DrLiao心腦血管藥理、食管癌放療第一頁，共53頁。RadiotherapyChemotherapyLocal-RegionalTumorDistantMicrometastasesCOMBINEDMODALITYTHERAPYConcurrentchemo-radiationimprovesbothlocal-regionaltumorcontrolandsurvivalofNSCLCpatientsbutattheexpenseofincreasedtoxicity第二頁，共53頁。02468LRCDMFSSurvivalTime(Years)SurvivalProportion0257550100OSOutcomeof265NSCLCtreatedwithconcurrentChemoradiation2-year OS41%5-year OS19%第三頁，共53頁。Wangetal.,IJROBP,2006第四頁，共53頁。TheOnsetTimeforMaximalEsophagitisScoreWei,Xiong,IJROBP,2006Grade1-4:93.0%,Grade>=3:20.5%

第五頁，共53頁。Chemo-Radiotherapy-

ImprovementStrategies:Technologyimprovements(IMRT,IGRT,Proton)Moreeffectivechemotherapeuticagentsorconjugates(orradioenhancers)MultimodalitytherapyChemotherapy+Radiotherapy+MolecularTargetingChemotherapy+Radiotherapy+ImmunotherapyChemotherapy+Radiotherapy+Protectors第六頁，共53頁。ThoracicirradiationEsophagealcancerNSCLCSCLCMesotheliomaMajordoselimitingtoxicities:PulmonarytoxicitiesEsophagealtoxicitiesCardiactoxicitiesThoracicRadiationTherapy

第七頁，共53頁。TreatmentRelatedToxicityGradedependsonscoringsystem(SWOG,RTOG,CTC)Patientfactors:smoking,intrinsicsensitivitytointervention,co-morbidity,lungfunctionTumorfactors:GTV,locationTreatmentfactors:

Chemotherapy:agents,schedule,intensityRadiation:dose,volume,fractionation,modality第八頁，共53頁。TRPandscoringsystems

SWOG/CTC第九頁，共53頁。TRPandscoringsystems-RTOG第十頁，共53頁。AuthorPtsno.Radiation-inducedlunginjuryIncreaseNoeffectDecreaseRobnett148Women,lowKPS,lowpre-RTPFTsChem,timingtumorsiteJearmic131Age,chemoSchaake-koning331chemoJohansson405SmokingYamada60Lowertumor,ConcurrentchemRobert43ChemoBrooks80ChemoAge,KPSPuon608ageByhardt461ConcurrentchemoLee79ChemoHernadoetal.intJRadiatOncolbiolphys2001,51:650-659ClinicalFactorsandSymptomaticTRP第十一頁，共53頁。Case1Case2a)b)c)d)CourtesyofDr.ThomasGuerrero,MD,PhDIntrinsicsensitivity第十二頁，共53頁。CourtesyofDr.ThomasGuerrero,MD,PhD第十三頁，共53頁。

Patients:higherincidenceofRPforlowerlobe tumors

YES Graham1995,Yorke2002

Seppenwoolde2004,Bradley2005 NO Yu2003Lungregions,tumorlocation

Responseofmouse/ratlungtopartialvolume base=moresensitivethanapex

Liao1995,TravisandTucker1997 Kahn1998,2002,Moiseenko2000

Vujaskovic,inpress第十四頁，共53頁。TumorlocationandheartdoseMarksetal.MeanheartdosehigherforlowerlobetumorsNoassociationbetweenmeanheartdoseandRT-associateddyspneaBUT:nohigherincidenceofTRPforlowerlobetumorsinthisdataset(Yu2003)Heartdosemaystillbeimportant

第十五頁，共53頁。LungfunctionlossandheartdoseinratsafterprotonirradiationPeterVanLuijkCancerResearch2005;65(15):6509-6511第十六頁，共53頁。ConcurrentChemotherapyandTRPTypeofchemotherapyIntensityofchemotherapyDifferentcombinationsofchemotherapy第十七頁，共53頁。ConcurrentchemotherapyCRTaloneSeppenwooldeetal.2003ConChTandCRTLiao2005TaxanesCisplatin/carboplatinEtoposide第十八頁，共53頁。ConcurrentchemotherapySeppenwooldeetal.2003,inregardtoTsujinoetal.2003

Cisplatin/carboplatinplustaxaneRPgrade

2第十九頁，共53頁。Freedomfromgrade

2TRPasafunctionoftimeWangetal.,inpress第二十頁，共53頁。Freedomfromgrade

2TRPasafunctionoftimeWangetal.,inpress第二十一頁，共53頁。Dose-volumeparametersPointestimatesinDVHspace:Volumeabovethresholddose:

V13,V20,V30

V5Minimumdoseto“hottest”%volume:

D15,D25,D45Overallparameters(wholeDVH)Meanlungdose(MLD)Effectivevolume(Veff)

第二十二頁，共53頁。MLDandTRP第二十三頁，共53頁。CorrelationoflungmeandoseandV5postoperativepneumonia/ARDSWangetal.,IJROBP,2005第二十四頁，共53頁。V5andTRPWangetal.,IJROBP,2006第二十五頁，共53頁。CorrelationofDosimetricfactorsWangetal.,IJROBP,2006第二十六頁，共53頁。NoRPRP02040608010005101520253035V13(%)MeanLungDose(Gy)DosevolumeparametersarehighlycorrelatedSeppenwooldeetal.2003,Liao,2005第二十七頁，共53頁。ReducingToxicityRadiationtechnology3DCRTvsIMRTPhotonvsprotonUnderstandingthebiologyofToxicityCytokineCytoprotectionMoleculartargetofTRTanddevelopmentoftargetedtherapy第二十八頁，共53頁。3D IMRTIntensityModulatedRadiationforLungCancer3DPTV3DTLIMRTIMRT3Deso3Dcord3DheartIMRTIMRTIMRT第二十九頁，共53頁。IMRTReducedTRPforNSCLCtreatedwithconcurrentchemoradiation第三十頁，共53頁。IMRTReducedTRPforNSCLCtreatedwithconcurrentchemoradiation第三十一頁，共53頁。DVHofpatientswith>grade3TRP第三十二頁，共53頁。DVHconsiderationinthoracicRadiotherapy

DoseconstraintforlungV20<35%MeanLungdose<20GyV5<=65%第三十三頁，共53頁。LowDoseRTandLungtoxicity第三十四頁，共53頁。RandomizedTrialof3DCRTvsIMRT第三十五頁，共53頁。PrimaryObjectives

ToComparethetimetodevelopingCTC3.0grade

3TRPinArm1andArm2第三十六頁，共53頁。StatisticalconsiderationsWeassumethepercentageof>=grade3radiationpneumonitis-freeratebyyearisestimatedaccordingtothefollowingtableWeassumeanannual2%or3-year6%loss-to-followup,toget80%power,weneed75patientspergrouporatotalof150evaluablepatients.

Adaptiverandomizationwillbeusedtohave40%:60%accrualinaperiodof2to3yearswithadditional1yearoff/u.Totalstudyduration=3to4years.Averageenrollmentwith2-yraccrual:average:6.3patients/month.Averageenrollmentwith3-yraccrual:average:4.2patients/month第三十七頁，共53頁。ReducingToxicityRadiationtechnology

3DCRTvsIMRTPhotonvsprotonUnderstandingthebiologyofToxicityCytokineCytoprotectionMoleculartargetofTRTanddevelopmentoftargetedtherapy第三十八頁，共53頁。Photon–ProtonComparison

Depthdosecurveforunmodulatedandmodulated160Mevprotonbeamcomparedwiththatof10MVx-raysThex-raybeamfallsexponentiallyafterinitialbuildupwhereasthemaximumintheprotoncurverisesslowlytotheBraggpeakwheretheprotonsstopIftheprotonbeamismodulated,theBraggpeakspreadsoutbutthedoseontheproximalsideoftheBraggplateauisthenlargerthanformonoenergeticprotons.FromVerheyandMunzenrider第三十九頁，共53頁。HighestLETOccursattheEndofBraggPeak150MeVProtons

Duetodecreasingprotonenergy,theLETandRBEincreaseswithdepthofpenetration.NotethattheBiologicalDoseisbothhigheranddeeperthanthePhysicaldose.ItcouldbemuchhigherforspecifictissuesPaganetti,MGH第四十頁，共53頁。T2N2NSCLCProtonsvIMRT第四十一頁，共53頁。ReducingToxicityRadiationtechnology

3DCRTvsIMRTPhotonvsprotonUnderstandingthebiologyofToxicityCytokineCytoprotectionMoleculartargetofTRTanddevelopmentoftargetedtherapy第四十二頁，共53頁。Cyto-protection-AmifostineMeta-analysis,Sasseetal.,IJROBP,2006第四十三頁，共53頁。PericardialEffusionXiongWeietal.,ASTRO,2006第四十四頁，共53頁。CardiacToxicity-PericardialEffusionXiongWeietal.,ASTRO,2006C第四十五頁，共53頁。RTNRTMyocardialIschemiaGayedetal.,第四十六頁，共53頁。AcuteEsophagitis-Sco