转移性结直肠癌治疗的新进展_ppt课件.ppt

转移性结直肠癌化疗的新进展,中山大学肿瘤医院内科何友兼教授,结直肠癌,西方国家中，结直肠癌占癌症死亡第二位（10%-12%）。发病率每年递增4.2%。外科手术五年生存率：期90%、期70%-75%、期35%-50%、期推注FOLFOX的疗效大致与FOLFIRI相当,但毒性各异三药方案(FOLFOXIRI)疗效和生存比二药略佳合用靶向药可提高疗效,改善生存用足三药(5FU.L-OHP.IRI)者中位生存可超过2年维持治疗或间歇休息(treatmentholiday)应个体化处理,效力和毒性:FOLFIRIvsFOLFOX,Efficacy/Toxicity5FU/LVIrinotecanOxaliplatinRR(firstline)56%54%OS(mo)21.520.4G3/4neutropenia24%44%G3/4febrileneutr.7%0%G3/4mucositis10%1%G2/3neurological0%71%G3/4diarrhea14%11%,Tournigandetal.JCO2004.22:229-237,III期试验:FOLFOXIRIvsFOLFIRI,SouglakosJ,etal.BrJCancer.2006;94:798-805.FalconeA,etal.JClinOncol.2007;25:1670-1676.,*Statisticallysignificantdifference.,用足三药.改善生存:Update200511PhaseIIITrials,5768Patients,OS(mos)=13.2+(%3drugsx0.1),R2=0.85,Grothey78:237-248.,mCRC:主要的一线化疗效果,1.GoldbergRM,etal.JClinOncol.2004;22:23-30.2.ColucciG,etal.JClinOncol.2005;23:4866-4875.3.CassidyJ,etal.JClinOncol.2008;26:2006-2012.4.CassidyJ,etal.BrJCancer.2011;105:58-64.5.FuchsCS,etal.JClinOncol.2007;25:4779-4786.,mCRC:分子靶点药,分子靶药物(inCRC):以往临床研究结果,Cet(Pan),Bev与化疗联合均可增效.延长生存,可用于各线(一.二.三)的治疗Cet(Pan)单药有效,Bev必须与化疗联合使用,两个单抗合用不增效Bev.在一线进展后用仍可获生存效益Cet(Pan)只能用于K-RAS野生型或G13d突变的病人,Bev.的使用不须测靶首次皮疹程度反映Cet(Pan)的疗效,与K-RAS无关Cet(Pan),Bev用于术后辅助治疗均未证实有效,VEGF和VEGF-受体家族,VEGFregulatesangiogenesisviainteractionwithreceptortyrosinekinasesVEGFR-2/KDRandVEGFR-1/Flt-1,VEGFR-1,(Flt-1),VEGF-A,Receptor,isoforms,Ligand,isoforms,VEGFR-2,(KDR),VEGF-B,VEGFR-1s,Angiogenesis,VEGF-E,VEGF-C,VEGF-D,VEGFR-3,(Flt-4),Lymphangiogenesis,tumormetastases,Extracellular,Intracellular,VEGF-A165,NRP-1,PlGF,ShinkarukS,etal.CurrMedChemAnti-CancAgents.2003;3:95-117.LuttunA,etal.AnnNYAcadSci.2002;979:80-93.,mCRC:一线化疗/贝伐单抗,1.HurwitzH,etal.NEnglJMed.2004;350:2335-2342.2.SaltzLB,etal.JClinOncol.2008;26:2013-2019.3.BendellJC,etal.Oncologist.2012;17:1486-1495.,1.Bevacizumabpackageinsert.SouthSanFrancisco,CA:Genentech;2011.2.NalluriSR,etal.JAMA.2008;300;2277-2285.3.HurwitzH,etal.JClinOncol.2011;29:1757-1764.,PotentialforincreasedVTEriskcontroversial;increasedrisknotedin1studybutnotinothers.2,3,*Predominantlygrade3.MayapplymoretoNSCLC.Whensurgeryconductedduringbevtherapy.,贝伐单抗:相关毒性,KRASWTmCRC:一线EGFR-靶向药,WorsePFSoutcomewithpanitumumab+FOLFOX4inmutantKRASdisease3,1.VanCutsemE,etal.JClinOncol.2011;29:2011-2019.2.BokemeyerC,etal.AnnOncol.2010;22:1535-1546.3.DouillardJY,etal.JClinOncol.2010;28:4697-4705.4.DouillardJY,etal.ASCO2013.Abstract3620.5.DouillardJY,etal.NEnglJMed.2013;369:1023-1034.6.MaughanTS,etal.Lancet.2011;377:2103-2114.,mCRC:个体化治疗应考虑,病变范围治疗目的(姑息vs可能根治)活动能力年龄合并疾病以往一年内的辅助治疗分子标记,器官(肝肾,造血)功能毒性风险:活动性出血,蛋白尿,伤口不愈,神经病变,过敏,是否方便花费/资源病人意愿,mCRC:化疗有关的选择,mCRC：化疗选择临床依据,无病间歇（DFI),缓解期PS（01，2）年龄（70，70）肿瘤分子生物学标记(TS.DDP.UGT.KRAS.NRAS.BRAF)化疗目的(新辅助,辅助)患者取舍,mCRC:临床处理程序,确定治疗目的,选择治疗策略,决定治疗强度,病人是否需要(渇望)积极治疗,Yes85%,No15%,KRAS,无法检测,野生型,突变型,5FU/CAPECITABINE,+/-Bevacizumab,二联化疗,+Bevacizumab,二联+Cet,二联+Bev,二联化疗,+Bevacizumab,KRASWTmCRC:一线EGFRvsVEGF单抗,TheprimaryendpointofORRwasnotsignificantlydifferentbetweentreatmentarmsintheFIRE-3study(62%vs58%;P=.183)2,1.SchwartzbergLS,etal.ASCOGI2013.Abstract446.2.HeinemannV,etal.ASCO2013.AbstractLBA3506.,*Statisticallysignificantdifference.,mCRC:其它的生物标志物,KRASG13D1综合有关预测和预后的资料大型随机研究抗EGFR治疗无价值BRAF2,3预后结局很差未见综合一线治疗有关预测资料ExpandedRASanalysis4,510%ofKRAS12/13野生型肿瘤有其它RAS突变KRASexons3,4NRASexons2,3,4抗-EGFR单抗无效,1.PeetersM,etal.JClinOncol.2013;31:759-765.2.RichmanSD,etal.JClinOncol.2009;27:5931-5937.3.VanCustemE,etal.JClinOncol.2011;29:2011-20194.PeetersM,etal.ClinCancerRes.2013;19:1902-1912.5.DouillardJY,etal.NEnglJMed.2013;369:1023-1034.,III期80405试验:一线化疗EitherCetuxorBevinKRAS-WTmCRC,Primaryendpoint:OSSecondaryendpoints:ORR,PFS,TTF,durationofresponse,PatientswithmCRCandKRASWT,ECOGPS0/1(N=2900),FOLFOXorFOLFIRI+Bevacizumabq2w,ClinicalT.NCT00265850.,FOLFOXorFOLFIRI+Cetuximabq1w,AthirdarmwithCT+bevacizumab+cetuximabwasclosedtoaccrualinSeptember2009,延续治疗策略上的考虑,增加病变得到长时间良好控制病人的数目大多数新治疗研究到病人病变进展或毒性受限而终止对病变得到良好控制病人的策略:继续治疗到病变进展或毒性而终止维持治疗治疗停息(Treatmentholidays),OPTIMOX:维持or间歇休息,OPTIMOX11Maintenancetherapy(n=620),FOLFOX4untilprogression,FOLFOX7,FOLFOX7,sLV5FU2,OPTIMOX22Chemotherapy-freeinterval(n=202),mFOLFOX7,mFOLFOX7,sLV5FU2,mFOLFOX7,mFOLFOX7,Chemotherapy-FreeInterval,1.TournigandC,etal.JClinOncol.2006;24:394-400.2.ChibaudelB,etal.JClinOncol.2009;27:5727-5733.,OPTIMOX:研究结果,OPTIMOX1(维持vs继续治疗)疾控期,PFS,orOS无明显差异OPTIMOX2(治疗休息vs维持治疗)维持治疗的疾控期,PFS明显为好但OS无差异,TournigandC,etal.JClinOncol.2006;24:394-400.ChibaudelB,etal.JClinOncol.2009;27:5727-5733.,维持贝伐单抗:MACROTrial,Capecitabine+Oxaliplatin+Bevacizumabx6cyclesq3w(n=241),Bevacizumabuntilprogression,Capecitabine+Oxaliplatin+Bevacizumabx6cyclesq3w(n=239),Capecitabine+Oxaliplatin+Bevacizumabuntilprogression,PatientswithnewlydiagnosedmCRCandECOGPS2,Diaz-RubioE,etal.Oncologist.2012;17:15-25.,MACRO:OS(ITT),Mos,XELOX-Bev,Bev,PatientsatRisk,n,241,239,SurvivalProbability,0,0.25,0.50,0.75,1.00,0,0,2,39,19,13,33,26,23,30,39,40,27,54,60,24,77,85,21,101,120,18,132,146,15,159,170,12,193,191,9,210,208,6,226,227,3,8,6,36,Bev,XELOX-Bev,Diaz-RubioE,etal.Oncologist.2012;17:15-25.,HR:1.05(95%CI:0.851-1.295),间歇休息:GISCADTrial,CR,PR,SD,PreviouslyuntreatedmCRC,RANDOMIZATION,FOLFIRIx2mos,2:1,FOLFIRIx2mos,EVALUATE,Progression:OffTrial,Breakx2mosthenFOLFIRIx2mos,FOLFIRIx4mos,LabiancaR,etal.AnnOncol.2011;22:1236-1242.,146,147,75,70,25,27,10,9,146,147,95,101,39,43,10,13,PtsatRisk,n,Continuous,Intermittent,Mos,0,Patients(%),0,6,12,18,Mos,100,80,60,40,20,0,Patients(%),6,12,18,24,30,36,130,124,60,68,19,29,LabiancaR,etal.AnnOncol.2011;22:1236-1242.,OS,PFS,100,80,60,40,20,0,间歇休息:GISCADTrial,ContinuousarmIntermittentarm,Events145143,Totals146147,ContinuousarmIntermittentarm,Events145143,Totals146147,ArmCBevacizumab(n=243),ArmAFOLFOX4+Bevacizumab(n=286),ArmBFOLFOX4(n=291),PatientswithpreviouslytreatedmCRC;nopreviousbevacizumab(N=820),FOLFOX4Oxaliplatin85mg/m2onDay1q2w5-FU400bolus/600mg/m2IVonDays1and2q2wLV200mg/m2onDays1and2q2wBevacizumab10mg/kgonDay1q2w,GiantonioBJ,etal.JClinOncol.2007;25:1539-1544.,StratifiedbyECOGperformancescore0vs1or2;previousXRT,E3200:二线用贝伐单抗formCRC,Alive,n,Dead,n,Median,Mos,Total,n,A:FOLFOX4+bevacizumab,286,254,32,12.9,B:FOLFOX4,291,264,27,10.8,C:Bevacizumab,243,219,24,10.2,GiantonioBJ,etal.JClinOncol.2007;25:1539-1544.,E3200:在以前治疗过的mCRCFOLFOX+Bev改善OS,OS(Mos),Probability,0,0.2,0,0.4,0.6,0.8,1.0,6,12,18,24,30,36,HR:0.76AvsB:P=.0018BvsC:P=.95,ML18147(TML):进展后继续用贝伐单抗,Arandomized,open-labelphaseIIIintergroupstudy,Standardsecond-lineCT(oxaliplatinoririnotecanbased)untilPD(n=411),BEV2.5mg/kg/wk+standardsecond-lineCT(oxaliplatinoririnotecan-based)untilPD(n=409),ProgressivemCRCafterBEV+standardfirst-lineCT(eitheroxaliplatinoririnotecanbased)(n=820),BennounaJ,etal.LancetOncol.2013;14:29-37.,Stratifiedbyfirst-lineCT(oxaliplatinoririnotecanbased),first-linePFS(9or9mos),timefromlastBEVdose(42or42days),ECOGPSatbaseline(0/1or2),Primaryendpoint:OS,ML18147(TML):改善OS(ITT),OS(%),Mos,CT(n=410)BEV+CT(n=409),100,80,60,40,20,0,0612182430364248,9.8mos,11.2mos,Unstratified*HR:0.81(95%CI:0.69-0.94;log-rankP=.0062),StratifiedHR:0.83(95%CI:0.71-0.97;log-rankP=.0211),*Primaryanalysismethod.Stratifiedbyfirst-lineCT(oxaliplatinbased,irinotecanbased),first-linePFS(9mos,9mos),timefromlastdoseofBEV(42days,42days),ECOGPSatbaseline(0,1).,BennounaJ,etal.LancetOncol.2013;14:29-37.,100,80,60,40,20,0,PFS(%),06121824303642,Mos,Unstratified*HR:0.68(95%CI:0.59-0.78;log-rankP.0001),StratifiedHR:0.67(95%CI:0.58-0.78;log-rankP.0001),4.1mo,5.7mo,一线治疗后继续用血管生成抑制剂?,Bevacizumabziv-aflibercept(阿帕西普),(阿帕西普),III期VELOUR研究:FOLFIRIziv-Aflibercept二线治疗mCRC,Primaryendpoint:OSSecondaryendpoints:PFS,ORR,safety,immunogenicityNocorrelatives,PatientswithmCRCprogressingonfirst-lineoxaliplatin-basedchemotherapy*(plannedN=1226),FOLFIRI+ziv-Aflibercept4mg/kgq2w(n=612),FOLFIRI+Placeboq2w(n=614),*30%hadpreviousbevacizumab.,Stratifiedbypreviousbevacizumab(yesvsno),ECOGPS(0vs1vs2),VanCutsemE,etal.JClinOncol.2012;30:3499-3506.ClinicalT.NCT00561470.,(阿帕西普),VELOUR研究:生存结果,VanCutsemE,etal.JClinOncol.2012;30:3499-3506.,OS(%),100,80,60,40,20,0,Mos,0,3,6,9,12,15,18,21,24,27,30,33,36,39,StratifiedHR:0.817(95.34%CI:0.713-0.937;log-rankP=.0032),Placebo/FOLFIRIMedian:12.06mos,Aflibercept/FOLFIRIMedian:13.50mos,PFS(%),100,80,60,40,20,0,Mos,0,3,6,9,12,15,18,21,24,27,30,StratifiedHR:0.758(95%CI:0.661-0.869;log-rankP.0001),Placebo/FOLFIRIMedian:4.67mos,Aflibercept/FOLFIRIMedian:6.90mos,(阿帕西普),(阿帕西普),VELOUR研究:按贝伐单抗分层OS,TaberneroJ,etal.EurJCancer.2013;Epubaheadofprint.,OS(%),100,80,60,40,20,0,Mos,0,3,6,9,12,15,18,21,24,27,30,33,36,39,HR:0.862(95.34%CI:0.673-1.104),Placebo/FOLFIRIMedian:11.7mos,Aflibercept/FOLFIRIMedian:12.5mos,PtsatRisk,nPlaceboAFL,187186,170178,138150,115121,8189,5459,3736,2222,1313,PreviousBevacizumab,OS(%),100,80,60,40,20,0,Mos,0,3,6,9,12,15,18,21,24,27,30,33,36,39,HR:0.788(95.34%CI:0.699-0.927),Placebo/FOLFIRIMedian:12.4mos,Aflibercept/FOLFIRIMedian:13.9mos,PtsatRisk,nPlaceboAFL,427426,403388,347348,286295,205222,139157,94112,6582,3862,NoPreviousBevacizumab,(阿帕西普),(阿帕西普),ziv-Aflibercept(阿帕西普):毒性,VanCutsemE,etal.JClinOncol.2012;30:3499-3506.,(阿帕西普),mCRC:二线EGFR单抗治疗,1.SobreroAF,etal.JClinOncol.2008;26:2311-2319.2.PeetersM,etal.JClinOncol.2010;28:4706-4713.3.HechtJR,etal.ASCO2013.Abstract335.,*Statisticallysignificantdifference.,(瑞格非尼),CORRECT:所有治疗肠癌方案失效后用Regorafenib(瑞格非尼),Primaryendpoint:OSApproximately50%ofpatientswith4systemictherapiesAllpatientshad