肺癌的诊断治疗进展课件

AdvancesintheManagementofNonSmallCellLungCancerThierryM.Jahan,MDThoracicOncologyProgramUCSFDillerFamilyComprehensiveCancerCenter肺癌的诊断治疗进展

PresenterDisclosures

Personalfinancialrelationshipswithcommercialinterestsrelevanttothispresentationduringthepast12months:Researchsupport:EliLilly,Genetech,OSIpharmaceuticalsPersonalfinancialrelationshipswithnon-commercialinterests(e.g.,governmentorothernonprofitfunding)relevanttothispresentation,withinpast12months:Relevantinstitutionalfinancialinterests:Personalfinancialrelationshipswithtobaccoindustryentitieswithinthepast3years:Norelationshiptodisclose肺癌的诊断治疗进展Jemal,CACancerJClin2008;58:71Cancer IncidenceDeathsColon 108,070 49,960Breast 184,450 40,930Prostate 186,320 28,660Total

478,840

119,550NSCLCEpidemiology

Lung 215,020

161,840Statisticsfor2008肺癌的诊断治疗进展NSCLC:StageatDiagnosisStageIV40%StageI10%StageII20%StageIIIA15%StageIIIB15%Ettingeretal.Oncology.1996;10:81-111.肺癌的诊断治疗进展AdaptedwithpermissionfromSchillerJHetal.NEnglJMed.2002

1yrsurvivalplateauatabout35-40%Noclearefficacybenefitfornon-platinumcombinationsortripletcombinationsNewparadigmisneededCisplatin/PaclitaxelCisplatin/GemcitabineCisplatin/DocetaxelCarboplatin/Paclitaxel1.00.80.60.40.20.0051015202530MonthsStage

IIIB/IV

Patient

Survival,

%WehadreachedaCeilingforImprovedBenefit

ofCytotoxicChemotherapyinAdvancedNSCLCECOG1594肺癌的诊断治疗进展PlatinumDoubletChemotherapyinAdvancedNSCLC11.NCCNNon-smallCellLungCancerClinicalPracticeGuideline,v.2.2008.Availableat:2.Frascietal.JClinOncol.1999;17:2316-23253.Kellyetal.ClinCancerRes.2000;6:3474-3479.Overallresponse25%-35%Time-to-progression4-6monthsMediansurvival8-12months1-yearsurvival30%-40%2-yrsurvival10%-15%FailedParadigms:TripletCytotoxicChemotherapy2,3Non-PlatinumChemotherapySingleAgentChemotherapy肺癌的诊断治疗进展StrategiestoimprovetreatmenteffectivenessBetterPatientSelection:Whatcriteria?BetterPredictiveMarkers:Whichones?BetterTreatments:LesstoxicMorespecific肺癌的诊断治疗进展Cisplatin75mg/m2day1plusGemcitabine1250mg/m2d1&8Randomization

Factors

StagePSGenderHistovscytodxBrainmetshxRCisplatin75mg/m2day1plusPemetrexed500mg/m2d1VitaminB12,folate,anddexamethasonegiveninbotharmsRoleofHistologyinPatientSelection:JMDBTrial:Pemetrexed-CisplationvsGemcitabine-CisplatininAdvNSCLCScagliotti&Gandara:JCO,2008肺癌的诊断治疗进展1st-lineNSCLC:PreplannedAnalysisPemetrexed+cisplatinMedianOS:12.6mosGemcitabine+cisplatinMedianOS:10.9mos

HR=0.844(95%CI:0.71–0.98)

p=0.011Pemetrexed+cisplatinMedianOS:9.4mosGemcitabine+cisplatinMedianOS:10.9mosHR=1.229(95%CI:1.00–1.51)p=0.051Nonsquamous*(n=1252)Squamous(n=473)SurvivalTime(months)SurvivalTime(months)SurvivalProbabilitySurvivalProbability*Non-squamous=adenocarcinoma,largecellcarcinoma,andother/indeterminateNSCLChistologyScagliotti,etal.JClinOncol2008 肺癌的诊断治疗进展JMDBTrial:Cisplatin-Pemetrexed(CP)vs.Cisplatin-Gemcitabine(CG)inAdvNSCLCNodifferenceinoverallPFSorSurvivalbetweenstudyarmsCPimprovesSurvivaloverCGinNon-SCCA(HR0.81,p=0.005)

CGimprovesSurvivaloverCPinSCCA(HR1.23,p=0.05)

肺癌的诊断治疗进展Ligand:IGF-I,IGF-II.LocalbioavailabilitysubjecttoregulationbybindingwithIGF-BPandreleasebyIGF-BPproteaseIGF-IR:bindstoIGF-I,IIIGF-IR/IR-A:Hybrids

withpreferentialbindingtoIGF-1>>insulin.IRexistsintwoisoforms:IR-B:traditionalinsulinreceptors.IR-A:preferentiallybindsIGF-II(afetalform;re-expressedinsometumors)IGF-IIR:non-signalingreceptor,actingasa“sink”forIGF-II.Insulin/IGFReceptorSystem

HybridReceptorsCNNIGF-IRIGF-IIRIGFBindingProteins(M6P-receptor)CCCIGF-IIGF-IINNIR-AIR-BCCCCNNNNInsulinRAS/MAPKmitogenesisPI3K/AKTsurvival4肺癌的诊断治疗进展0,1110AdjustedRelativeRiskColorectalcancer

Maetal,1999Kaaksetal,2001Probst-Henschetal,2001Giovannuccietal,2000ProstatecancerStattinetal,2000(<59yrs)Stattinetal,2000Harmanetal,2000Chanetal,2002BreastcancerTonioloetal,2000(premenopausal)Tonioloetal,2000Hankinsonetal,1998Hankinsonetal,1998(<50yrs)Lungcancer

Londonetal,2002Lukanovaetal,2000BladdercancerZhaoetal,2003IschemicHeartdiseaseIGT/NIDDMOsteoporoticfracturesJuuletal,2002Sandhuetal,2002Garneroetal,2000IGF-IandriskofCancers

prospectivepopulation-basedcase-controlstudies肺癌的诊断治疗进展2:1randomizationN=150,2stages

of73and77ptsTC:paclitaxel200mg/m2,carboplatin(AUC=6)TCI:paclitaxel200mg/m2,carboplatin(AUC=6),Stage1:CP-751,871

10mg/kgStage2:CP-751,871

20mg/kgTCIn=97n=53CP-751,871SingleagentOptionaluponprogressiononTCaloneCP-751,871SingleagentIGF1RInhibitorTherapy:RandomizedPhaseIITrialPaclitaxel/Carboplatin+/-CP-751,871inadvancedNSCLCKarp:ASCO08TCI:paclitaxel200mg/m2,carboplatin(AUC=6)CP-751,87120mg/kgStage3:single-arm,post-studyextensioninSCCn=30,14ptsevaluable肺癌的诊断治疗进展ResponseRatebyDoseandHistologyHistologyTaxCarboTaxCarbo+CP(10mg/kg)TaxCarbo+CP(20mg/kg)Squamous

(randomized)6/13(46%)4/7(57%)7/9(78%)

Squamous

(singlearm)––11/14(78%)Adenoca5/20(25%)8/21(38%)16/28(57%)NOS8/15(53%)3/6(50%)9/18(50%)Karp:ASCO08肺癌的诊断治疗进展-100.0-80.0-60.0-40.0-20.00.020.040.0MajorResponsesofTCIinBulkySquamous

RR78%vs57%October2005February2006August2007October2007April2008November2007BESTRESPONSEINVISCERALLESIONS>5cm0mg/kg20mg/kg10mg/kgChangeinLesionsize肺癌的诊断治疗进展Choiceoftreatmentaccordingtohistology:Adenocarcinoma: PemetrexedbasedSquamouscellcarcinoma:GemcitabinebasedPac/carbo+IGFinhibitorCP27181?16肺癌的诊断治疗进展HistologywillultimatelyprovetobeSuboptimalforSelectingChemotherapy(orTargetedTherapy)Histologicalsubtypinggroupstumorsbasedonmicroscopicpatternrecognitionbyapathologist(using18thcenturytechnology)Atbest,Histologyisthephenotypicexpressionofcomplexgeneticandmolecularinteractions21stcenturyapproachwillrefinechoiceatthemolecularlevelRobertHookeTissueMicroarray肺癌的诊断治疗进展SquamousSmallCellAdenocarcinomaNormallungTSSCLC–HighTSSquamous–HighTSAdeno–LowTSThymidylateSynthtaseExpressioninLungCancerBhattacharjeePNAS2001肺癌的诊断治疗进展PossibleexplanationtoSQCCAsensitivitytoCP721871De-regulationoftheIGFRpathwayseemsapossibilityinsquamouscellcarcinoma:ILGFbindingprotein3levels,whichregulatesactivityofIGF-1,arelowinSQCCAIGF-RappearstobeexpressedmoreinSQCCAIGF-IIRgenewhichcodesforanegativeregulatoroftheIGF-IRpathwayismutatedinupto60%ofSQCCAKarpJCO2009肺癌的诊断治疗进展StrategiestoimprovetreatmenteffectivenessBetterPatientSelection:Whatcriteria?BetterPredictivemarkers:WhichOnes?BetterTreatments:LessToxicMoreSpecific肺癌的诊断治疗进展PI3kPPPPIGF-1R/IRHERC-METPPPPPPPPEGFRHGFIGF-1/InsulinSrcRasRasRafMEKErkPIP3PTENPIP2PDK-1AktraptormTORrictormTORp70s6k4EBPHif-1αProteinTranslationFoxO3aTranscriptionAngiogenesisCellCycleProgressionProliferationDifferentiationBADApoptosisAnti-HERLapatinibBMS599626BMS690514PF00299804XL647BIBH2992ARRY334543Anti-cMETXL880ARQ197PF02341066JNJ388MGCD265SU11274PHA665752HGFmAbAMG102OA5D5IGF-1mAbCP721871AMG479IMC-A12R1507BIIB022Anti-IGF-1RXL228OSI906NDGAAnti-SrcBosutinibXL999AZD0530KX010107Anti-mTOREverolimusDeforolimusUCN01Anti-AktPerifosineGSK690693Anti-PI3kPI103BGT226BEZ235XL765XL147Anti-RasTipifarnibLonafarnibBMS214662Anti-RafSorafenibRAF265XL281PLX4032Anti-MEKAZD6244RDEA119XL518IRSHDACDNMTAnti-DNMT5-azacitadine5-aza-2’-deoxycitidineAnti-HDACSNDX275CI994ApicidinDesipeptideTrapoxinDepeudecinSK7068vorinostat肺癌的诊断治疗进展Thetrickis:TopickrighttargetTohavetherightagentTohavetherightpairing肺癌的诊断治疗进展ManyTargetedTherapiesFailedtoShowAdditional

BenefitwhenCombinedwithPlatinumBasedCTMedianSurvivalresultsinmonthsPlaceboAgentINTACT-1CG±gefitinib 10.99.9/9.9NSINTACT-2CP±gefitinib 9.99.8/8.7NSTRIBUTECP±erlotinib 10.510.6NSTALENTCG±erlotinib 10.010.3NSSPIRIT-1VC±bexarotene 9.98.7NSSPIRIT-2CP±bexarotene 9.28.5NSPaz-Aresetal.CG±aprinocarsen 10.410.0NSISIS-3521CP±aprinocarsen 9.710.0NSAG-3340-017CG±prinomastat 10.811.5NSBR.18CG±BMS-275291 9.28.6NSStudy5404CP±panitumumab8.08.5NSESCAPECbP±sorafenibPhaseIIIstudystoppedduetohighmortality

BR.24CbP±cediranibWillnotproceedtoPhaseIIIbecauseoftoxicityCourtesy:E.Vokes肺癌的诊断治疗进展

BevacizumabBlocksAngiogenesisRecombinanthumanizedmonoclonalantibodytoVEGF-A肺癌的诊断治疗进展E4599.PhIIIRCT:BevacizumabandCPvsCPinnon-squamousNSCLCRANDOMIZEPaclitaxel200mg/m2IVCarboplatinumAUC6q21dX6cyclesPaclitaxel200mg/m2IV+CarboplatinumAUC6q21dX6cyclesBevacizumab15mg/kgq3wktilPDStratificationby:Stage(IIIBorIV)GeographicregionSandler.NEJM2006;355:2542IIIBandIVnon-squamousNobrainmetsNohemoptysisNopriorchemotherapy肺癌的诊断治疗进展HR:0.79,0.67-0.92

P=.003Pac/carbo+bev,n=43451%23%Pac/carbo,n=44444%15%0.00.20.40.60.81.0Proportionsurviving0642481830

12mo 24mo122436Months12.310.3SandlerAB,etal.NewEnglJMed.2006;355:2542-2550.~37%ofpatientswithadvancedNSCLCareeligibletoreceivebevacizumab,<20%ifalsoexcludeage≥70yearsPhaseIIIECOG4599trial:Paclitaxel/Carboplatin±BevacizumabNon-Squamoushistology,nohemoptysis,brainmetastases肺癌的诊断治疗进展PCn=427PCBn=420HemorrhageHemoptysis05GIBleed12NeutropenicFever15CNS02*PulmonaryEmbolus01Total215ECOGTrial(E4599):TreatmentRelatedDeaths*SandlerAB,etal.NewEnglJMed.2006;355:2542-2550.肺癌的诊断治疗进展Justwhenyouthinkyou’vegotitright…..28肺癌的诊断治疗进展AVAILStudydesignPDPDPDBevacizumabBevacizumab2211Placebo7.5+CGBevacizumab15mg/kg+CGBevacizumab7.5mg/kg+Cis/Gem(CG)Placebo15+CGPreviouslyuntreated,stageIIIb,IVorrecurrentnon-squamousNSCLCN=1050RANDOMIZEManegold,etal.ASCO2007,LBA7514Positiveforprimaryendpoint:PFSNegativeforOverallSurvival肺癌的诊断治疗进展AVAILEfficacyPlaceboCGBevacizumab7.5mg/kg+CGBevacizumab15mg/kg+CGPFS(mos)6.26.8HR0.75(0.64-0.87)P=0.00036.6HR0.85(0.73-1.00)P=0.0456OS(mos)13.113.6HR0.93(0.78-1.11)P=0.4213.4HR1.03(0.86-1.23)P=0.76The1oendpointforthetrial:PFSSothatthiswasreportedasapositivetrialButisitreallyclinicallysignificant?肺癌的诊断治疗进展EpidermalGrowthFactorReceptor(EGFR)InhibitorsinNSCLC:StatusofPredictiveBiomarkersSignalTransductionBlockedSignalTransductionBlockedTKIMoAbLigandKKTKIKKGefitinibErlotinibSingleAgentEGFRmut=predictiveEGFRFISH=predictiveKRASmut=predictiveTKIs+Chemo

arenegative(INTACTI/IITRIBUTE,TALANTallnegative)CetuximabSingleAgentBiomarkersUnclearCetux+Chemo

(FLEX=positive)肺癌的诊断治疗进展IgG1monoclonalantibodyBindstoEGFRandcompetitivelyinhibitsligandbinding(e.g.EGF)MechanismsdifferentfromTKI:ReceptorInternalizationAntibody-DependentCellularCytotoxicity(ADCC)CombinationswithRadiationorChemotherapyeffectiveinothertumortypesRadiation:H&NCancerChemotherapy:ColonCancerHarari:ClinCancerRes,2004CetuximabEGFRADCCIgG1MAbCetuximabMechanismofAction肺癌的诊断治疗进展Chemotherapy-naïveadvancedNSCLCVinorelbine25mg/m2d1,8

+cisplatin80mg/m2d1,Q3WFLEX:PivotalTrial

Cetuximab+Chemotherapyin1st-LineAdvancedNSCLCPrimaryendpoint:OSSecondaryendpoints:PFS,ORR,DCR,QoL,Safety,PKn=557n=568Cetuximab400mg/m2d1wk1,then250mg/m2,QW

+Vinorelbine25mg/m2d1,8

+cisplatin80mg/m2d1,Q3WRANDOMIZEUpto6cyclesofchemotherapy;patientsnotprogressingcontinueoncetuximabmaintenanceStratifiedbyIIIBorIVECOGPS0,1

or2AllhistologicsubtypesincludedECOGPS0–2NoknownbrainmetastasesEGFRexpressionbyIHC(≥1positivetumorcells)PirkerR,etal.

Lancet373(9674):1525–1531,2009.肺癌的诊断治疗进展FLEX:ResultsCV+CetuximabCVPRR36%29%0.012PFS4.8mos4.8mosNSTTF4.2mos3.7mos0.015NS=notsignificant;TTF=timetotreatmentfailure.MonthsOS(%) MedianOS1-YrSurv.CV+Cetuximab

11.3mos47%

CV

10.1mos42%HR:0.871;P=0.044PirkerR,etal.

Lancet373(9674):1525–1531,2009.肺癌的诊断治疗进展FLEX:DifferencesinEthnicityCaucasian(N=946)Asian

(N=121)PrognosticFactors Adenocarcinoma44%72% Female27%46% Neversmoker17%52% ECOGPS0/181%94%PoststudyTreatment EGFRTKIs17%61%MedianOS9.6mos19.5mos [95%CI][9.0–10.4][16.4–23.3]PirkerR,etal.

Lancet373(9674):1525–1531,2009.肺癌的诊断治疗进展FLEX:AsianSubgroup(N=121)CV+Cetuximab(N=62)CV

(N=59)PValueBaselinePrognosticFactors Adenocarcinoma65%80%Post-StudyTreatment EGFRTKIs50%73%OS17.6mos20.4mosNSRR50%44%NSCannotdrawdefinitiveconclusionsbecauseofsmallsamplesize(10%oftotal),differencesinhistologyanddifferencesinpost-studyEGFRTKItreatmentPirkerR,etal.

Lancet373(9674):1525–1531,2009.肺癌的诊断治疗进展MedianOS1-YearSurvivalCV+Cetuximab

(N=466)10.5mos45%CV

(N=480)9.1mos37%HR=0.803;P=0.003FLEX:OS–Caucasians(N=946)

PrespecifiedAnalysisMonthsPvalue:stratifiedlog-ranktest(2-sided)OverallSurvival(%)MedianOSCV+CetuximabCVHRCaucasians(N=946)10.5mos9.1mos0.803Adenocarcinoma(N=413)12.0mos10.3mos0.815SquamousCell(N=347)10.2mos8.9mos0.794Other(N=185)9.0mos8.2mos0.807CV=cisplatin/vinorelbine.PirkerR,etal.

Lancet373(9674):1525–1531,2009.肺癌的诊断治疗进展CV+CetuximabAnygradeGrade0OS15.0mos8.8mosRR44%28%PFS5.4mos4.3mosOverallSurvival(%)MonthsAnygrade: CT+Cetuximab(N=290)Grade0: CT+Cetuximab(N=228)HR=0.631(95%CI:0.515-0.774)*P<0.001PatientsatRiskGrade02281458854150AnyGrade290238163101383*Landmarkanalysis.FLEX:OSEarlyAcne-LikeRash

Pre-PlannedAnalysisGatzemeieretal,JTO2008,Vol3,No.11,S4(abstract8)肺癌的诊断治疗进展Cetuximab+Platinum-BasedChemotherapyin1stlineNSCLC:ConsistentEfficacy*Randomizedtoconcurrentvssequentialcetuximab;

†Randomizedtopac/carboq3wvspacqw/carboq4w

‡Pacqw/carboq4w**PressreleaseAug2008ReferencePhaseRegimenNORR,%TTP/PFS,mOS,mThieneltetal,2005I/IICet+pac/carbo3126511Robertetal,2005I/IICet+gem/carbo3528.65.510.3Herbstetal,2007IICet+pac/carbo20434/31*4/411/11Socinskietal,2009IICet+pac/carbo16829.6/25†4.7/4.311.4/9.8Langeretal,2007IICet+pac/carbo‡53575.513.8Belanietal,2007IICet+doc/carbo7614.54.711Roselletal,2008IICet+vin/cis43355.08.3Kimetal,2008IICet+bev/pac/carb9953714.0Buttsetal,2007IICet+gem/pla6527.75.112.0Lynchetal,2007IIICet+tax/carbo33825.74.49.7**Pirkeretal,2009IIICet+vin/cis1125364.811.3肺癌的诊断治疗进展StructureoftheEGFR-ATPBindingSiteRed:deletionsLightblue:missensemutationsDarkblue:gefitinibFrom:LynchTJetal.NEnglJMed.2004;350:2129-2139.Exons18,19,20and21-TyrosinekinasedomainInframedeletionsandmissensemutations肺癌的诊断治疗进展IndividualizingAnti-EGFRTherapy:MethodologyEGFRmutationstatusby

genesequencingEGFRgenecopynumberbyfluorescenceinsituhybridization(FISH)EGFRproteinexpressionbyimmunohistochemistry(IHC)SerumProteomicsbyMALDIMSGGCGGGCCAAACTGCTGGGTGCG肺癌的诊断治疗进展NCIC-CBR.21TRIALNSCLC1priorcombinationregimen(nomorethan2)Elderlymayhavehadsingle-agentNorequirementforPDRANDOMIZEErlotinib150mgdailyn=488Placebon=243Shepherdetal.NEJM,2005肺癌的诊断治疗进展*HRandP-valueadjustedforstratificationfactorsatrandomizationplusHER1/EGFRstatus.BR-21Overallsurvival:allpatients42.5%improvementinmediansurvivalSurvivaldistributionfunctionSurvivaltime(months)TarcevaTMPlaceboHR=0.73,P<0.0011.000.750.500.2500 5 10 15 20 25 3031%21%肺癌的诊断治疗进展Log-rank:p=0.13

HR=0.73(0.49,1.10)BR.21SurvivalAccordingtoEGFRMutationpvalueforinteraction=0.97Nomutation100806040200Percentage 0 6 12 18 24 30MonthsErlotinibPlacebo+EGFRmutation100806040200PercentageMonthsErlotinibPlaceboLog-rank:p=0.45

HR=0.77(0.40,1.50) 0 6 12 18 24 30EGFRMutationisNOTaPrognosticMarker肺癌的诊断治疗进展BR.21:EGFRFISHpredictsSurvivalLog-rank:p=0.008

HR=0.44(0.23,0.82)Log-rank:p=0.59

HR=0.85(0.48,1.51)BR21FISH+BR21FISH-Time(months)0.00.20.40.60.81.00612183024ErlotinibPlaceboTime(months)0.00.20.40.60.81.00612183024ErlotinibPlaceboTsao:NEJM,2005FISHpositivityisaprognosticmarker肺癌的诊断治疗进展BiomarkersforEGFR-directedTherapy:SummaryofCurrentStatusEGFRTKIsEGFRprotein(IHC)equivocalforpredictivevalueEGFRmutationpredictsresponseEGFRFISHpredictssurvival(BR.21)KRASmutationpredictslackofactivityCetuximabEGFRprotein(IHC):selectionfactorforFLEXEGFRmutation:notpredictive(preclinical)EGFRFISH:conflictingdata(S0342,BMS-099)KRASmutation:notpredictive(S0342,BMS-099)肺癌的诊断治疗进展N0723:PredictiveMarkerStudyDesign2ndlineNSCLCwithspecimenInitialRegistrationFISHTestingEGFRFISH+(~30%)EGFRFISH−(~70%)ErlotinibPemetrexedErlotinibPemetrexedStrataRandomizeOutcome1°PFS2°OS,ORRPower:validationofEGFRFISHaspredictivebiomarker90%todetect50%PFSimprovementfavoringerlotinibinFISH+90%todetect30%PFSimprovementfavoringpemetrexedinFISH−>90%todetectinteractionSWOG:Tumorrepository&EGFRpathwayanalysisNCCTG(StudyChair:AlexAdjei)+CALGB,ECOG,SWOG,NCICOthers:C-Path&industrypartners,Pharma957patients4yearsaccrual,1196patients1-2yearsminimumadditionalfollow-up肺癌的诊断治疗进展PossibleSelectionFactorsfor

IndividualizingTherapyofNSCLCCharacteristicDrugClassPopulationClinicalFactorsEGFRTKIsBevacizumabFemale,Never-smoker,AsianNoHemoptysisTumorHistologyEGFRTKIsBevacizumabPemetrexedIGF1RInhibitorsAdenocaNoSCCAb/oriskNon-SCCASCCA(?)MolecularFactorsEGFRTKIsCetuximabERCC1/RRM1TSAnti-AngiogenicsEGFRMut/FISHEGFRIHC/FISH(?)PlatinumChemoPemetrexed(?)fromGandara:CLC,2008肺癌的诊断治疗进展IressaPanAsianStudy(IPASS)PhaseIIITrial:GefitinibvsCarboplatin/PaclitaxelinSelectedPatientsWithAdvancedNSCLCNeverorlightex-smoker*withadenocarcinomahistologyPS0-2StageIIIBorIVchemotherapy-naïveNSCLCN=1217RANDOMIZEGefitinib(250mg/day)Offeredcarboplatin/paclitaxelonprogressionCarboplatin(AUC5or6