肝癌综合治疗课件

肝癌的综合治疗

MultidisciplinaryStrategiestoManagementofHCC背景绝大多数（80-90％）的HCC合并肝硬化HCC治疗策略应考虑对肿瘤作用，并避免肝功能损害HCC的分期系统也应同时考虑肿瘤因素，和肝功能损害的严重性至今尚未有公认的HCC的分期系统肝癌的BCLC分期系统目前在西方国家应用较广，对治疗有指导意义。HCC的BCLC分期系统和治疗推荐LivertransplantPEI/RFCurativetreatmentsTACEHCCSingleIncreasedAssociated

diseasesNormalNoYesNoYesTerminal

stagePST0-2,Child-PughA-BMultinodular,PST0Portalinvasion,

N1,M1SorafenibPortalpressure/bilirubin3nodules≤3cmIntermediatestagePST>2,Child-PughCVeryearlystageSingle<2cmEarlystageSingleor3nodules

≤3cm,PST0AdvancedstagePortalinvasion,

N1,M1,PST1-2PST0,Child-PughAResectionSymptomatic(unlessLT)LlovetJM,etal.JNatlCancerInst.2008;100:698-711.

BruixJ,etal.Hepatology.2005;42:1208-1236.治疗的目的肿瘤缩小改善生命质量延长生存QALYHCC治疗选择早期HCC外科切除（肝部分切除）肝移植经皮毁损（PEI，RFA，HIFU，冷冻，微波）进展期HCCTACE系统治疗（化疗）新治疗（分子靶向，放疗…）早期肝癌Pre-operativeTACE+ResectionDownstagingresection：术后5年生存率≈小肝癌 肝动脉插管＋结扎/TACE/Chemotherapy？减小瘤体：手术简单，且控制微小病灶减少血供：手术安全减少术中播散Zhou2009AnnSurg2009;249:195–202Pre-operativeTACERisk：可切除－－不可切除对肝功能差的病人：进一步损害肝功能Japan：RCT结果类似（SasakiA.EurJSurgOncol.2006;32:773–9.）肝移植术后复发（周俭教授）肝源等待：BridgeTreatmentsofHepatocellularCarcinomainCirrhoticPatientsSubmittedtoLiverTransplantation.DigDisSci(2008)53:2830–2831TACE:BridgetoOLTDoesnotimprovelong-termsurvival(gradeC).NoconvincingevidencethatTACEallowstoexpandthecurrentselectioncriteriaforOLT,northatTACEdecreasesdropoutratesonthewaitinglist(gradeC).TACEdoesnotincreasetheriskforpostoperativecomplications(gradeC).ThereisinsufficientevidencethatTACEoffersanybenefitwhenusedpriortoOLT,neitherforearlynorforadvancedHCC.Americanjournaloftransplantation2006;6(11):2644-50.小肝癌2.8cmPEIorRFA?

PEI

3y 5y

ChildA(survival3vs.5y.) 79% 47%ChildB(survival3vs.5y.) 63% 29%ChildC(survival3vs.5y.) 12% 0% AASLD2004:Leoncinietal.(n=104):

PEI RFATumordestruction 82% 98%2-ySurvival 96% 98%2-yRecurrence 32% 10%RFvsPEILocalablativetherapiesinHCC:percutaneousethanolinjectionandradiofrequencyablationRFAissuperiortoPEIfortreatingsmallHCCsurvivalafterPEIorRFAincomparisonwithsurgeryTACE+PEI/RFAsurvivalwasimprovedfurther.DigDis.2009;27(2):148-56.RFvsResectionAnnSurg2006;243:321–328)ChenMS.AnnSurg2006;243:321–328PuzzlePre-TACE+ResectionnousePre-TACE+RFimprovedRF=ResectionRadicalresection＋IFN-a

resection+IFNresectionOS:63.8months38.8monthsP=0.0003DFS:31.2months17.7monthsP=0.142SunHC.JCancerResClinOncol2006;132:458-65PostadjuvantTACEPostadjuvantTACEApproved&InvestigationalNoncurativeAgentsforUnresectableHCCAASLD2005recommendationsChemoembolization(TACE)(withdoxorubicin,cisplatin,ormitomycin)isrecommendedasfirst-line,noncurativetherapyfornonsurgicalpatientswithlarge/multifocalHCCwhodonothavevascularinvasionorextrahepaticspread(andarenoteligibleforpercutaneousablation)(levelI)Tamoxifen,octreotide,antiandrogens,andhepaticarteryligation/embolizationarenotrecommended(levelI);otheroptionssuchasdrug-elutingbeads,radiolabelledyttriumglassbeads,radiolabelledlipiodol,orimmunotherapycannotberecommendedasstandardtherapyforadvancedHCCoutsideclinicaltrialsBruixJ,etal.Hepatology.2005;42:1208-1236.TACEIntra-arterialLocoregionalTherapyEstablishedTACERadioembolization:yttrium-90radioactivemicrospheresUndergoingclinicaltrialsDrug-elutingbeadsPrimaryTreatmentModalityUsedinKoreaTACE48.2%RFA1.5%Surgery11.2%Chemotherapy7.5%Radiotherapy2.1%Conservativetreatment29.5%N=1078Joong-WonPark,MD,NationalCancerCenter.Adaptedwithpermission.Chemoembolization:RandomizedTrials(NearlyIdenticalTechniques)TechniqueSurvival,%Year1Year2Year3TACE573126Supportivecare32113TechniqueSurvival,%Year1Year2TACE8263Supportivecare6327Llovetetal[2]:N=112withunresectableHCC,80%to90%HCVpositive,

5-cmtumors(~70%multifocal)Loetal[1]:N=80withnewlydiagnosedunresectableHCC,80%HBVpositive,7-cmtumors(60%multifocal)1.LoCM,etal.Hepatology.2002;35:1164-1171.

2.LlovetJM,etal.Lancet.2002;359:1734-1739.Chemoembolization:PredictorsofSurvivalLoetal[1]Absenceofpresentingsymptoms(ECOGPS<2)AbsenceofportalveinobstructionTumorsize(≤vs>5cm)Okudastage(IvsII)Llovetetal[2]Absenceofconstitutionalsyndrome(ECOGPS<2)LowserumbilirubinTreatmentresponse(modifiedWHOcriteria,>6months)1.LoCM,etal.Hepatology.2002;35:1164-1171.

2.LlovetJM,etal.Lancet.2002;359:1734-1739.LargestProspectiveStudyofTACEforUnresectableHCCtoDateN=8510patientsPrimaryendpoint:OSMultivariateanalysisconductedoffactorsaffectingsurvivalOSYear1:82%;Year3:47%;Year5:26%;Year7:16%OSbetterwithlesserdegreeofliverdamageFactorsaffectingsurvivalChild-PughstageTNMstage(OSbetterwithstageI,increasinglyworseprogressingtowardstageIV)Alpha-fetoproteinlevelTakayasuK,etal.Gastroenterology.2006;131:461-469.TACEvsSurgicalResection:ACase-ControlProspectiveStudyTechniqueSurvival,%Year1Year2Year3Year5TACE96805630Surgicalresection90807052N=182,~70%HBVpositive,99%OkudastageI,76%withtumors<3cmSurgerysuperiortoTACEfortumorssmallerthan2cmand/orCLIPstage0BUTfortumors>3cmand/orCLIPstage1-2,5-yearsurvivalidenticalforbothgroups(27%)MedianOS(P=.1529)Resection:65.1monthsTACE:50.4monthsLeeHS,etal.JClinOncol.2002;20:4459-4465.Chemoembolization:EfficacyBeforeTransplantation

Majorissue:dropoutrate(~20%)LowerinUSsinceadoptionofMELDcriteriaRoleofTACEControltumorandpreventprogressionShouldbeconsideredifwaitingtime>6monthsComplicationsfromTACE:rare(noincreasedrateofhepaticarterycomplications)RichardHM3rd,etal.Radiology.2000;214:775-779.GraziadeiIW,etal.LiverTranspl.2003;9:557-563.AlbaE,etal.AmJRoentgenol.2008;190:1341-1348.CanTACEBeUsedasaDeterminantofTumorBiology?

96consecutivepatientstreated

withTACE62exceededMilancriteria34meetingMilancriterialistedimmediately50patientstransplanted27exceededMilancriteriaOttoG,etal.LiverTranspl.2006;12:1260-1267.FunctionalDecompensation(n=1)PatientswithHCC;

age£65yearswithoutcontraindicationagainstLT

(n=96)Milancriteriafulfilled

(n=34)ListingTACEMilancriteriaexceeded

(n=62)6weeks6weeks6weeksTACEListing(n=34)WL(n=4)WL(n=1)Progress(n=6)Functionaldecompensation(n=5)Functionaldecompensation(n=1)Extrahepatic

disease(n=5)Stable 18Progress* 927LTStable 21Progress223LTTACERegressStableorprogress(n=23)RestagingOttoG,etal.LiverTranspl.2006;12:1260-1267.TransplantedAllpatientsTACEnonrespondersOverall5-yearsurvival:51.9%Highlysignificantdifferencein5-yearsurvivalbetweendownstaged(transplanted)patientsandpatientsnotrespondingtoTACE

(P<.0001)SurvivalcalculatedfromthebeginningofTACEtreatmentSurvival00.81.00365730109514601825Days80.9%51.9%0%ResponsetoTACEasaBiologicalSelectionCriterionforLTinHCCTACEnonrespondersTACErespondersOttoG,etal.LiverTranspl.2006;12:1260-1267.ResponsetoTACEasaBiologicalSelectionCriterionforLTinHCC0FreedomFromRecurrence00.81.0365730109514601825Days35.4%94.5%P=.0017AbsolutecontraindicationsChild-PughclassCdiseasePoorperformancestatus(ECOGPS>2)RelativecontraindicationExtrahepaticdisease(benefitunclear)FormercontraindicationPVTMinimizeembolizationandbemoreselectiveChemoembolization:IneligibilityCriteria32patientswithHCCandPVTMedianOS:10monthsChild-Pughscore:bestprognosticfactor(ie,moststronglyrelatedtosurvival)30-daymortality:0%NoevidenceofTACE-relatedhepaticinfarctionoracuteliverfailureSafety&EfficacyofTACEinPatientsWithUnresectableHCC&PVTGeorgiadesCS,etal.JVascIntervRadiol.2005;16:1653-1659.

Radioembolization:Useofintra-arteriallydeliveredyttrium-90microspheresemittinghigh-doseradiationforthetreatmentoflivertumorsYttrium-90microspheresAveragediameter:20-30µm

100%purebetaemitter(0.9367MeV)Physicalhalf-life:64.2hoursIrradiatestissuewithaveragepathlengthof2.5mm

(maximum:11mm)Intra-arterialRadioembolizationWithYttrium-90:RationaleandHistoryMurthyR,etal.BiomedImagingIntervJ.2006;3:e43.

ClinicalResponsetoYttrium-90MicrospheresOutcomeDancey

etal[1]

(N=20)Carretal[2]

(N=65)Geschwind

etal[3]

(N=80)Salem

etal[4]

(N=43)Responserate,%3947Mediansurvival378days

(>104Gy)OkudastageI649days628days24.4mosOkudastageII302days384days12.5mos1.DanceyJE,etal.JNuclMed.2000;41:1673-1681.2.CarrBI.LiverTranspl.2004;10(2suppl1):S107-S110.3.GeschwindJF,etal.Gastroenterology.2004;127(5suppl1):S194-S205.4.SalemR,etal.JVascIntervRadiol.2005;16:1627-1639.PhaseIIstudy:N=108(37withPVT,71withoutPVT)Stratifiedbytoxicity:Child-Pughscore(incirrhotics),dose,locationofPVTMediandose:134GyPartialresponserate:42%(WHO),70%(EASL)AdverseeventratehighestinpatientswithmainPVTandcirrhosisMediansurvival,mainPVT:260daysBranchPVT:370daysNoPVT:460daysYttrium-90RadiotherapyforHCCPatientsWithandWithoutPVTKulikLM,etal.Hepatology.2008;47:5-7.

LessonsLearnedPatientselectionGoodperformancestatus(ECOGPS<2)Totalbilirubin<2.0mg/dL(possibly<1.4mg/dL)Tumorburden<50%90YorTACE:Whichisbestfor

first-linetreatmentofHCC?27patientswithChild-PughAstagediseaseResponserate(assessedbyCT)at6

months:75%1-and2-yearsurvivalrates:92%and89%

Medianfollow-up:28

monthsVarelaM,etal.JHepatol.2007;46:474-481.Doxorubicinat

Serum(ng/mL)Doxorubicinat

Serum(ng/mL)DEB-TACEConventionalTACETimePostprocedureTimePostprocedure0200400600800100002004006008001000BL5mins20mins40mins60mins2hrs6hrs24hrs48hrs7daysBL5mins20mins40mins60mins2hrs6hrs24hrs48hrs7daysTACEWithDoxorubicin-ElutingBeads:EfficacyandPharmacokineticsCourtesyJean-FrancoisGeschwind,MD.65-Year-OldWoman,Child-PughBDisease,andLargeHCC:FirstTreatmentPosttreatment1:ResidualViableTumorPretreatmentPretreatmentandPosttreatment1CourtesyJean-FrancoisGeschwind,MD.SecondTreatmentCourtesyJean-FrancoisGeschwind,MD.UnderwentsuccessfulresectionTumorfree16monthsafterinitialtreatmentMRIPosttreatment2CourtesyJean-FrancoisGeschwind,MD.TACEacceptedastreatmentofchoiceforunresectable(nonablatable?)HCCProlongedsurvivalestablishedthroughrandomizedtrialsandprospectivestudiesBestvsgoodperformancestatus,Child-PughclassA-BRoleforyttrium-90microspheresGrowingrolefordoxorubicin-loadedbeads,pendingoutcomeofclinicaltrialsConclusionsChemotherapyChemo-immunotherapyRadiotherapyConclusionThereislackofeffectivetreatmentforpatientswithadvancedHCCNewtreatmentoptionsareneeded分子靶向TreatmentofAdvancedHCC

(BCLCStageC)AASLD2005recommendation:nostandardtherapy;patientsshouldenrollinarandomizedclinicaltrial[1]2008recommendation:sorafenibhasbecomethestandardofcareforadvancedHCC[2]ProlongsOSby3months[3]1-yearsurvival:44%[4]

1.BruixJ,etal.Hepatology.2005;42:1208-1236.

2.LlovetJM,etal.JHepatol.2008;48:S20-S37.

3.LlovetJ,etal.ASCO2007.AbstractLBA1.

4.LlovetJ,etal.NEnglJMed.2008;359:378-390.Intermediate/AdvancedHCC:

FutureDforHCCasof

August21,2008,includingImprovingefficacyofRFandTACE(drug-elutingbeads)ExploringalternativetreatmentsforintermediateHCC(yttrium-90)Molecularlytargetedagentsincombinationregimens(advancedHCC)Molecularlytargetedagentsincombinationwithcurrentmodalities(early/intermediateHCC)ImprovingtumortargetingofchemotherapeuticagentsNewmoleculartargetsandnewmolecularlytargetedagentsSorafenib:OngoingStudiesinHCCEurope10studiesapproved4TACE+sorafenib(1phaseI,

1phaseII,2phaseIII)Sorafenib+tegafurSorafenib+erlotinibSorafenib+temsirolimusSorafenibdoseescalationSorafenib+gemcitabine/oxaliplatinBiomarkersAsia-Pacific4studiesapprovedSorafenib+tegafurSorafenib+capecitabine/oxaliplatinSorafenib+bevacizumabSorafenib+gemcitabineUnitedStates4studies(nonactivated)2TACE+sorafenibSorafenib+erlotinibSorafenib+lapatinibEvidenceofBenefitinTreatment

ofHCCTreatmentBenefitEvidenceSurgicaltreatmentsResectionIncreasedsurvivalCaseseriesAdjuvanttherapiesUncertainRandomizedtrial,

meta-analysis,nonblindedLivertransplantationIncreasedsurvivalCaseseriesNeoadjuvanttherapiesTreatmentresponseNonrandomizedtrialsLocoregionaltreatmentPercutaneoustreatmentIncreasedsurvivalCaseseriesRFAvsPEIBetterlocalcontrolRandomizedtrial,

meta-analysis,nonblindedChemoembolizationIncreasedsurvivalRandomizedtrial,

meta-analysis,nonblindedArterialchemotherapyTreatmentresponseCaseseriesInternalradiationTreatmentresponseCaseseriesLlovetJM,etal.JNatlCancerInst.2008;100:698-711.EvidenceofBenefitinTreatment

ofHCC(cont’d)TreatmentBenefitEvidenceSystemictherapiesSorafenibIncreasedsurvivalRandomizedtrial,meta-analysis,doubleblindedTamoxifenNobenefitRandomizedtrial,meta-analysis,doubleblindedChemotherapyNobenefitRandomizedtrial,meta-analysis,nonblindedIFNNobenefitRandomizedtrial,meta-analysis,nonblindedLlovetJM,etal.JNatlCancerInst.2008;100:698-711.KeyPathwaysinHepatocarcinogenesis:PossibleTargetsforNovelTherapiesGrowthfactor-stimulatedreceptortyrosinekinasesignalingWnt/beta-cateninpathwayp13Kinase/AKT/mTORJAK/STATsignalingAngiogenicsignalingpathwaysp53andcellcycleregulatorypathwaysUbiquitin-proteasomepathwayEpigeneticpromotermethylationandhistoneacetylationpathwaysRas-Raf-MEK-MAPKpathwayRobertsLR,etal.SeminLiverDis.2005;25:212-225.

SorafenibinAdvancedHCC:

TheSHARPTrialEntrycriteriaAdvancedHCCNoteligiblefororfailedsurgicalorlocoregionaltherapiesChild-PughclassAdiseaseAtleast1untreatedtargetlesionExclusionsPreviouschemotherapyPreviousmolecularlytargetedtherapyLlovetJM,etal.NEnglJMed.2008;359:378-390.226discontinuedsorafenib86hadanadverseevent61hadradiologicandsystematicprogression28withdrewconsent1hadECOGscoreof43died47hadotherreason297receivedsorafenib(safetypopulation)71includedintheongoingstudy1hadanadverseevent1hadaprotocolviolation299wereassignedtoreceivesorafenib(intent-to-treatpopulation)602underwentrandomization902patientswerescreened300wereexcluded244hadprotocolexclusioncriteria24withdrewconsent15hadanadverseevent11died6werelosttofollow-up303wereassignedtoreceiveplacebo(intent-to-treatpopulation)1hadaprotocolviolation302receivedplacebo(safetypopulation)242discontinuedplacebo90hadanadverseevent62hadradiologicandsystematicprogression25withdrewconsent7hadECOGscoreof46died52hadotherreason60includedintheongoingstudyLlovetJM,etal.Sorafenibinadvancedhepatocellularcarcinoma.NEnglJMed.2008;359:378-390.©2008,MassachusettsMedicalSociety.Allrightsreserved.SorafenibinAdvancedHCC:

TheSHARPTrialSHARPTrial:BaselineCharacteristicsCharacteristicSorafenib

(n=299)Placebo

(n=303)Medianage,yrs64.966.3Male,%8787BCLCstage,%B(intermediate)1817C(advanced)8283Vascularinvasion,%7070LlovetJM,etal.NEnglJMed.2008;359:378-390.LlovetJM,etal.Sorafenibinadvancedhepatocellularcarcinoma.NEnglJMed.2008;359:378-390.©2008,MassachusettsMedicalSociety.Allrightsreserved.MedianOS

Sorafenib:10.7mos

Placebo:7.9mosMedianTTSP

Sorafenib:4.1mos

Placebo:4.9mosMedianTTRP

Sorafenib:5.5mos

Placebo:2.8mosTheSHARPTrial:OSandTimetoProgressionMonthsSinceRandomizationProbabilityof

Survival0.000.250.500.751.0001234567891011121314151617P<.001AOSMonthsSinceRandomizationProbabilityofNo

Symptomatic

Progression01234567891011121314151617P-0.77BTimetoSymptomaticProgression180.000.250.500.751.00MonthsSinceRandomizationProbabilityof

Radiologic

Progression01234567891011PlaceboSorafenibP<0.001CTimetoRadiologicProgression0.000.250.500.751.0012LlovetJM,etal.Sorafenibinadvancedhepatocellularcarcinoma.NEnglJMed.2008;359:378-390.©2008,MassachusettsMedicalSociety.Allrightsreserved.TheSHARPTrial:OSandBaselinePrognosticFactors0.00.51.01.5Sorafenib

BetterPlacebo

BetterSubgroupECOGscore01-2ExtrahepaticspreadNoYesMacroscopicvascularinvasionNoYesMacroscopicvascularinvasion,extrahepaticspread,orbothNoYesHazardRatio(95%CI)00.68(0.50-0.95)0.71(0.52-0.96)0.55(0.39-0.77)0.85(0.64-1.14)0.74(0.54-1.00)0.68(0.49-0.93)0.52(0.32-0.85)0.77(0.60-0.99)LlovetJM,etal.Sorafenibinadvancedhepatocellularcarcinoma.NEnglJMed.2008;359:378-390.©2008,MassachusettsMedicalSociety.Allrightsreserved.AEs,%Sorafenib(N=297)Placebo(N=302)PValueAnyGradeGrade3Grade4AnyGradeGrade3Grade4AnyGradeGrade3or4Overallincidence8052ConstitutionalsymptomsFatigue2231163<1.071.00WeightLoss920100<.001.03DermatologiceventsAlopecia1400200<.001NADryskin800400.04NAHand-footskinreaction21803<10<.001<.001Pruritus8007<10.651.00Rashordesquamation16101100.12.12Other510100<.001.12TheSHARPTrial:Drug-RelatedAEsTheSHARPTrial:Drug-RelatedAEs(Cont’d)AEs,%Sorafenib(N=297)Placebo(N=302)PValueAnyGradeGrade3Grade4AnyGradeGrade3Grade4AnyGradeGrade3or4GastrointestinaleventsAnorexia14<10310<.0011.0Diarrhea39801120<.001<.001Nausea11<10810.16.62Vomiting510310.14.68Voicechanges600100<.001NAHypertension520210.05.28Liverdysfunction<1<10000.50.50Abdominalpainnototherwisespecified820310.007.17Bleeding71041<1.071.00LlovetJM,etal.Sorafenibinadvancedhepatocellularcarcinoma.NEnglJMed.2008;359:378-390.©2008,MassachusettsMedicalSociety.Allrightsreserved.ScheithauerW,etal.Oncology(WillistonPark)2004;18:1161.Hand-FootSyndromeGradingofHand-FootSyndromeGradeSymptom1Minimalskinchangesordermatitis(eg,erythema)withoutpain2Skinchanges(eg,peeling,blisters,bleeding,edema)orpain,

notinterferingwithfunction3Skinchangeswithpain,interferingwithfunctionCommonTerminologyCriteriaforAdverseEvents,Version3.0.Availableat:.AccessedOctober13,2008.StrategiesforManagingAEsHand-footsyndromeCreamsandlotionsAvoidtightfootwearMayrequiredosereductionDiarrheaAntidiarrhealagentsifsevereFatigueConsidermodafinil[新型提神醒脑药物莫达芬尼酸]ormethylphenidate[利他林]ifsevereHypertensionStartoradjustantihypertensivesOriental中位OS：索拉非尼：6.5月安慰剂：4.2月HR=0.68ErlotinibinHCC:EG