晚期结直肠癌的规范化治疗.ppt

晚期结直肠癌的规范化治疗,Tianshuliu,M.D.,Ph.D.ZhongshanHospital,FudanUniversityDeptofMedicalOncologyCenterofEvidence-basedmedicine,mCRC分组全程管理,整体治疗策略的应用显著延长了mCRC患者的OS,1.Cunningham,etal.Lancet1998;2.VanCutsem,etal.BJC2004;3.Rothenberg,etal.JCO20034.Hurwitz,etal.NEJM2004;5.Cunningham,etal.NEJM2004;6.VanCutsem,etal.NEJM20097.VanCutsem,etal.JCO2007;8.VanCutsem,etal,JCO2012;9.Grothey,VanCutsem,etal.Lancet2012,改善mCRC生存的关键,提高一线治疗的疗效-个体化选择最佳治疗,创造“治愈的机会”-转移灶的手术切除（和其他局部毁损性治疗）,采用“治疗的延续”-在不同线数的治疗中采用最佳疗法,改善mCRC生存的关键,提高一线治疗的疗效-个体化选择最佳治疗,创造“治愈的机会”-转移灶的手术切除（和其他局部毁损性治疗）,采用“治疗的延续”-在不同线数的治疗中采用最佳疗法,一线治疗决策制定的驱动因素,mCRC患者的一线治疗决策需充分考虑三大特征,化疗+/-贝伐珠单抗,化疗+/-靶向药物,再评估/每2-3个月评估肿瘤缓解情况,RASWT,RASMT,BRAFMT,疾病控制,治疗特征,肿瘤特征,右半,左半,化疗+/-贝伐珠单抗,化疗+/-贝伐珠单抗,化疗+/-西妥昔单抗,Fit,Unfit,Unfit(但可能获益）,患者的临床分类,疾病进展,高强度治疗,继续治疗,暂停治疗,维持治疗,患者特征,化疗+/-西妥昔单抗,OXA,CPT-11,FOLFOXXELOXFLOX,FOLFIRIIFLXELIRI,5-FUCAPE,中国可获取的药物,氟尿嘧啶的作用机制,1.LongleyDB,etal.NatRevCancer2003;3:330338;2.PetersGJ.TherAdvMedOncol2015;7:340356;3.WilsonPM,etal.NatRevClinOncol2014;11:282298;4.VanCutsemE,etal.AnnOncol2014;25(Suppl3):iii1iii9;5.LonsurfUSPI,September2015;6.TaihoPharmaceuticalsCo.Ltd.Availableat:www.taiho.co.jp.;7.http:/www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_Initial_authorisation/human/003897/WC500202369.pdf.,雷替曲赛,奥沙利铂1,2,奥沙利铂和伊立替康的作用机制,1.AdaptedfromBoulikasT,etal.CancerTher2007;5:537583;2.OxaliplatinSmPC,September/2008;3.AdaptedfromFreseS,DiamondB.NatRevRheumatol2011;7:733738;4.VanCutsemE,etal.AnnOncol2014;25(Suppl3):iii1iii9.,DNAsynthesis,Celldeath,Inter-andintra-strandDNAcross-links,伊立替康,Inductionofapoptosis,晚期结直肠癌尽量暴露于所有有效药物的理念,11个III期临床研究（n=5768）结果分析：晚期结直肠癌整个治疗过程中用过所有3个有效细胞毒药物（5-FU/LV、伊立替康和奥沙利铂）的患者生存期最长,AdaptedfromGrothey355:10411047.,*Primaryendpoint.,TTP,OS,p0.001,p=0.031,PFSprobability,Months,OSprobability,Months,RandomizedPhaseIIItrialofFOLFIRIvs5-FU/LVin1stlinetreatmentof(K)RAS-unselectedmCRC,4.4,6.7,14.1,17.4,FOLFIRI(n=198)5-FU/LV(n=187),FOLFIRI(n=198)5-FU/LV(n=187),FOLFIRIvs5FU：显著的生存获益,*Primaryendpoint.,FOLFOXvs5FU：显著的生存获益,RandomizedPhaseIIItrialofFOLFOX4vs5-FU/LVin1stlinetreatmentof(K)RAS-unselectedmCRC,deGramontA,etal.JClinOncol2000;18:29382947.,化疗药物的次序分布,mCRC,交叉研究设计,V308疗效结果,Tournigandetal.JClinOncol.2004;22:229-237.,FOLFOXIRIvsFOLFIRI：结果不一致,1.FalconeA,etal.JClinOncol2007;25:16701676;2.SouglakosJ,etal.BrJCancer2006;94:798805.,*Primaryendpoint;NR,notreported.GONO,GruppoOncologicoNordOvest;HORG,HellenicOncologyResearchGroup.,ItalianGONOstudy1,GreekHORGstudy2,分子靶向治疗,肿瘤细胞,表达水平,正常细胞,靶点,细胞受体信号转导细胞周期血管生成,VEGF及受体家族,PlGF,VEGF-R1,VEGF-R3,VEGF-R2(mostprominent),VEGF-A,VEGF-D,VEGF-C,Endothelialprogenitorrecruitment,Migration/invasion,Proliferation,Lymphangiogenesis,Permeability,Survival,Ligands:VEGF-AVEGF-CVEGF-DVEGF-E,Ligands:VEGF-CVEGF-D,Ligands:VEGF-AVEGF-BPlGF,VEGF-B,PlGF,VEGF-A,VEGF-B,VEGF-D,VEGF-C,VEGF-E,VEGF-A,1.AdaptedfromWangT-FandLockhartAC.ClinMedInsightsOncol2012;6:1930;2.AvastinSmPC,October/2015;3.ZaltrapSmPC,September/2014;4.StivargaSmPC,October/2015;5.CyramzaPI,April/2015.,PlGF,VEGF-R1,VEGF-R3,VEGF-R2(mostprominent),VEGF-A,VEGF-D,VEGF-C,Ligands:VEGF-AVEGF-CVEGF-DVEGF-E,Ligands:VEGF-CVEGF-D,Ligands:VEGF-AVEGF-BPlGF,VEGF-B,PlGF,VEGF-A,VEGF-B,VEGF-D,VEGF-C,VEGF-E,VEGF-A,Aflibercept3,Bevacizumab2,Regorafenib4,Ramucirumab5,1.AdaptedfromWangT-FandLockhartAC.ClinMedInsightsOncol2012;6:1930;2.LambrechtsD,etal.JClinOncol2013;31:121930;3.ZaltrapSmPC,September/2014;4.StivargaSmPC,October/2015;5.CyramzaPI,April/2015.,Endothelialprogenitorrecruitment,Migration/invasion,Proliferation,Lymphangiogenesis,Permeability,Survival,抗血管生成药物的作用机制,apatinib,贝伐珠单抗一线治疗,AVF2107药物注册研究,Hurwitz,etal.NEJM2004,贝伐珠单抗一线治疗:NO16966研究,贝伐珠单抗一线治疗的III期研究,ARTIST（中国本土数据）,1.0,0.8,0.6,0.4,0.2,0.0,0,6,12,18,24,时间(月),13.4m,18.7m,OS,贝伐珠单抗+mIFL(n=142)mIFL(n=72),HR=0.62P=0.014,1.0,0.8,0.6,0.4,0.2,0.0,6,12,18,24,0,mlFL(n=72),贝伐珠单抗+mlFL(n=142),时间(月),PFS,HR=0.44;95%CI=0.31-0.63PRASMTBRAFMT,Sinicrope.2015.,以5-Fu为基础的辅助化疗的III期结直肠癌(n=737),0,10,20,30,40,50,60,70,80,90,100,0,12,347311265236215197270233187163148140282218151313332726231919595146444039,24,36,48,60,5-yrDFS率(95%CI)P-值无BRAFV600E148(1):88-99.Slide12BRAFMTdeck,无论进行何种靶向治疗，BRAF突变的mCRC患者的预后都较差,*仅BRAFWT;RAS和BRAFWT.#所有治疗组的中位OS.1.Maughan.2011;2.Bokemeyer.2012;3.Douillard.2013;4.Peeters.2014;5.Price.2011;6.Cremolini.2014;7.Loupakis.2015;8.Stintzing.2014;9.Stintzing.2015.,目前其他新研药物,国外上市药物帕尼单抗：EGFR阿柏西普：VEGF瑞格菲尼：多靶点小分子在研呋喹替尼阿帕替尼,患者特征不同患者给予不同治疗强度,三药治疗靶向诱导+维持,单药治疗靶向,治疗强度,患者特征,肿瘤特征不同RAS基因状态不同治疗选择,准确的RAS检测必须包括完整的KRAS及NRAS,RAS检测,不同分子分型指导不同靶向药物选择,RASWT47%,RASMT46%,BRAFMT7%,Sorich