大肠癌标准-徐瑞华

ProgressionofchemotherapyformetastaticCRCRui-huaXu(徐瑞华)SunYat-senUniversityCancerCenterxurh@TelystemicTherapyforMetastaticCRCEvolvingstandardregimensPrognosticandpredictivemarkersinCRCNewtargetsandnewagentsAdvancesintheTreatment

ofColorectalCancer198019851990199520002005TherapeuticconceptsPalliativeCTAdjuvantCTNeoadjuvantCTCapecitabineOxaliplatinCetuximabBevacizumabIrinotecan5-FUPanitumumabTargetedtherapies{5-FU=5-fluorouracil;CT=chemotherapy.ContinuumofCare:DefiningaStrategicApproachTheTreatmentContinuumisastrategicframeworkConsiderationofallavailabletreatmentoptionsandregimensequencesacrossmultiplelinesoftherapyUpfrontplanningforeachpatienttoextendsurvivalwhileminimizingsideeffectsFlexibilitytoadjustthetreatmentplanReplacementofastrictly“treat-as-you-go”approachTheTreatmentContinuumconceptisconsistentwiththecurrentNCCNGuidelinesformCRCtreatmentandputstheguidelinesinthecontextofpatientbenefits.Advanced/mCRCPatientsCanTolerateIntensiveTherapy一线方案二线方案TreatmentSelectionFactorsPersonalizetreatmentbasedon:PrioradjuvanttherapyAbilitytoberesectedIncorporationoftargetedagentsWhentochangeregimensPatientconditionComorbiditiesQoLissues主要的内容一线、二线化疗方案的选择如何更好的改善晚期病人的生活质量、降低化疗毒性2010年ASCO，主要探索肠癌预后指标、疗效预测指标、化疗联合靶向药物的研究一、二线化疗：我们知道了什么IrinotecanandoxaliplatinareequivalentalternativesinfirstlinetreatmentXeloxisequivalenttoFolfoxFolfiriissuperiortoIFLInitialtherapywithfluoropyrimidinesisproperinsomepatientsn=111n=109GERCORC97-3:

含5-FU联合化疗的比较Primaryendpoint:TTPonsecond-linetherapySecondaryendpoints:ORR,OS,PFS,andsafetyPreviouslyuntreatedMCRCWHOPS0-2FOLFOX6FOLFIRIRANDOM

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A

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ONFOLFIRIFOLFOX6PDPDTournigandetal.JClinOncol.2004;22:229.EndPointFOLFIRIFOLFOXP-valueRR5654.26TTP8.58.0.26OS21.520.6.99TournigandC,etal.JClinOncol2004;22:229-237GERCORC97-3;疗效数据GERCORC97-3：结论ActivityFOLFOXFOLFIRIToxicityFOLFOX:NeuropathyandneutropeniaFOLFIRI:GI,alopeciaFOLFOX和FOLFIRI有何区别?StudyYearPatientnumbersMedianPFS/TTPMedianOSWeightedPFSaverageWeightedOSaverageFOLFIRIDouillard20001996.7mo17.4mo7.6mo18.9moTournigand20041138.5mo20.9moColucci20051647.0mo14.0moKohne20052148.5mo20.1moFuchs(BICC)20071447.6mo23.1moFOLFOX/XELOXdeGramont20002109.0mo16.2mo8.2mo18.2moGoldberg20042678.7mo19.5moTournigand20041118.0mo21.5moColucci20051727.0mo15.0moCassidyFOLFOX20063177.7mo17.7moCassidyXELOX20063177.3mo18.8moDucreuxFOLFOX20071509.7mo18.4moDucreuxXELOX20071509.3mo19.9mo一、二线化疗：我们知道了什么IrinotecanandoxaliplatinareequivalentalternativesinfirstlinetreatmentXeloxisequivalenttoFolfoxFolfiriissuperiortoIFLInitialtherapywithfluoropyrimidinesisproperinsomepatientsXELOX+安慰剂

N=350FOLFOX4+安慰剂

N=351XELOX+

贝伐单抗N=350FOLFOX4+

贝伐单抗N=350XELOX

N=317FOLFOX4N=317最初的2组是开放性研究（N=634）在贝伐单抗治疗结直肠癌III期临床数据正式公布后，该研究方案被调整为2×2的研究，加入了贝伐单抗/安慰剂组进行联合化疗。（N=1401）入组

2003年6月–2004年5月入组2004年2月

–2005年2月NO16966研究设计1HurwitzH,etal.ProcASCO2003;22（Abstract3646） 0 5 10 15 20 25 30月PFS估计值HR=1.04[97.5%CI0.93~1.16]1.00.80.60.40.208.58.0上限≤1.23

（非劣效性范围）FOLFOX/FOLFOX+安慰剂/FOLFOX+贝伐单抗

N=1017；826次事件

XELOX/XELOX+安慰剂/XELOX+贝伐单抗

N=1017；813次事件

XELOX方案在无进展生存率上的非劣效性检验：基于意向-分析（ITT）人群的统计，该研究达到了原先设定的目标OS(ITT意向性人群)：

XELOX与FOLFOX4相当FOLFOX/FOLFOX+placebo/FOLFOX+bevacizumabXELOX/XELOX+placebo/XELOX+bevacizumabX/PF/PX/BVF/BVXF0.00.10.20.30.40.51.00.90.80.70.60510152025303540Monthsn=1017,695eventsn=1017,692eventsHR=0.99[97.5%CI:0.88–1.12](ITT)19.619.8Proportionofpatients一、二线化疗：我们知道了什么IrinotecanandoxaliplatinareequivalentalternativesinfirstlinetreatmentXeloxisequivalenttoFolfoxFolfiriissuperiortoIFLInitialtherapywithfluoropyrimidinesisproperinsomepatientsBICC-C:Fuchs等1st-linemCRCFOLFIRImIFLCapeIRIRANDOMIZATIONn=547430例患者：疗效mIFLCapeIRIFOLFIRIP-valueResponserate(%)43.3-47.2N.S.PFS(mos)6.0-8.20.01OS(mos)17.6-23.1N.S.AdverseEventGrade3-4FOLFIRIn=137(%)m-IFLn=137(%)CapeIRIn=141(%)Nausea8.87.3-Vomiting8.87.3-Diarrhea13.919-Dehydration5.87.3-Neutropenia43.140.9-Febrileneutropenia3.612.4-Hand-footsyndrome00-MI/stroke0.73.6-60-daymortality3.65.1-3-4级不良事件一、二线化疗：我们知道了什么IrinotecanandoxaliplatinareequivalentalternativesinfirstlinetreatmentXeloxisequivalenttoFolfoxFolfiriissuperiortoIFLInitialtherapywithfluoropyrimidinesisproperinsomepatientsA:(700pts)

FUuntilitfails,thenchangetoirinotecanB(ir):(350)

FUuntilitfails,thenaddirinotecanB(ox):(350)

FUuntilitfails,thenaddoxaliplatinC(ir):(350)

FU+irinotecanfromthestartuntilitfailsC(ox):(350)

FU+oxaliplatinfromthestart

untilitfailsDesignOx+fluoropyrimidineOx+fluoropyrimidineIr+fluoropyrimidineOx+fluoropyrimidineIr+fluoropyrimidinetimetofailureoffirst2drugs.2100patientsFOCUSSchemaFocusStrategyA5FUfollowedbysalvagetreatmentStrategyB5FUfollowedbyeitherFOLFIRIorFOLFOXStrategyCFOLFIRIorFOLFOXatstartoftreatmentOverallsurvivalPlanFirst2drugsscheduleMedianOSAFUthenIr13.9B(ir)B(ox)FUthenFU/IrFUthenFU/Ox14.815.2C(ir)C(ox)1st-lineFU/Ir1st-lineFU/Ox16.315.2SeymouretalLancet,2007Focus

NumberofpatientsreceivingsalvagetreatmentStrategyA+B 43%StrategyC 55%Focus

Numberofpatientsthatreceivedall3drugs**StrategyA 16%StrategyB 19%StrategyC 33%Nodifferencewhetheririnotecanoroxaliplatingivenfirst** Seymouretal,LancetJuly2007FOCUSSummaryUseofsequentialchemotherapy,withdeferreduseofcombinations,appearsaseffectiveasusingthecombinationupfront;HOWEVER…SequentialsingleagentsappeartobeinferiorthanasingleagentfollowedbyanappropriatecombinationQuestionsremainregardingexposuretoallagentsNotallagentsshouldbeusedalone谁应该首先考虑联合化疗?化疗后有手术切除机会的病人化疗后可改善生活质量的病人没有机会接受二、三线化疗的病人(如进展性肿瘤)谁应该首先考虑单药治疗?肿瘤恶性程度较低，患者有机会接受二、三线治疗患者生活质量较好，不愿为提高疗效而接受联合化疗Conceptof“All-3-Drugs”-Update2005

11PhaseIIITrials,5768PatientsOS(mos)=13.2+(%3drugsx0.1),R^2=0.85Grothey&Sargent,JCO200501020304050607080Infusional5-FU/LV+irinotecanInfusional5-FU/LV+oxaliplatinBolus5-FU/LV+irinotecanIrinotecan+oxaliplatinBolus5-FU/LVLV5FU2FOLFOXIRICAIRO2221201918171615141312MedianOS(mo)Patientswith3drugs(%)P=.0001First-LineTherapyMultivariateanalysis:EffectonOS PFirst-linedoublet 0.69All3drugs 0.0052007小结晚期病人一线化疗方案选择FOLFOX、FOLFIRI具有同等的有效性而毒性谱不同卡培他滨在与奥沙利铂的联合中与c.i.v.的5FU/LV等效二线治疗可以延长病人的生存期，接受现有的三个化疗药物治疗的病人生存期延长治疗过程中要对病灶进行评估，有切除可能的肝、肺转移病人要及时进行多学科讨论主要的内容一线、二线化疗方案的选择如何更好的改善晚期病人的生活质量、降低化疗毒性不可切除的MCRC：

一线化疗持续多久?持续化疗——直至肿瘤进展，改为二线方案无化疗“假期”——全部停止所有药物维持治疗——只停止产生明显累积性毒性的

药物，继续使用其余的药物Comparisonofintermittentandcontinuouspalliativechemotherapyforadvancedcolorectalcancer:amulticentrerandomisedtrial.MaughanTS,JamesRD,KerrDJ,LedermannJA,SeymourMT,TophamC,McArdleC,CainD,StephensRJ;MedicalResearchCouncilColorectalCancerGroup.Lancet.2003Feb8;361(9356):457-64.Lancet.2003Feb8;361(9356):457-64.Intermittent10.8mthContinuous11.3mthP=0.23

Overallandprogression-freesurvivalLancet.2003Feb8;361(9356):457-64.ConclusionOurfindingsprovidednoclearevidenceofabenefitincontinuingtherapyindefinitelyuntildiseaseprogression.Theyshowedthatitissafetostopchemotherapyafter12weeksandre-startthesametreatmentonprogressioninpatientswithchemosensitiveadvancedcolorectalcancer.Lancet.2003Feb8;361(9356):457-64.FOLFOX4直至疾病进展FOLFOX7x6cysLV5FU2x12cyFOLFOX7x6cyRTournigand,C.deGramontetal.JClinOncol;24:394-4002006OPTIMOX1：设计FOLFOX7：Oxa130mg/m2LV400mg/m25FU2.4~3.6g/m2每2周1次sLV5FU2：LV400mg/m25FU400mg/m2

5FU2.4~3.6g/m2每2周1次RRPFS58.5%9.0m58.3%9.2mOPTIMOX1:生存期02550751001251500.000.250.500.751.00FOLFOX4FOLFOX7周概率20.0m21.6mP=0.68OPTIMOX1:毒性TournigandC,etal.JClinOncol2006.051357911131517192123CyclesPatients(%)10152025021357911131517192123CyclesPatients(%)1046812141618FOLFOX4FOLFOX7

sLV5FU2

FOLFOX7Anygrade3/4toxicityNeurologicalgrade3toxicityOPTIMOX1studyASCO2008ReducingPSNbyIntermittentoxaliplatin(OPTIMOX1-likestrategy)andUseofIVcalcium/magnesiumasneuroprotectantReducingmyelosuppression(mFOLFOX7=no5-FUbolus)Intermittentoxaliplatin(IO)willallowpatientstoremainontherapylongercomparedwithconventionalschedule(continuousoxaliplatin;CO)270ptsOPTIMOX1-likedesignwithmFOLFOX7with85mg/m2oxaliplatinq2wPlannedreintroductionofoxaliplatinafter16weeksProvisionforearlierreintroductionofoxaliplatinIftumorprogression≥50%inmaintenancephaseTTFforIOvsCOPFSforIOvsCOIOisassociatedwithsignificantimprovementofTTFcomparedwithCO–withoutcompromisingPFSCOleadstohighnumberofdiscontinuationfromthestudyduetoPSNcomparedwithIO随机分组维持治疗

vs

伴无化疗间歇期的治疗mFOLFOX7x6cysLV5FU2

直至基线进展mFOLFOX7重新诱导mFOLFOX7x6cy中断治疗直至基线进展mFOLFOX7重新诱导ABOPTIMOX2：伴无化疗间歇期（CFI）的治疗OPTIMOX1：维持治疗OPTIMOX2

研究设计Chibaudel,B.etal.JClinOncol;27:5727-57332009Chibaudel,B.etal.JClinOncol;27:5727-57332009Fig3.Definitionofdurationofdiseasecontrol(DDC)Chibaudel,B.etal.JClinOncol;27:5727-57332009Chibaudel,B.etal.JClinOncol;27:5727-57332009两组再引入后的疗效维持治疗CFI再引入率81.8%84.6%RR20.4%30.3%RR+SD59.3%57.6%PFS4.8月3.9月ConclusionTheplannedcompletediscontinuationofchemotherapyhadanegativeimpactonDDCandPFScomparedwiththemaintenancetherapystrategy.MaintenancetherapywithsimplifiedLV5FU2aftermFOLFOX7isanactivestrategyfortreatmentofpatientswithpreviouslyuntreatedmetastaticcolorectalcancer.Bevacizumabplusirinotecan,fluorouracilandleucovorin(IFL)forthetreatmentofmetastaticCRCPhaseIII,randomized

placebo-controlledtrialHurwitzH,etal.NEnglJMed2004;350:2335–42AVF2107g:PFSandOSProbabilityofbeingprogression-free1.00.80.60.40.20 0 10 20 30MedianPFS(months)

IFL+placebo:6.2

IFL+bevacizuma