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1、肝癌的综合治疗肝癌的综合治疗Multidisciplinary Strategies to Management of HCC复旦大学肝癌研究所背景背景绝大多数（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的的BCLC分期系统和治疗推荐分期系统和治疗推荐Liver transplantPEI/RFCurative treatmentsTACEHCCSingleIncreasedAssociateddis
2、easesNormalNoYesNoYesTerminalstagePST0-2,Child-PughA-BMultinodular,PST0Portalinvasion,N1,M1SorafenibPortalpressure/bilirubin3nodules3cmIntermediate stagePST2,Child-PughCVery early stageSingle2,Child-PughCVery early stageSingle2,Child-PughCVery early stageSingle2cmEarly stageSingleor3nodules3cm,PST0A
3、dvanced stagePortalinvasion,N1,M1,PST1-2PST0,Child-PughAResectionSymptomatic(unless LT)LlovetJM,etal.JNatlCancerInst.2008;100:698-711.BruixJ,etal.Hepatology.2005;42:1208-1236.RCTs(50%)Median survival:11-20 mosApproved&Investigational Noncurative Agents for Unresectable HCCAASLD2005recommendationsChe
4、moembolization(TACE)(withdoxorubicin,cisplatin,ormitomycin)isrecommendedasfirst-line,noncurativetherapyfornonsurgicalpatientswithlarge/multifocalHCCwhodonothavevascularinvasionorextrahepaticspread(andarenoteligibleforpercutaneousablation)(levelI)Tamoxifen,octreotide,antiandrogens,andhepaticarterylig
5、ation/embolizationarenotrecommended(levelI);otheroptionssuchasdrug-elutingbeads,radiolabelledyttriumglassbeads,radiolabelledlipiodol,orimmunotherapycannotberecommendedasstandardtherapyforadvancedHCCoutsideclinicaltrialsBruixJ,etal.Hepatology.2005;42:1208-1236.TACEIntra-arterial Locoregional TherapyE
6、stablishedTACERadioembolization:yttrium-90radioactivemicrospheresUndergoingclinicaltrialsDrug-elutingbeadsPrimary Treatment Modality Used in KoreaTACE 48.2%RFA1.5%Surgery 11.2%Chemotherapy7.5%Radiotherapy2.1%Conservative treatment 29.5%N=1078Joong-Won Park,MD,National Cancer Center.Adapted with perm
7、ission.Chemoembolization:Randomized Trials(Nearly Identical Techniques)TechniqueSurvival,%Year 1Year 2Year 3TACE573126Supportivecare32113TechniqueSurvival,%Year 1Year 2TACE8263Supportivecare6327Llovet et al2:N=112withunresectableHCC,80%to90%HCVpositive,5-cmtumors(70%multifocal)Lo et al1:N=80withnewl
8、ydiagnosedunresectableHCC,80%HBVpositive,7-cmtumors(60%multifocal)1.LoCM,etal.Hepatology.2002;35:1164-1171.2.LlovetJM,etal.Lancet.2002;359:1734-1739.Chemoembolization:Predictors of SurvivalLoetal1Absenceofpresentingsymptoms(ECOGPS5cm)Okudastage(IvsII)Llovetetal2Absenceofconstitutionalsyndrome(ECOGPS
9、6months)1.LoCM,etal.Hepatology.2002;35:1164-1171.2.LlovetJM,etal.Lancet.2002;359:1734-1739.Largest Prospective Study of TACE for Unresectable HCC to Date N=8510patientsPrimaryendpoint:OSMultivariateanalysisconductedoffactorsaffectingsurvivalOSYear1:82%;Year3:47%;Year5:26%;Year7:16%OSbetterwithlesser
10、degreeofliverdamageFactorsaffectingsurvivalChild-PughstageTNMstage(OSbetterwithstageI,increasinglyworseprogressingtowardstageIV)Alpha-fetoproteinlevelTakayasuK,etal.Gastroenterology.2006;131:461-469.TACE vs Surgical Resection:A Case-Control Prospective StudyTechniqueSurvival,%Year 1Year 2Year 3Year
11、5TACE96805630Surgicalresection90807052N=182,70%HBVpositive,99%OkudastageI,76%withtumors3cmand/orCLIPstage1-2,5-yearsurvivalidenticalforbothgroups(27%)MedianOS(P=.1529)Resection:65.1monthsTACE:50.4monthsLeeHS,etal.JClinOncol.2002;20:4459-4465.Chemoembolization:Efficacy Before Transplantation Majoriss
12、ue:dropoutrate(20%)LowerinUSsinceadoptionofMELDcriteriaRoleofTACEControltumorandpreventprogressionShouldbeconsideredifwaitingtime6monthsComplicationsfromTACE:rare(noincreasedrateofhepaticarterycomplications)RichardHM3rd,etal.Radiology.2000;214:775-779.GraziadeiIW,etal.LiverTranspl.2003;9:557-563.Alb
13、aE,etal.AmJRoentgenol.2008;190:1341-1348.Can TACE Be Used as a Determinant of Tumor Biology?96consecutivepatientstreatedwithTACE62exceededMilancriteria34meetingMilancriterialistedimmediately50patientstransplanted27exceededMilancriteriaOttoG,etal.LiverTranspl.2006;12:1260-1267.FunctionalDecompensatio
14、n(n=1)PatientswithHCC;age65yearswithoutcontraindicationagainstLT(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)Extrahepaticdisease(n=5)Stable18Progress*927
15、LTStable21Progress223LTTACERegressStableorprogress(n=23)RestagingOttoG,etal.LiverTranspl.2006;12:1260-1267.TransplantedAllpatientsTACEnonrespondersOverall5-yearsurvival:51.9%Highlysignificantdifferencein5-yearsurvivalbetweendownstaged(transplanted)patientsandpatientsnotrespondingtoTACE(P2)Relativeco
16、ntraindicationExtrahepaticdisease(benefitunclear)FormercontraindicationPVTMinimizeembolizationandbemoreselectiveChemoembolization:Ineligibility Criteria32patientswithHCCandPVTMedianOS:10monthsChild-Pughscore:bestprognosticfactor(ie,moststronglyrelatedtosurvival)30-daymortality:0%NoevidenceofTACE-rel
17、atedhepaticinfarctionoracuteliverfailureSafety&Efficacy of TACE in Patients With Unresectable HCC&PVTGeorgiadesCS,etal.JVascIntervRadiol.2005;16:1653-1659.Radioembolization:Useofintra-arteriallydeliveredyttrium-90microspheresemittinghigh-doseradiationforthetreatmentoflivertumorsYttrium-90microsphere
18、sAveragediameter:20-30m 100%purebetaemitter(0.9367MeV)Physicalhalf-life:64.2hoursIrradiatestissuewithaveragepathlengthof2.5mm(maximum:11mm)Intra-arterial Radioembolization With Yttrium-90:Rationale and HistoryMurthyR,etal.BiomedImagingIntervJ.2006;3:e43.Clinical Response to Yttrium-90 MicrospheresOu
19、tcomeDancey et al1(N=20)Carr et al2(N=65)Geschwind et al3(N=80)Salem et al4(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,et
20、al.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)Adverseeventratehighestinpatientswith
21、mainPVTandcirrhosisMediansurvival,mainPVT:260daysBranchPVT:370daysNoPVT:460daysYttrium-90 Radiotherapy for HCC Patients With and Without PVTKulikLM,etal.Hepatology.2008;47:5-7.Lessons LearnedPatientselectionGoodperformancestatus(ECOGPS2)Totalbilirubin2.0mg/dL(possibly1.4mg/dL)Tumorburden50%90Y or TA
22、CE:Which is best for first-line treatment of HCC?27patientswithChild-PughAstagediseaseResponserate(assessedbyCT)at6months:75%1-and2-yearsurvivalrates:92%and89%Medianfollow-up:28monthsVarelaM,etal.JHepatol.2007;46:474-481.Doxorubicin at Serum(ng/mL)Doxorubicin at Serum(ng/mL)DEB-TACEConventional TACE
23、Time PostprocedureTime Postprocedure0200400600800100002004006008001000BL5mins20mins40mins60mins2hrs6hrs24hrs48hrs7daysBL5mins20mins40mins60mins2hrs6hrs24hrs48hrs7daysTACE With Doxorubicin-Eluting Beads:Efficacy and Pharmacokinetics CourtesyJean-FrancoisGeschwind,MD.65-Year-Old Woman,Child-Pugh B Dis
24、ease,and Large HCC:First TreatmentPosttreatment 1:Residual Viable TumorPretreatmentPretreatment and Posttreatment 1CourtesyJean-FrancoisGeschwind,MD.Second TreatmentCourtesyJean-FrancoisGeschwind,MD.UnderwentsuccessfulresectionTumorfree16monthsafterinitialtreatmentMRI Posttreatment 2CourtesyJean-Fra
25、ncoisGeschwind,MD.TACEacceptedastreatmentofchoiceforunresectable(nonablatable?)HCCProlongedsurvivalestablishedthroughrandomizedtrialsandprospectivestudiesBestvsgoodperformancestatus,Child-PughclassA-BRoleforyttrium-90microspheresGrowingrolefordoxorubicin-loadedbeads,pendingoutcomeofclinicaltrialsCon
26、clusionsChemotherapyChemo-immunotherapyRadiotherapyConclusionThereislackofeffectivetreatmentforpatientswithadvancedHCCNewtreatmentoptionsareneeded分子靶向分子靶向Treatment of Advanced HCC(BCLC Stage C)AASLD2005recommendation:nostandardtherapy;patientsshouldenrollinarandomizedclinicaltrial12008recommendation
27、:sorafenibhasbecomethestandardofcareforadvancedHCC2ProlongsOSby3months31-yearsurvival:44%41.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/Advanced HCC:Future Directions499t
28、rialsregisteredatforHCCasofAugust21,2008,includingImprovingefficacyofRFandTACE(drug-elutingbeads)ExploringalternativetreatmentsforintermediateHCC(yttrium-90)Molecularlytargetedagentsincombinationregimens(advancedHCC)Molecularlytargetedagentsincombinationwithcurrentmodalities(early/intermediateHCC)Im
29、provingtumortargetingofchemotherapeuticagentsNewmoleculartargetsandnewmolecularlytargetedagentsSorafenib:Ongoing Studies in HCCEurope10studiesapproved4TACE+sorafenib(1phaseI,1phaseII,2phaseIII)Sorafenib+tegafurSorafenib+erlotinibSorafenib+temsirolimusSorafenibdoseescalationSorafenib+gemcitabine/oxal
30、iplatinBiomarkersAsia-Pacific4studiesapprovedSorafenib+tegafurSorafenib+capecitabine/oxaliplatinSorafenib+bevacizumabSorafenib+gemcitabineUnited States4studies(nonactivated)2TACE+sorafenibSorafenib+erlotinibSorafenib+lapatinibEvidence of Benefit in Treatment of HCCTreatmentBenefitEvidenceSurgical tr
31、eatmentsResectionIncreasedsurvivalCaseseriesAdjuvanttherapiesUncertainRandomizedtrial,meta-analysis,nonblindedLivertransplantationIncreasedsurvivalCaseseriesNeoadjuvanttherapiesTreatmentresponseNonrandomizedtrialsLocoregional treatmentPercutaneoustreatmentIncreasedsurvivalCaseseriesRFAvsPEIBetterloc
32、alcontrolRandomizedtrial,meta-analysis,nonblindedChemoembolizationIncreasedsurvivalRandomizedtrial,meta-analysis,nonblindedArterialchemotherapyTreatmentresponseCaseseriesInternalradiationTreatmentresponseCaseseriesLlovetJM,etal.JNatlCancerInst.2008;100:698-711.Evidence of Benefit in Treatment of HCC
33、(contd)TreatmentBenefitEvidenceSystemic therapiesSorafenibIncreasedsurvivalRandomizedtrial,meta-analysis,doubleblindedTamoxifenNobenefitRandomizedtrial,meta-analysis,doubleblindedChemotherapyNobenefitRandomizedtrial,meta-analysis,nonblindedIFNNobenefitRandomizedtrial,meta-analysis,nonblindedLlovetJM
34、,etal.JNatlCancerInst.2008;100:698-711.Key Pathways in Hepatocarcinogenesis:Possible Targets for Novel TherapiesGrowthfactor-stimulatedreceptortyrosinekinasesignalingWnt/beta-cateninpathwayp13Kinase/AKT/mTORJAK/STATsignalingAngiogenicsignalingpathwaysp53andcellcycleregulatorypathwaysUbiquitin-protea
35、somepathwayEpigeneticpromotermethylationandhistoneacetylationpathwaysRas-Raf-MEK-MAPKpathwayRobertsLR,etal.SeminLiverDis.2005;25:212-225.Sorafenib in Advanced HCC:The SHARP TrialEntrycriteriaAdvancedHCCNoteligiblefororfailedsurgicalorlocoregionaltherapiesChild-PughclassAdiseaseAtleast1untreatedtarge
36、tlesionExclusionsPreviouschemotherapyPreviousmolecularlytargetedtherapyLlovetJM,etal.NEnglJMed.2008;359:378-390.226 discontinued sorafenib86hadanadverseevent61hadradiologicandsystematicprogression28withdrewconsent1hadECOGscoreof43died47hadotherreason297 received sorafenib(safetypopulation)71 include
37、d in the ongoing study1 had an adverse event1 had a protocol violation299 were assigned to receive sorafenib(intent-to-treatpopulation)602 underwent randomization902 patients were screened300 were excluded244hadprotocolexclusioncriteria24withdrewconsent15hadanadverseevent11died6werelosttofollow-up30
38、3 were assigned to receive placebo(intent-to-treatpopulation)1 had a protocol violation302 received placebo(safetypopulation)242 discontinued placebo90hadanadverseevent62hadradiologicandsystematicprogression25withdrewconsent7hadECOGscoreof46died52hadotherreason60 included in the ongoing studyLlovetJ
39、M,etal.Sorafenibinadvancedhepatocellularcarcinoma.NEnglJMed.2008;359:378-390.2008,MassachusettsMedicalSociety.Allrightsreserved.Sorafenib in Advanced HCC:The SHARP TrialSHARP Trial:Baseline CharacteristicsCharacteristicSorafenib(n=299)Placebo(n=303)Medianage,yrs64.966.3Male,%8787BCLCstage,%B(interme
40、diate)1817C(advanced)8283Vascularinvasion,%7070LlovetJM,etal.NEnglJMed.2008;359:378-390.LlovetJM,etal.Sorafenibinadvancedhepatocellularcarcinoma.NEnglJMed.2008;359:378-390.2008,MassachusettsMedicalSociety.Allrightsreserved.Median OSSorafenib:10.7mosPlacebo:7.9mosMedian TTSPSorafenib:4.1mosPlacebo:4.
41、9mosMedian TTRPSorafenib:5.5mosPlacebo:2.8mosThe SHARP Trial:OS and Time to ProgressionMonths Since RandomizationProbability of Survival0 1 2 3 4 5 6 7 8 9 101112 1314151617P.001A OSMonths Since RandomizationProbability of No Symptomatic Progression0 1 2 3 4 5 6 7 8 9 10 11121314151617P B Time to Sy
42、mptomatic Progression18Months Since RandomizationProbability of Radiologic Progression01234567891011PlaceboSorafenibP C Time to Radiologic Progression12LlovetJM,etal.Sorafenibinadvancedhepatocellularcarcinoma.NEnglJMed.2008;359:378-390.2008,MassachusettsMedicalSociety.Allrightsreserved.The SHARP Tri
43、al:OS and Baseline Prognostic FactorsSorafenib BetterPlaceboBetterSubgroupECOGscore01-2ExtrahepaticspreadNoYesMacroscopicvascularinvasionNoYesMacroscopicvascularinvasion,extrahepaticspread,orbothNoYesHazard Ratio(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(
44、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)P ValueAny GradeGrade 3Grade 4Any GradeGrade 3Grade 4Any GradeGrade 3 or 4Overallincidence
45、8052ConstitutionalsymptomsFatigue22311631.071.00WeightLoss920100.001.03DermatologiceventsAlopecia1400200.001NADryskin800400.04NAHand-footskinreaction2180310.001.001Pruritus800710.651.00Rashordesquamation16101100.12.12Other510100.001.12The SHARP Trial:Drug-Related AEsThe SHARP Trial:Drug-Related AEs(
46、Contd)AEs,%Sorafenib(N=297)Placebo(N=302)P ValueAny GradeGrade 3Grade 4Any GradeGrade 3Grade 4Any GradeGrade 3 or 4GastrointestinaleventsAnorexia1410310.0011.0Diarrhea39801120.001.001Nausea1110810.16.62Vomiting510310.14.68Voicechanges600100.001NAHypertension520210.05.28Liverdysfunction110000.50.50Ab
47、dominalpainnototherwisespecified820310.007.17Bleeding710411.071.00LlovetJM,etal.Sorafenibinadvancedhepatocellularcarcinoma.NEnglJMed.2008;359:378-390.2008,MassachusettsMedicalSociety.Allrightsreserved.ScheithauerW,etal.Oncology(WillistonPark)2004;18:1161.Hand-Foot SyndromeGrading of Hand-Foot Syndro
48、meGrade Symptom1Minimalskinchangesordermatitis(eg,erythema)withoutpain2Skinchanges(eg,peeling,blisters,bleeding,edema)orpain,notinterferingwithfunction3Skinchangeswithpain,interferingwithfunctionCommonTerminologyCriteriaforAdverseEvents,Version3.0.Availableat:http:/.AccessedOctober13,2008.Strategies
49、 for Managing AEsHand-footsyndromeCreamsandlotionsAvoidtightfootwearMayrequiredosereductionDiarrheaAntidiarrhealagentsifsevereFatigueConsidermodafinil新型提神醒脑药物莫达芬尼酸ormethylphenidate利他林ifsevereHypertensionStartoradjustantihypertensivesOriental中位中位OS：索拉非尼：月索拉非尼：月安慰剂：月安慰剂：月Erlotinib in HCC:EGFR Inhibito
50、rPhaseIIstudyinpatientswithunresectableHCC(N=40)Oralerlotinib150mg/day,28-daycyclesNoCRsorPRsPFSrateat16weeks:43%Drug-relatedadverseevents:diarrhea,folliculitis,fatigue,pruritus,dryskin,xerostomia,epistaxisThomasMB,etal.Cancer.2007;110:1059-1067.Possible Future Studies in HCCNewtargetedmolecularagen