消化道肿瘤ESMO.ppt

ESMOHighlights2010UpperGI,1,ESPAC-3PANCREASLIVER/BILIARYNETsGASTRICGIP-1ABC-02PROMIDTOGAAIO-PK0104EACHA6181111AVAGASTProdigeIV-Accord11RADIANT-1AIO(2ndline)NCT00219557Conko-4/FRAGEMVEGFRpolymorphisms,ADVANCED,ADJUVANT,Pancreaticcancerbackground,Adjuvant:BothFUandgemcitabineshowntoimproveOSRoleofRTcontroversialAdvanced:Gemcitabinemonotherapy=standardfor10yearsClinicalbenefitin20-30%ofpts;medianOS6-8m;1-yS20-30%Controversialimprovementaddingasecondcytotoxic(fluoropyrimidines,platinumderivatives:positivemeta-analysisbutnegativesinglestudies)Smallimprovement(clinicalrelevancequestioned)addingerlotinib;noimprovementwithotherbiologics(cetuximab,bevacizumab)Oxaliplatin/FU/LV:bestoptionaftergemcitabinefailure(2ndline)Highincidenceofvenousthromboembolism(17-30%),Resectedpancreaticductaladenocarcinoma,FU/LVvsGemcitabine(ESPAC-3),Neoptolemosetal.ASCO2009;AbstractLBA4505,NodifferenceinefficacyBettertoxicityprofilewithgemcitabine(moremyelotoxicitybutlessstomatitisanddiarrhea;lesstxrelatedSAEsoverall)GlobalQLscoresnodifference-ESPAC-4:GEM+/-capecitabine,Survivalbytreatment,PFSbytreatment,Survival(%),12,24,36,48,60,0,25,50,75,100,Monthsfromresection,X2LR=0.74,p=0.39,HRGEMVSSFU/FA=0.94(95%CI:0.81,1.08),0,MedianS(t)=23.0months(95%CI:21.1,25.0),MedianS(t)=23.6months(95%CI:21.4,26.4),5FUFA,GEM,No.atrisk5FUFA5514132491093615GEM5374152511034213,PFS(%),12,24,36,48,60,0,25,50,75,100,Monthsfromresection,X2LR=0.59,p=0.44,HRGEMVSSFU/FA=0.95(95%CI:0.83,1.09),0,MedianPFS(t)=14.1months(95%CI:12.5,15.3),MedianPFS(t)=14.3months(95%CI:13.5,15.7),5FUFA,GEM,No.atrisk5FUFA551296160642311GEM537319152682211,AdvancedpancreaticcancerGemcitabine+/-cisplatin(GIP-1),Additionalnegativerandomizedstudyonagemcitabinedoubletcomparedtogemcitabinealone(previousmeta-analysisnotconfirmed),Coluccietal.ASCO2009:Abstract4504;Coluccietal.JClinOncol2010;28:1645-1651,AdvancedpancreaticcancerAIO-PK0104,Boecketal.ASCO2010;AbstractLBA4011,SimilarOSandoverallTTFwitheithersequence.Gemcitabinemoreactive(responserateandTTF)thancapecitabine(bothas1stand2ndline),AAplacebo,Overallsurvival,TTFafter2ndline(1ryendpoint),Gemcitabine+Erlotinib-CapecitabineCapecitabine+Erlotinib-Gemcitabine,R,(n=281),MetastaticpancreaticcancerGemcitabinevsFOLFIRINOX,(ProdigeIV-Accord11study)n=342(ECOGPS0-1;2/3bodyandtail),Conroyetal.ASCO2010;Abstract4010,Progression-freesurvival,Overallsurvival(1ryendpoint),HR=0.47:95%CI0.37-0.59p0.0001,HR=0.57:95%CI0.45-0.73p0.0001,mPFS:6.4vs3.3mo,mOS:11.1vs6.8mo,Firststudytoshowasuperioroutcome(OS,PFS,andRR)comparedwithgemcitabine.Newtreatmentoptionformetastaticpancreaticcancerbuttoxicitylimitsroutineapplication(grade3-4neutropenia:46%;grade3-4fatigue:25%).Adjuvantstudyplanned,Probability,Months,Months,0.00,0.25,0.50,0.75,1.00,Probability,0,3,6,9,15,18,21,24,27,30,33,36,12,0.00,0.25,0.50,0.75,1.00,0,3,6,9,12,15,18,21,24,27,30,33,36,FOLFIRINOX,FOLFIRINOX,AdvancedpancreaticcancerGemcitabine+/-Axitinib(NCT00219557),AdditionalnegativerandomizedstudyofaVEGFinhibitorcombinedwithgemcitabinecomparedtogemcitabinealone,Kindleretal.ECCO-ESMO2009;AbstractO-6502,Overallsurvival,Months,Probability,0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,0.0,0.20,0.40,0.60,0.80,1.00,Axitinib+gemcitabine8.5months(95%CI:6.9-9.5)Placebo+gemcitabine8.3months(95%CI:6.9-10.3)HR=1.014(95%CI:0.786-1.309)1-sidedp=0.5436,Advancedpancreaticcancer,Lambrechtsetal.ECCO-ESMO2009;Abstract16LBA,OS(overallpopulation),AnalysisofVEGFR-1polymorphismsmayhelpidentifyasubsetderivingbenefitfrombevacizumab,RetrospectiveanalysisofVEGFpolymorphismsintheAVITAtrial,OSbygenotype,Metastaticpancreaticcancer(n=607),Gemcitabine+erlotinib+placebo(n=301),Gemcitabine+erlotinib+bevacizumab(n=306),Survival(%),0,0.4,0.6,0.8,1.0,0,0.2,Time(months),3,6,9,12,15,18,21,24,MedianOSGemcitabine+erlotinib+bevacizumab:7.1MonthsGemcitabine+erlotinib+placebo:6.0monthsp=0.2087;HR=0.89(95%CI:0.74-1.07),0,0.4,0.6,0.8,0,0.2,Timeonstudy(days),200,400,600,800,1.0,AAbeva,AAplacebo,AdvancedpancreaticcancerRoleoflowmolecularweightheparin,ProphylacticLMWHconcomitanttochemotherapy(atleast3months)significantlyreducestherateofthromboembolicevents(butdoesnotimprovesurvival),FRAGEMSTUDY,CONKO-41st-linechemo+/-enoxaparin,FRAGEM1st-linechemo+/-dalteparin,VTE(first3months),p0.01,%,RiessASCO2009-2010;PelzerECCO-ESMO2009,MaraveyasECCO-ESMO2009,%,0.00,4.00,6.00,8.00,10.00,2.00,Observation,Enoxaparin,9.9%,1.3%,VTEprofile,ControlLMWH,0,10,20,25,35,5,RR=0.38p0.02,RR=0.138p0.002,RR=0.046p0.001,RR=0.083p0.028,AllOverall,100D,ClinicalVTEpotentialtargetforanti-angiogenicagents(promisingactivityofmultipleanti-vascularagentsinphaseIIstudiessupportsthehypothesis),Well-differentiateduntreatedmid-gutNETs,OctreotideLARvsplacebo,PROMID,Arnoldetal.ASCO200;Abstract4508:Rinkeetal.JClinOncol2009;27:4656-4663,SignificantTTPimprovementindependentoffunctionalandCgAstatus-supportananti-proliferativeeffectofoctreotideLAR,HR:0.3395%CI:0.19-0.55p=0.000017,0.00,0.50,0.75,1.00,0.25,0,12,24,36,48,Time(months),54,66,78,90,Proportionwithoutprogression,OctreotideLAR:42patients/27eventsMedian15.6months95%CI:11.0-29.4,Placebo:43patients/41eventsMedian5.9months95%CI:5.5-9.1,6,18,30,42,60,72,84,Progressing,well-differentiatedpancreaticNETs,Sunitinibvsplacebo*,StudyA6181111,*WithBSC.Somatostatinanalogswerepermitted,Raouletal.ECCO-ESMO2009:AbstractO-6501;Raymondetal.ASCO2010;Abstract4031,PFS(primaryendpoint),Earlyterminationduetodifferenceinefficacyatinterimanalysis(154of340ptsrandomized),Strongsupportforclinicaluse(1ryendpointmet/initialeffectonsurvivalobserved/efficacymaintainedacrossdifferentsubtypesinsubgroupanalysis)VEGFconfirmedtobeacrucialtargetinNETs,Overallsurvival,0,0.6,0.8,1.0,0.4,0,5,10,Time(months),15,20,25,HR=0.418(95%CI0.263,0.662)p=0.0001,SunitinibPlacebo,MedianPFS11.4months(95%CI7.4,19.8)5.5months(95%CI3.6,7.4),Proportionofpatients,0.2,0,0.6,0.8,1.0,0.4,0,5,10,Time(months),15,20,25,HR=0.409(95%CI0.187,0.894)p=0.0204,SunitinibPlacebo,Proportionofpatients,0.2,PancreaticNETsprogressingafter1st-lineTx,Oraleverolimus,Paveletal.ECCO-ESMO2009:AbstractPD-6514;Yaoetal.JClinOncol2010;28:69-76,Stratum1Stratum2RR,%9.64.4mPFS,m9.716.7mOS,m24.9notreachedCgAreponse,%50.760.0,RADIANT-1(PHASEIISTUDY),Dailyeverolimushasanti-tumoractivityinpre-treatedpancreaticNETs(consistentwithpreviousdataonuntreatedNETs),Stratum1notbeingtreatedwithoctreotideLARatstudyentry(n=115),Stratum2onoctreotideLARsince3monthsatstudyentry(n=45),Gastriccancerbackground,Early:Peri-operativeCT:13%5-ysurvivalimprovementPost-opchemoradiation:10%3-ysurvivalimprovementPost-opchemotherapy:5%5-ysurvivalimprovementAdvanced:PalliativechemotherapyimprovessurvivalandQoLCombinationchemobetterthansingleagent(butthreedrugregimensnotclearlybetterthanplatinum/FUdoublets):CF(CIFU+cisplatinum)RR:20-30%;mOS:8-9monthsCapecitabinemayreplaceCIFUECF(CIFU+cisplatinum+epidoxorubicin)RR:40-45%;mOS:9monthsCapecitabinemayreplaceCIFU;oxaliplatinmayreplacecisplatinumDCF(CIFU+cisplatinum+docetaxel)RR:36%;mOS:9monthsToxicityisanissue,VanCutsemetal.ASCO2009;AbstractLBA4509:VanCutsemetal.ECCO-ESMO2009;Abstract7BA,TrastuzumabsignificantlyimprovestheefficacyandactivityofchemotherapyinHER-2+advancedgastriccancer(greaterbenefitinptswithhigherimmunoreactivityinexploratoryanalysis)-standardoptioninthisgroupofpatients,AdvancedgastriccancerToGAtrial,0,0.6,0.8,1.0,0.4,0,4,12,Time(months),20,24,32,HR=0.71(95%CI0.59,0.85)p=0.0002,0.2,8,16,28,PFS,5.5,6.7,0,0.6,0.8,1.0,0.4,0,Time(months),HR=0.74(95%CI0.60,0.91)p=0.0046,0.2,OS(1ryendpoint),11.1,13.8,3807patientsscreened810HER-2positive(22.1%),HER-2positiveadvancedGC(n=584),R,5-FUorcapecitabine+cisplatin(n=290),5-FUorcapecitabine+cisplatin+trastuzumab(n=294),34,30,26,22,18,14,10,6,2,0,4,12,20,24,32,8,16,28,34,30,26,22,18,14,10,6,2,36,Advancedgastriccancer,Kangetal.ASCO2010;AbstractLBA4007,Cape/CDDP+/-bevacizumab(AVAGAST),Useofbevacizumabinadvancedgastricadenocarcinomanotsupported(1ryend-pointOSnotmet-negativestudy).The(modest)effectonRRandPFS(andOS)andtheapparentheterogeneityinefficacyresultsacrossgeographicregionsmaywarrantfurtherstudies,Thuss-Patienceetal.ECCO-ESMO2009;AbstractO-6504,IrinotecansignificantlyprolongsoverallsurvivalcomparedwithBSCinpre-treatedadvancedgastriccarcinoma(firstrandomize