 5,200 1UpgradeoftheHEbeamline 500 41protongantry 12,000 6

Total 17,700 11MOT

UpgradeofOIS 1,400 4UpgradeofTPS 500 -UpgradeCSS 150 -

Total 2,050 4TOTAL 19,750 15

Fig.2.6C

AOT

1ionsource(PKisis) 2,600 1UpgradeoftheHEbeamline 500 4EquipmentforexperimenthallEH2 1,700 31Iongantry 27,000 19

Total 31,800 28MOT

UpgradeofOIS 700 2UpgradeofTPS 250 -UpgradeCSS 150 -1Nozzleassembly(forEH2) 1,000 1

Total 2,100 2

TOTAL 34,900 30

Thetotalcostofthetwoupgradescanbeestimatedbyaddingto19.8M€and34.9M€thecostof15and30man-yearsrespectively.AtleasthalfofthispersonnelwillbelocalandtheiryearlycosttotheInstitutewillbelowerthantheaverage110,000k€/yearoftheexpertsofTable2.8.Assuming80,000k€/yearthetotalcostsare19.8+1.2=21M€and34.9+2.5=37.5M€respectively.

2.10 COSTSOFPERSONNELANDMAINTENANCEDURINGTHEEXPLOITATION

PersonnelneededforrunningtheFacilityTable2.9showsthatduringtheoperationperiod(i)37peopleareneededforrunningthefacility,(ii)33fortheclinicalprogramand(iii)8and5,respectively,fortheradiobiology(invitroandinvivo)programsandforthephysicsprogram.

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Table2.9–Compositionof theRunningTeamduring the runningphaseexpressed in “FullTimeEquivalent”experts.

AOT

MACHINE

ElectronicEngineers 3

SoftwareEngineers 4

MachinePhysicists 9

Techniciansrunningthefacility 20

SiteManager 1

Total 37

MOT

CLINICALPR.

SeniorradiationOncologists 5

JuniorradiationOncologists 2

SeniorMedicalPhysicists 2

JuniorMedicalPhysicists 4

NuclearMedicineDoctors 1

Anaesthesiologists 1

MedicalRadiologists 2

RadiationTechnicians 12

SecretariesandNurses 4

Totalfortheclinicalprogram 33

BIOL.

SeniorBioengineers 1

JuniorBioengineers 2

Radiobiologytechnicians(alsofortheanimalfacility) 5

Totalfortheradiobiologyprogram 8

PHYS.

Seniorphysiciststosupportmedicalphysicsexperim. 1Juniorphysicists 2Technician 2

Totalforthemedicalphysicsprogram 5

TOTAL 83Globally83peoplewillformtheRunningTeam.

Personnelandinvestmentsfortheexploitationyears

Asshowninthetable,attheendofthecommissioningphaseabout37personswillformtheMachineRunningTeam,whichwilltakecareoftheAOTsbyrunningthecentreandupgrading it. This personnel is scaled to run the accelerator H24,7/7. Four shortmaintenanceperiodare foreseen,oneperquarter,duringwhich the technical staffwillbeinchargeofperformingandcoordinatingthesystems’maintenance.

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TheteamtakingcareofMOTs(includingtheanimalfacility)willbeformedbyadditional33+8+5 = 46 persons, mainly radiation oncologists, bioengineers, medical physicists,techniciansandnurses.ThesenumbersappearinthefirsttworowsofTable2.10,

Table2.10Personnelandoperationcostsperyear.

Item Yearlyinvestment

PersonnelforAcceleratorandbeamsOrientedTechnologies(AOTs) 37persons

PersonnelforMedicalandresearchOrientedTechnologies(MOTs)(*) 46persons

Maintenanceofhardwareandsoftware,spares 5.7M€

Powerat100€/MWh 1.2M€

Personnel(83persons) 4.0M€

Total 10.9M€

Incomeduetothetreatmentof250patients/year -5.0M€

NetSum 5.9M€

(*)Itincludesradiationoncologists,anaesthesiologists,bioengineers,medicalphysicistsetc.

With an average European cost per expert of 70 k€/year the total cost of 83 full timeequivalent personswould be 6.0M€/ year. Since at least 2/3 of the staff running theFacility will be recruited in the Region, one can estimate that the actual cost will bereducedby30%,sothattheinvestmentinthepersonnelwillbeabout4.0M€/year.ThisisthefigureappearinginTable2.10,whereit isseenthatthetotaloperationcostsumsupto11M€/year.

About 50% of the personnel are devoted toMOTs and this produces a non-negligibleincome since, as said above, the two treatment roomsof thebaseline layoutwill treat(afterarampingupperiodofabout3years)250patients/year.Assuminganaveragefeeof20k€perfullcourse(whichissomewhatlowwithrespecttoEuropeanstandards)afterabout3yearsofrunning-in,theincomewillbeabout5M€/yearsothat,asindicatedinthelastrowofthetable,thenetyearlyoperationcostwillbeabout6M€/year.

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APPENDIXA

WORLDCARBONCENTRESANDTHEIRCONSTRUCTORSTen centres provide carbon ions: 5 in Japan, 3 in Europe and 2 in China. It should beremarked that five of these running centres, Heidelberg, Hyogo, Marburg, Pavia andShanghaihave“dualionaccelerators”acceleratingbothprotonsandcarbonions;insomecasesotherionsarealsoaccelerated.

Table 1.1 summarizes themain characteristics of the existing carbon ion facilities. Thedata have been obtained from official publications and the websites of the centresinvolved.

InspiteofthefactthatBobWilsoninhis1946seminalpapermentionednotonlyprotonsandheliumbutalsocarbonions26,carboniontherapyinitiatedfiftyyearslaterwhen,asalreadysaid, in1994theNational InstituteofRadiologicalSciences (NIRS,Chiba, Japan)treated the first patients using a large synchrotron system named Heavy Ion MedicalMachineAccelerator (HIMAC, shown inFig.1.11). In2010 thecentre,whichwasstill inoperationwitharecordofmorethan11.000treatedpatients,hasbeenenlargedwiththeadditionofthreeadditionaltreatmentroomswithactivescanningandasuperconductinggantry.

FigureA.1–TheHIMACacceleratoratNIRS,Chiba.

NIRShasactedastheprototypeandthetechnologyincubatorfortheotherfourcentresinJapanthatcamelaterandisstillattheforefrontoftechnologyandresearchinhadrontherapy.Japaneseindustries–suchasMitsubishi,Toshiba,SumitomoandHitachi-wereinvolvedintherealizationofNIRSandexploitedthatoccasiontodevelophadrontherapyproductsthattheyarenowofferingontheinternationalmarket.

26 Wilson RR, Radiological use of fast protons, Radiology 1946;47:487-491.

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TableA.1–Characteristicsofthelightioncentresworldwide.

Yearoffirstpatienttreatment 1994 2001 2006

HIMACChiba(J)

HIBMCHyogo(J)

LanzhouHIRFL+CSR(RC)

PatientsTreated(Dec2015) 10486C 5024p

2366C 213

Particles p,C,O,Ar,Xe p,He,C C

AcceleratorType 2Synchrotrons Synchrotron Synchrotron

IonSources PIGforlowZECRforhighZ 2ECR ECR

Injector

RFQ(800keV/u)AlvarezLINAC(6MeV/u)

RFQ(1MeV/u)

AlvarezLINAC(5MeV/u)

Cyclotron

ParticleEnergy(MeV/u) C<430

p&He70-230C70-320

430(1000max)

Beamparticlesperspill(pps) C6x109

p:7.3x1010

He:1.8x1010

C:1.2x109

6x109

(physics)

RepetitionRate 0.3 p:1HzHeandC0.5Hz

SpillLength(ms) 1000 400

DoseRate(GyRBE/min/l) 5 5

BeamRange(mm) 30-300 p,He:40–300C:13-200

BeamDeliveryTechnique

PassivescatteringIntensitycontrolled

3Drasterscan

Passive,respirationgated

Passiveandactive

BeamSSize(mmFWHM) 4–10

TreatmentRooms 3H,1V,and1H&V+1gantry

p:1Hand2gantryroomsC:1H&Vand145degree

1H

TreatmentFieldSize(cm2)

Passive:30x40Active:20x20 15x15

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Yearoffirstpatienttreatment 2009 2010 2011

HITHeidelberg(D)

GUNMA(J)

CNAOPavia(I)

PatientsTreated(Dec2015)

1187p2086C 1909C 195p

591C

Particles p,He,C,O C p,He,C,O

AcceleratorType Synchrotron Synchrotron Synchrotron

IonSources 2ECR ECR 2ECR

Injector

RFQ(400keV/u)IH-DTLLINAC(7MeV/u)

RFQ

APFIH

RFQ(400keV/u)IH-DTLLINAC(7MeV/u)

ParticleEnergy(MeV/u)

P50–250C80–430

C140-400p60-250C120–400

Beamparticlesperspill(pps)

p4x1010

He1x1010

C:1x109

O:5x108

C:1.2x109p:2x1010

C:4x108

RepetitionRate 0.3 0.5 0.3

SpillLength(ms) 1000 500 250-10,000

DoseRate(GyRBE/min/l) 5 5 2

BeamRange(mm) 20-300 30-250 30-270

BeamDeliveryTechnique

Intensitycontrolled3Drasterscan

Passive,respirationgated

Intensitycontrolled3Drasterscan

BeamSSize(mmFWHM) 4-10 4–10

TreatmentRooms 2Hand1gantryroom H,V,H&V 2Hand1H&V

TreatmentFieldSize(cm2) 20x20 15x15 20x20

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Yearoffirstpatienttreatment 2013 2014 2015 2015

SAGA-HIMAT

(J)Shanghai

(RC)Kanagawai-Rock

(J)Marburg

(D)

PatientsTreated(Dec2015) 1136 76p

149C 0 2p5C

Particles C p,C C p,C

AcceleratorType Synchrotron Synchrotron Synchrotron Synchrotron

IonSources ECR 2ECR ECR 2ECR

Injector

RFQ(600keV/u)IH-DTL

(4MeV/u)

Linac

RFQ(400keV/u)IH-DTLLINAC(7MeV/u)

ParticleEnergy(MeV/u) 100-400 C85-430 140-430 C85-430

Beamparticlesperspill(pps)

Passive<1.3x109

Active<3x108p2x1010C1x109 1.2x109 p2x1010

C1x109

RepetitionRate 0.19Hz 0.3 0.3

SpillLength(ms) 3200 1000 <10000* 1000

DoseRate(GyRBE/min/l) 5 2Gy/l/min 5

BeamRange(mm) 270 20-300 270 20-300

BeamDeliveryTechnique Passiveandactive

Intensitycontrolled3Drasterscan

Wobblingandscanning

Multienergyextraction.

Intensitycontrolled3Drasterscan

BeamSSize(mmFWHM) 2.4-13.7 4-10 4-8 4-10

TreatmentRooms 2H+V,1H+45° 3H 2H,2H+V 3Hand145°

TreatmentFieldSize(cm2)

Passive15x15Active22x22

20x20 20x20 20x20

77

APPENDIXB

STATUSOFTHECOMPARISONSWITHX-RAYTHERAPYANDABLATIVEPROCEDURES

Protontherapy

The table below lists all current prospective comparative and randomized studies ofprotontherapyversussomethingelse.

Ithastobenotedthattheproblemofverylong-termsideeffectsandsecondarycancersarenotendpointsofthecurrentstudies27.

Table B.1 – Prospective comparative and randomized studies of proton therapy versus X-rays(photons)andablativeprocedures.

Nameofthestudy NCTNumber

Typeofstudy(patients)

Datesofenrolment

Centres Results

ComparisonofprotonsversusX-rays

RadiationtherapyintreatingpatientswithstageIorstageIIprostatecancer.Protonsversusphotons

NCT00002703

Randomized(390)

January1996

Endoffollow-upSeptember2005

LomaLindaUniversityMedicalCentreandMassachusettsGeneralHospital,Boston,USA

NoResultsAvailable

Proton/photonRT-benignmeningiomas

NCT02947984

Randomized(44)

March1999

September2016

MassachusettsGeneralHospital,Boston,USA

HasResults*

Trialofimage-guidedadaptiveconformalphotonvsprotontherapy,withconcurrentchemotherapy,forlocallyadvancednon-smallcelllungcarcinomas

NCT00915005

Randomized(250)

June2009

June2019

MassachusettsGeneralHospital,Boston,USA

NoResultsAvailable

Studyofhypo-fractionatedprotonradiationforlowriskprostatecancer

NCT01230866

Randomized(150)

November2010

December2018

MayoClinicCancerCentre,USA

NoResultsAvailable

27 Mishra MV, Aggarwal S, Bentzen SM, Knight N, Mehta MP, Regine WF, Establishing Evidence-Based Indications for Proton Therapy: An Overview of Current Clinical Studies, Int J Radiat Oncol Biol Phys. 2017;97:228-235.

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Protontherapyvs.IMRTforloworintermediateriskprostatecancer

NCT01617161

Randomized(400)

July2012

December2018

NorthwesternMedicineChicagoProtonCentre,USA

NoResultsAvailable

Stereotacticbodyradiotherapy(SBRT)versusstereotacticbodyprotontherapy(SBPT)ofnon-smallcelllungcarcinoma

NCT01511081

Randomized(21)

August2012

October2016

UniversityofTexasMDAndersonCancerCentre,USA

NoResultsAvailable

Randomizedtrialofintensity-modulatedprotonbeamtherapy(IMPT)versusIMRT(photons)fororopharyngealcanceroftheheadandneck

NCT01893307

Randomized(360)

August2013

August2023

UniversityofCaliforniaatSanDiego,USA

NoResultsAvailable

Comparingphotontherapytoprotontherapytotreatpatientswithlungcancer

NCT01993810

Randomized(560)

February2014

December2020

UniversityofFloridaHealthScienceCentre,USA

NoResultsAvailable

Protontherapytoreduceacutenormaltissuetoxicityinlocallyadvancednon-small-celllungcancer

NCT02731001

Randomized(98)

August2016

April2020

DepartmentofRadiotherapyandRadiationOncology,Dresden,Germany

NoResultsAvailable

Phaseiitrialofstandardchemotherapy(carboplatin&paclitaxel)+variousprotonbeamtherapy(PBT)dosesfornon-smallcelllungcarcinoma

NCT03132532

Randomized(120)

July31,2017

December2023

MayoClinicinArizonaandRochester,USA

NoResultsAvailable

Comparisonofprotonversusnonirradiationablativeprocedures

Comparisonbetweenradiofrequencyablationandhypo-fractionatedprotonbeamradiationforrecurrent/residualhepatocellularcarcinoma

NCT01963429

Randomized(144)

October2013

December2018

NationalCancerCentre,Korea

NoResultsAvailable

79

Protonradiotherapyversusradiofrequencyablationforpatientswithmediumorlargehepatocellularcarcinoma

NCT02640924

Randomized(166)

January2016

December2018

ChangGungMemorialHospital,Taiwan

NoResultsAvailable

Datasource:ClinicalStudies.gov;October2017

* Sanford NN, Yeap BY, Larvie M, Daartz J, Munzenrider JE, Liebsch NJ, Fullerton B, Pan E,LoefflerJS,ShihHA,Prospective,RandomizedStudyofRadiationDoseEscalationWithCombinedProton-PhotonTherapyforBenignMeningiomas,IntJRadiatOncolBiolPhys.2017;99:787-796.

From these studies one can expect an objective reduction in rates and grades ofcomplications but without very significant impact on either tumour cure rates or onpatients’qualityof lifeexcept for thehighly functional regionsofbody:headandneck,brain,thorax,spine.

Toanswer thequestionofhow toprogress in this areawithout resorting tounfeasiblestudies, radiation oncologists propose to rely on amodelling of themedium and long-term sideeffects aswell as the riskof secondary cancers.Works in this directionhavebeencarriedout since the1980s,buta recentaccelerationof thesedevelopmentshasbeenpromptedbysocietaldemandforthemostefficientallocationofmedicalresources.

Thepossibilityofpredictingforeachpatienttheeffectofavailabletreatmentsmakes itpossibletooptimizethecosts.Thus,thefieldofModelBasedMedicine,intheserviceofpersonalizing therapeutic choices and optimizing the usefulness of treatments, is thebasisfororganizationsaimingtodevelopprotontherapyinEuropeforyearstocome,inthe framework of ESTRO and EORTC. In this sense the Dutch and French projects areexemplary28.

Carbonionsandotherlightions

Asfaras light ionsareconcerned,thestateofcomparisonwithX-raysorprotonsisnotmuchadvancedbutthedevelopmentofthenumerousNIRSprotocols(Chiba,Japan)hasundoubtedly demonstrated that carbon therapy is effective in the treatment of manyradioresistant tumours. In Europe, treatment reimbursement has been conditioned bythe implementation of prospective studies, some of which are comparative andrandomizedasshowninthetablebelow.Theprocessisbeginningandthereisnoyetamaturestudytoreachaconclusiontoday.

ItshouldbenotedthatthehigherRelativeBiologicalEfficiency(RBE)comparedtotheX-raymakes it difficult to preciselymodel and anticipate the effect of these treatments.Thereforethemedicalmeasurementoftheeffectsproducedbythesetreatmentsreallyrequires making prospective comparisons where the two populations compared and

28 Cheng Q, Roelofs E, Ramaekers BL, Eekers D, van Soest J, Lustberg T, Hendriks T, Hoebers F, van der Laan HP, Korevaar EW, Dekker A, Langendijk JA, Lambin P., Development and evaluation of an online three-level proton vs photon decision support prototype for head and neck cancer - Comparison of dose, toxicity and cost-effectiveness, Radiother. Oncol. 2016;118(2):281-285. See also: http://luz2016.sfpm.fr/Luz/Biblio/S5/05_chaikh.pdf

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treateddifferentlyareasmuchaspossibleidentical.Onlyrandomizationallowsthisinahumanpopulation.

Table B.2 – Prospective comparative and randomized studies of proton therapy versus X-rays(photons)andablativeprocedures.

Nameofthestudies NCTNumber

Typeofstudy(patients)

Datesofenrolment

Centres Results

ComparisonofcarbonionsversusX-ray

Carbonionradiotherapyforprimaryglioblastomavsprotonasaboost.(CLEOPATRA)

NCT01165671

Randomized(150)

July2010

June2014

University ofHeidelberg,Germany

NoResultsAvailable

Carbonionradiotherapyforrecurrentgliomasvsstereotacticrt(CINDERELLA)

NCT01166308

Randomized(436)

August2010

July2014

University ofHeidelberg,Germany

NoResultsAvailable

Randomizedcomparisonofprotonandcarbonionradiotherapywithadvancedphotonradiotherapyinskullbasemeningiomas:thepinocchiotrial.(PINOCCHIO)

NCT01795300

Randomized(80)

March2013

February2015

University ofHeidelberg,Germany

NoResultsAvailable

Randomizedcarbonionsvsstandardradiotherapyforradioresistanttumours(PHRC-ETOILE)

NCT02838602

Randomized(250)

October2017

November2023

France HADRON,Lyon and Pavia,FranceandItaly

NoResultsAvailable

Comparisonofcarbonionsversusprotons

Trialofprotonversuscarbonionradiationtherapyinpatientswithchordomaoftheskullbase

NCT01182779

Randomized(319)

July2010

August2015

End of follow-upAugust2023

University ofHeidelberg,Germany

NoResultsAvailable

81

Trialofprotonversuscarbonionradiationtherapyinpatientswithlowandinter-mediategradechondrosarcomaoftheskullbase

NCT01182753

Randomized(154)

August2010

August2022

University ofHeidelberg,Germany

NoResultsAvailable

Ionirradiationofsacrococcygealchordoma.Carbonvsprotons.(ISAC)

NCT01811394

Randomized(100)

January2013

June2019

University ofHeidelberg,Germany

NoResultsAvailable

Comparisonofhadrontherapyversussurgery

Sacralchordoma:surgeryversusdefinitiveradiationtherapyinprimarylocalizeddisease.(SACRO)

NCT02986516

Randomized(100)

March16,2017

September2021

Europeanmulticentric,Italian sarcomagroup

NoResultsAvailable

Datasource:ClinicalStudies.gov;October2017

Evenifthereisnodoubtthatthesestudieswilldemonstratetheadvantageoflightionscompared with low LET irradiations, randomized studies in this field are even morenecessarythanforprotons.Theimportanceandconditionsofthedifferenceremaintobestudiedandestablished.Itisthereforenecessary,whentheSEEFacilitywillbeopened,tosetupandexpandcollaborativenetworkstoparticipateandinitiatemulti-centricstudies.

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83

APPENDIXC

RADIOTHERAPYDEPARTMENTSINTHESEECOUNTRIESContributedbyAleksandarCelebic

ClinicofOncologyandRadiotherapy,Podgorica,Montenegro

ThenumbersofunitspercentrearelistedinTableC1infollowingtheorder: C1:Electronlinacs, C2:Xraygenerators, C3:Radioisotopes,

C4:Brachytherapysystems,C5:Simulators,C6:ComputerTomography,C7:TreatmentPlanningSystems.

TableC1.Numberofunits

Centre C1 C2 C3 C4 C5 C6 C7

ALBANIA

HygeiaHospital,Tirana 2 1 1 1

MotherTeresaUniHospital,X-KnifeUnit 1 1 2

"MotherTeresa"UniversityHospital,Tirana 1 1 1 2 1

Total 4 1 1 1 4 4

BOSNIAandHERZEGOVINA

Int.MedicalCenter,BanjaLuka 3 2 1 1 5

SveucilišnaKlinickaBolnica,Mostar 2 2 1 2

ClinicalCentreofSarajevoUniversity,Sarajevo 1 1 2 1 1 2

UniversityClinicalCenter,Tuzla 2 1 1 1

KantonalnaBolnica,Zenica 1 1 1

Total 9 1 7 2 5 11

BULGARIA

RegionalCancerCenterHospital,Blagoevgrad 2

ComplexOncologyCenter,Burgas 2 1 1 2

UniversityHospital,Panagyurishte 1

UniversityHospital,Pleven 2 1

84

UniversityHospital,Plovdiv 2 1 3 1

ComplexOncologyCenter,Ruse 1 1 1

InterregionalCancerHospital,Shumen 2 1 2

AcibademCityClinic,TokudaHospital,Sofia 1

AcibademCityClinic,UniGeneralHospital,Sofia 2 1

UniversityHospital"QueenGiovanna-ISUL”,Sofia 2 1 1 4

UniversityHospital"St.IvanRilski",Sofia 1 1

UniHosp.forActiveTreatmentinOncology,Sofia 3 1 1 2 1 1 3

InterregionalCancerCenterHospital,StaraZagora 2 1 2 1 1

SbalozDr.M.Markov,Varna 1 1 1 1

UniversityHospital“SaintMarina”,Varna 3 1 4

RegionalCancerCenterHospital,VelikoTarnovo 1 2 2 1 2

ComprehensiveCancerCenter,Vratsa 1 1 1 2

Total 25 8 6 15 2 10 19

CROATIA

UniversityHospital,Osijek 1 2 1 1

UniversityHospital,Rijeka 2 1 1 2

UniversityHospital,Split 2 2 1 2 1

GynaecologicalCancerCentre,Zagreb 2 1 1 1

UniversityHospitalforTumours,Zagreb 3 1 1 1 2

UniHospitalCentre“Sestremilosrdnice”,Zagreb 1 2 1 1 2

UniversityHospitalCentre,Zagreb 3 1 2 8

Total 14 2 7 5 8 17

GREECE

DemocritusUniversityofGreece,Alexandroupolis 1 1 2 1 1 1

401ArmyGeneralHospital,Athens 1 1

6thOncologyHospital"GeorgeGennimatas",Athens 1 1 1

AgiosSavasOncologicalHospital,Athens 3 2 3 1 1 2

AlexandraHospital,Athens 0 1 2 1 1 1

AreteionHospital,UniversityofAthens 1 1 1 1

AthensChildren'sHospital"P.A.Kyriakou",Athens 1 1 1

85

AthinaionClinic,Athens 1 1 1 1

EvgenidioFoundationHospital,Athens 1 1 1 1

GeneralHospitalof"Attikon",Athens 3 1 2

HygeiaDiagnostic&TherapyCentre,Athens 3 1 4 1 1 6

IASOCenter,Athens 4 2 1 1 3

IatrikoAthinon,Athens 2 2 1 3

IatropolisMagnitikiTomographiaA.E.,Halandri 3 1 2

UniversityHospital,Heraklion 2 3 2 1 2

UniversityHospital,Ioannina 2 1 1

OncologyHospital"AgioiAnargyroi”,Kifissia 1 1 1

UniversityHospital,Larissa 2 1 2 2

IASOThessalias,Larissa 1 1 1

GeneralHospital"OAgiosAndreas",Patras 1 1 1 1

UniversityHospital,Patras 2 1 1 3

MetaxaAnticancerHospital,Pireus 2 1 1 1 2

MetropolitanHospital,Pireus 2 2 1 2 3

GeneralMilitaryArmyHospital,Thessaloniki 1 1 1

AxepaUniversityGeneralHospital,Thessaloniki 2 1 2

CancerHospital"Theagenio”,Thessaloniki 2 1 1 1 2

InterbalcanHospital,Thessaloniki 2 1 2

PapageorgiouGeneralHospital,Thessaloniki 2 2 1 3

Total 47 9 22 17 28 52

KOSOVO*

UniversityClinicalCentreofKosovo,Pristhina 2

FORMERYUGOSLAVREPUBLICOFMACEDONIA

AcibademSistinaHospital,Skopje 1 1 1

UniClinicofRadiotherapyandOncology,Skopje 3 2 1 1 5

Total 4 2 1 2 6

MONTENEGRO

ClinicalCentreofMontenegro,Podgorica 2 2 1 1 5

86

SERBIA

InstituteforOncologyandRadiology,Belgrade 5 2 1 2 3

MilitaryMedicalAcademy,Belgrade 1 1 2 3

NationalGammaCenter,Belgrade 1 1 1

HealthCenter,Kladovo 1 1 2 1

ClinicalCentre,Kragujevac 3 2 1 1 2

ClinicalCenter,Nis 3 2 1 1

InstituteofOncology,SremskaKamenica 4 2 1 1 3

InstofPulmonaryDiseases,SremskaKamenica 1 1

Total 17 2 10 4 9 15

SLOVENIA

InstituteofOncology,Ljubljana 9 1 9 1 2 5

UniversityMedicalCentre,Maribor 2 1 3

Total 11 1 9 1 3 8

TOTALFORALLCOUNTRIES 133 10 21 74 34 70 137

87

APPENDIXD

MATERIALSSCIENCEWITHTHELOW/MEDIUMENERGYBEAMLINEIonbeamsintheMeV/uenergyrangeareparticularlysuitablealsoformaterialsscienceapplications. The installation of a dedicated beam line for materials research,nanoscience,solidstatephysics,mineralogy,geosciencesandmanyotherfieldswouldbehighly valuable in order to substantially broaden the potential user community of theproposed facility. In the following Subsections, the main research fields are brieflysummarized.

IonBeamAnalysis

Ionbeamanalysis(IBA)includesaseriesofanalyticaltechniqueswithMeVionsinordertoprobethecomposition,elementaldepthprofile,localchemistryandstructureofsolids.IBAmethodsarequantitativewithanaccuracyofafewpercentandhighlysensitivewithadepthresolutionoftypicallyfewnanometerstoafewtennanometers.Dependingonthe beamenergy, the analyzeddepth ranges froma few ten nanometers to a few tenmicrometers. Typical examples are PIGE or PIXE (particle induced gamma or X-rayemission) often combined with a microbeam that allows the destruction-freedeterminationof thechemicalcompositionwithmicrometer resolution.Othermethodsmakeuseofback-scatteredprojectiles (RutherfordBack-Scattering,RBS)orrecoils fromthetargetmaterial(ElasticRecoilDetectionAnalysis,ERDA)toprovideinformationaboutmaterialproperties.Nuclearreactionanalysis(NRA)isanuclearmethodthatissensitivetoparticularisotopesandallowsconcentrationmeasurementsvs.depth.

MaterialModification

MeV ions can induce pronouncedmodification of the structural, physical and chemicalproperties of a given material. By implantation of a suitable number of specific ionspecies,e.g.,theelectrical,oxidationorcorrosionbehaviourcanbechanged.

Another interesting application is the production ofmicrofilters by irradiating thin foilsand subsequent track etching. Depending on the choice of ion species, energies andetchingconditions,thesize,lengthandshapeoftheresultingchannelscanbeadjusted.By electrodeposition, the channels in ion-track filters can be filled, thereby allowingproducingnanostructuressuchasnanotips,nanowires,nano-antennasandmanymore.

RadiationHardnessstudies

Ionbeamsarealsousefulfortestingtheradiationhardnessofmaterialsusedfornuclearwastestorageorofelectroniccomponentsforapplicationinspace.Targetedirradiationwith micrometer resolution, using a microbeam, allows identification of the mostsensitivestructuresinmicrochipsandthedevelopmentofappropriatecountermeasures.

88