东西方肝癌的分析比较

东西方肝癌的分析比较当前第1页\共有40页\编于星期二\22点Asian(n=342)Non-Asian(n=1350)ProportionsurvivingTime(months)0.01.00.202468101214160246810121416GefitinibPlaceboImportanceofEthnicityforMTA

─thelessonsofISELtrial当前第2页\共有40页\编于星期二\22点EGFRmutationratesineachsubgroupStudyCentreNo.ofpatientsAdenoCa(+BAC)(%)M(%)F(%)Smokers(%)n-smokers(%)Taiwan1NTUH624925612956Taiwan2VGH-T3767.452724469Korea3SeoulNU90219331326Japan4NCCTokyo666153693568Japan5AichiCCH596444704271HK6ChineseU7232————China7PekUMCH7648.632.334.8——Italy8*UChieti37510630725Shihetal,IJC2005Chouetal,CCR2005Hanetal,JCO2005Takanoetal,JCO2005*onlyAdenoCaMitsudomietal,JCO2005Lungetal,PAACR2005Muetal,CCR2005Machettietal,JCO2005当前第3页\共有40页\编于星期二\22点LiverCancerintheWorld

FerlayJetal.IARCPress,2001.Men(396,364)/Women(165,972)NorthAmerica(%)2.07/2.61Central&SouthAmerica(%)2.09/4.33Africa(%)6.90/8.69Europe(%)8.21/10.45Asia(%)81.54/74.13Oceania(%)0.25/0.27当前第4页\共有40页\编于星期二\22点GeographicdifferencesintheresultsofclinicaltrialsforadvancedHCC当前第5页\共有40页\编于星期二\22点Sorafenib

Median:46.3weeks(10.7mo)

(95%CI:40.9,57.9)SurvivalProbabilityWeeksHazardratio(S/P):0.69(95%CI:0.55,0.88)

P=0.00058*Placebo

Median:34.4weeks(7.9mo)

(95%CI:29.4,39.4)1.0000.750.500.250808162432404856647202742412051611086738120Patientsatrisk

Sorafenib:027622417912678472572Placebo:299303PhaseIIISHARPTrial

Overallsurvival(Intention-to-treat)LlovetJetal,NEnglJMed.2008Jul24;359(4):378-90

(7.9mo)当前第6页\共有40页\编于星期二\22点ComparisonofTx(-)ControlArmsP’tNoMedianOSPVTTNMStageIVOkudaStageIIIECOGIII/IVSpain10217M23.5%54.9%0%*0%*HK1063M60.0%90.6%14%13%*Spanishtrialsexcluded“End-stagedisease”LlovetJM,Hepatology1999;29:62-7YeungYP,AmJGastroenterol2005;100:1995-2004EASTVSWEST当前第7页\共有40页\编于星期二\22点Randomizedtrials-octreotidevsplacebo当前第8页\共有40页\编于星期二\22点StudySchemaofSHARPandAPStudiesSorafenib400mgbidPlaceboEligibilityAdvancedHCCECOG0-2Child-PughANopriorsystemictherapyStratificationMacroscopicvascularinvasion(portalvein)and/orextrahepaticspreadECOGPSGeographicareaRANDOMIZE当前第9页\共有40页\编于星期二\22点PhaseIIISHARPandAsia-PacificOverallSurvivalSorafenib

Median:10.7months

(95%CI:40.9,57.9)SurvivalProbabilityMonthsHazardratio(sor/pla):0.69

(95%CI:0.55,0.87)

P=0.00058*Placebo

Median:7.9months

(95%CI:29.4,39.4)1.0000.750.500.2502024681012141618SurvivalProbabilitySorafenib

Median:6.5months

(95%CI:5.6-7.6)Placebo

Median:4.2months

(95%CI:3.7-5.5)HR(S/P):0.68P=0.0140.250.500.751.0000Months248101214162022618LlovetJM,etal.NEnglJMed2008:359:378-90

ChengAL,etal.ASCO2008,Abstract4509.

SHARPAsia-Pacific当前第10页\共有40页\编于星期二\22点Asia-PacificLiverCancerStudyvsSHARP:

BaselinePatientCharacteristicsAsia-Pacific

(N=226)SHARP1

(N=602)Medianage(range),years51(23-86)67(21-89)Hepatitisvirusstatus(HBV/HCV),%73/818/28Sex(Male),%8587ECOGPS(0/1/2),%26/69/5 54/38/8Macroscopicvascularinvasion,%3538Extrahepaticspread,%6951BCLCStage(B/C),%4/9617/82No.oftumorsites,%111442353132012≥43513Sitesofdisease,% Lung5021 Lymphnode32261LlovetJ,etal.NEnglJMed2008:359:378-90

.当前第11页\共有40页\编于星期二\22点LlovetJMetal.Lancet.2003;362:1907-1917.EndStageAdvancedStageIntermediateStageEarlyStageSurgicalTreatmentsLocalAblationNewAgentsTACEHCC(30%)Potentiallycurativetreatments5-yrsurvival:50-70%(50-60%)Randomizedtrialsmediansurvivalifuntreated:6-16mo(10%)BSCsurvival<3moHCCtreatmentschedule(BCLC)当前第12页\共有40页\编于星期二\22点Meta-analysisofPhaseIIIclinicalTrialsofHCCDatabasesMedline,Cancerlit,CochraneDatabaseofSystematicReviews,CochraneCentralRegisterofControlledTrials,DatabaseofAbstractsofReviewsofEffect,andASCOProceedings,2005–2007Articles/abstractspublishedJan1996toJun2007TthathavecompletedpatientrecruitmentKeywords:‘Hepatocellularcarcinoma’OR‘livercancer’OR‘HCC’‘Randomizedcontrolledtrial’OR‘randomizedcontrolledstudy’InclusioncriteriaRandomizedcontrolledtrialsofsystemictherapyforHCCpatientswhowerenotresectableandnotsuitableforlocaltherapy(TACE,PEIT,etc.)Placebo/supportivecareasthecontrolarm当前第13页\共有40页\编于星期二\22点Meta-regression:Predictorsofsurvivalofthecontrolgrouppatients(1)VariablesNParameterestimateSETPvalueIntercept113.145960.7443024.2267250.003904ChildA%110.033530.0097333.4450430.010763HBV%110.050190.0167462.9970640.020025Asian11-5.704470.983315-5.801270.000663R2=0.6463.571.88monthsinAsiantrials

5.961.46monthsinnon-Asiantrials.P=0.02ThemeanSDofthemedianoverallsurvivaltimewas

当前第14页\共有40页\编于星期二\22点HCCPS0-2,ChildAorBPS>2orChildCPVT(-)PVT(+)Single2or3,3cm4,3cmICGgood*ICGbad*ResectionAblation,Transplan-tationTACEMainPV(-),extra-hepaticspread(-)MainPV(+)orextra-hepaticspread(+)TACEBSCNewagentsBSCBil.2mg/dlBil.2mg/dlBil.2mg/dlBil.2mg/dlEarlystage(singleor3nodules3cm,PS0)Intermediatestage(multi-nodular,PS0)Advancedstage(portalinvasion,N1,M1,PS1-2Terminalstage(PS>2,ChildC)NTUHpracticeBCLCguidelineResectionAblation,Transplan-tationTACENewagentsBSCSingle,PH(-)Multiple,PH(+)当前第15页\共有40页\编于星期二\22点MakuuchiM.etal,HepatologyResearch2007JapanGuidelineEmbolizationhepaticarterialinfusionchemotherapy当前第16页\共有40页\编于星期二\22点GeographicdifferencesintheetiologyofHCCimplicationinthedevelopmentofMTAs当前第17页\共有40页\编于星期二\22点EtiologyofHCC

—DistinctGeographicDistribution

RiskFactorsHepatitisBvirusHepatitisCvirusAlcoholTobaccoOralcontraceptivesAflatoxinOtherandemergingriskfactors/cofactors

EstimateRange22 4~-5860 12~72458~5712 0~14---10~50

Limitedexposure<5---

EstimateRange20 18~-4463 48~942015~3340 9~51

--- ---

Limitedexposure--- ---

EstimateRange60 40~9020 9~56---11~4122 ---8---

Importantexposure<5 ---BoschFXetal.Gastroenterology2004;127:S5-16.EuropeandUnitedStates(%)Japan(%)AsiaandAfrica(%)当前第18页\共有40页\编于星期二\22点IsHBV-relatedHCCamoreaggressivetumor?IsHBV-relatedHCCassociatedwithmolecularchangeswhichaffectmoleculartherapy?HBV-relatedHCC当前第19页\共有40页\编于星期二\22点HCC─EastvsWestLong-termresultsaftersurgicaltreatmentweresimilarinWestandEastwhenclinicopatnologicfactorswereaccountedfor.PawlikTMetalLiverTransplantation2004;10(suppl1)74-80TaeckDetalLiverTransplantation2004;10(suppl1)58-63

当前第20页\共有40页\编于星期二\22点HBVvs.HCVHCC

ItalianLiverCancergroupSurvivalinpatientswithadvancedHCC.HBV-HCCpatientshadalowersurvivalthanHCV-HCCpatients(p=0.025)PatientswithHBV-HCCtendedtohavepoorprognosis;~CantariniMCetal:AmJGastroenterol2006;101:91-8.

andthedifferencebecamestatisticallysignificantamongpatientswithadvancedHCC当前第21页\共有40页\编于星期二\22点HBVvs.HCVHCCinNTUH

Survivalforpatientswithadvancedds.927patientsreceivingsupportivecareorchemotherapy.EtiologyMedian survival(M)1year(%)3year(%)5year(%)10year(%)HBV2.50.5HCV3.41.1B+C3.40NBNC2.61.0HCV+HCV-HCCpatientshadbettersurvivalthanHBV-HCCpatientsChenCHetal.

EurJCancer.2006Oct;42(15):2524-9.Epub2006Aug22当前第22页\共有40页\编于星期二\22点IsHBV-relatedHCCamoreaggressivetumor?IsHBV-relatedHCCassociatedwithmolecularchangesthatwillaffectmoleculartherapy?HBV-relatedHCC当前第23页\共有40页\编于星期二\22点HBV-vs.HCV-associatedHCC

—GenomicsandProteomicsIizukaNetal.CancerRes2002;62:3939-44.KimWetal.ClinCancerRes2003;9:5493-500.HBVandHCVcausehepatocarcinogenesisbydifferentmechanisms.TheexpressionpatternofproteomeinHCCtissuesiscloselyassociatedwithetiologicfactors当前第24页\共有40页\编于星期二\22点ViralProteinsAndSignalTransductionPathwaysHCVcoreHCVcoreByHsuC,ShenYC,ChengAL当前第25页\共有40页\编于星期二\22点TranscriptomeclassificationofHCC~BoyaultSetal:Hepatol2007;45:42.basedon120surgicallyresectedHCC,includingtranscriptomeanalysison57HCCsand3adenomas,andqRT-PCRvalidationinadditional63HCCs26当前第26页\共有40页\编于星期二\22点MolecularEpidemiologyofHBV

—notallHBVsarethesameGenotypeCisassociatedwithanincreasedriskofHCCinTaiwan.(OR=5.11)

YuMWetal.JNatlCancerInst2005;97:265-72.GenotypeAHBVhasagreaterhepatocarcinogenicpotentialinsub-saharanAfricans.

KewMCetal.JMedVirol2005;75:513-21.GenotypeBisassociatedwithlessdecompensatedlivercirrhosisthangenotypeA,C,orDinUSA.

ChuCJetal.Gastroenterology2003;125:444-51.当前第27页\共有40页\编于星期二\22点SorafenibphaseIIHCCstudy

HCV-vs.HBV-relatedHCCP’tNo.MedianageRace(%) CaucasiansClinicalbenefit(%)PFS(median,M)TTP(median,M)OS(median,M)HCV+337182756.56.512.4HBV+136654533.547.3~Huitzil-MelendezFDetal:ASCO-2007GISymposiumAbstract#173.AretrospectiveanalysisP

.27.05.29当前第28页\共有40页\编于星期二\22点Sub-groupanalysisoftheSHARPtrialHCV1Alcohol2PS3MVI/EHS4(178)(159)0(325)1-2(277)-(421)+(181)OSSorafenib14.010.313.38.914.58.9(m)Placebo7.98.08.85.610.26.7HR0.58(0.37-0.91)0.76(0.50-1.16)0.68(0.50-0.95)0.71(0.52-0.96)0.52(0.35-0.85)0.77(0.60-0.99)TTPSorafenib(m)PlaceboHR0.44(0.25-0.76)0.64(0.40-1.03)0.55(0.40-0.77)0.61(0.42-0.88)0.40(0.23-0.70)0.64(0.48-0.84)1.BolondiL,etal.Abstract129.PosterandoralpresentationatASCO-GI;Orlando,FL;January2008.

2.CraxiA,etal.Posterpresentation.Chicago.USA3.RaoulJ,etal.JClinOncol.2008;25:abstract4587.4.ShermanM,etal.JClinOncol.2008;25:abstract4584.当前第29页\共有40页\编于星期二\22点ThalidomidephaseIIHCCstudy

HCV-vs.HBV-relatedHCCP’tNo.MedianageObjectiveresponse+ AFPresponse(%)TTP(median)OS(median)HCV+3367.527.314.1W32.6WHBV+6153.613.18.3W21.4W~HsuCetal:Proc.ASCO2004:Abs#4198.P61<.001.09.03.08当前第30页\共有40页\编于星期二\22点GeographicfactorsshouldbetakenintoconsiderationintheinterpretationanddesignofclinicaltrialsofadvancedHCC.当前第31页\共有40页\编于星期二\22点PhaseIIstudyofbevacizumab+capecitabineinpatientswithadvanced/metastatichepatocellularcarcinomaHsuC-H1,YangT-S2,HsuC1,TohHC3,EpsteinR4,

HsiaoL-T5,LinZ-Z1,ChengA-L1

(ProcAmSocClinOncol2008:26;#4603)当前第32页\共有40页\编于星期二\22点MedianOS:5.9M(95%CI:4.1-9.7)MedianPFS:2.7M(95%CI:1.5-4.1)Bevacizumabpluscapecitabine

foradvancedHCCOSMedian:5.9M(95%CI:4.1-9.7)PFSMedian:2.7M(95%CI:1.5-4.1)~HsuCHetal:ProcASCO2008:Abstract#4603.

当前第33页\共有40页\编于星期二\22点Worldwide,multicenter,open-label, 1,200ptswithadvancedHCCStratifyGeographicRegionPriorTACETumorInvasionRandomize1：1Sunitinib37.5mg,qdaslongasclinicalbenefitSorafenib400mg,bidaslongasclinicalbenefitSTUDYA6181170

AMULTI-NATIONAL,RANDOMIZED,OPEN-LABEL,PHASEIIISTUDYOFSUNITINIBVERSUSSORAFENIBINPATIENTSWITHADVANCEDHEPATOCELLULARCARCINOMA当前第34页\共有40页\编于星期二\22点ConclusionSignificantgeographicdifferencesinclinicalpracticeandetiologyareobservedinHCC.Thesedifferencessignificantlyaf