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结直肠癌的化疗和分子靶向治疗策略潘宏铭浙江大学医学部附属邵逸夫医院肿瘤内科1.结直肠癌术后可以用分子靶向药物联合辅助化疗吗？MOSAICLVOxaliplatinRLV5FU2FOLFOX4:LV5FU2+oxaliplatin85mg/m²Every2weeks,12cyclesoftreatmentD15-FUbolusD25-FUbolusLVLV5-FUinfusion*5-FUinfusion*D15-FUbolusD25-FUbolusLVLV5-FUinfusion*5-FUinfusion*AndréTetal.NEnglJMed2004;350:2343–51MOSAIC:2007ASCO的6年DFS结果deGramontetal,ASCO2007,Abstract40070020406080100Disease-freesurvival(%)HR[95%CI]:0.85[0.71–1.01]75.8%FOLFOX4279/1123(21.5%)LV5FU2345/1123(24.2%)Months612182430364248546066p0.003Datacutoff:16Jan.200778.5%72MOSAIC:2007ASCO的6年DFS结果:StageIIandStageIIIpatientsdeGramontetal.ASCO2007;Abstract4007Datacut-off:16January2007MonthsHR(95%CI):1.00(0.70–1.43)StageII0.80(0.66–0.98)StageIII1.00.90.80.70.60.50.30.40.20.10.00FOLFOX4:LV5FU2:6661218243036424854606-yr:4.6%6-yr:0.0%3-yr:7.2%672StageIII675StageIII451StageII448StageIIFOLFOX4:LV5FU2:DFSprobabilityP＝0.0034-yr:8.6%4-yr:3.5%X-ACT:Xeloda辅助化疗Dukes’C结肠癌•首要研究终点:DFSBolus5-FU/LV5-FU425mg/m2+LV20mg/m2d1–5q4wXeloda1250mg/m2bidd1–14q3wDukes’C患者术后≤8周ScheithauerWetal.AnnOncol2003;14:1735–43n=1004n=983随机X-ACT:显著提高疗效–多变量分析希罗达单药优于5-FU/LV•分析因素:年龄,性别,淋巴结,术后到随机分组的时间,CEA基线值,国籍•采用希罗达治疗，各种治疗风险均降低20%左右HR95%CIp-valueDFS0.8260.709–0.9620.0141RFS0.8090.691–0.9460.0080OS0.7880.643–0.9640.0208TwelvesCetal.NEnglJMed2005;352:2696–704希罗达改善无病生存率:5年数据更新5年Xeloda(n=1004)60.8%5-FU/LV(n=983)56.7%HR=0.88(95%CI:0.77–1.01)NImargin1.20优效性检验p=0.0682ITTpopulation0123456780.40.60.81.0概率YearsTwelvesetal.ECCO2007)5年绝对差异4.1%0123456780.40.60.81.0Years概率HR=0.86(95%CI:0.74–1.01)优效性检验p=0.06希罗达改善总体生存率:5年数据更新5年Xeloda(n=1004)71.4%5-FU/LV(n=983)68.4%ITTpopulationTwelvesetal.ECCO20075年绝对差异3.0%NSABPC-08研究mFOLFOX6方案12个周期或mFOLFOX6+贝伐单抗1年2.晚期结直肠癌是否有最佳的联合治疗方案?晚期结直肠癌的一线联合化疗N9741研究设计Goldbergetal.JClinOncol.2004;22:23-30.随机795例IFL:CPT-11：125mg/m2;5FU:500mg/m2;LV:20mg/m2，d1,8,15,22，每6周重复FOLFOX:oxaplatin:85mg/m2,d1;5FU:400mg/m2iv+600mg/m222hciv，d1,2LV:200mg/m2，d1,2;每2周重复IROX:oxaplatin:85mg/m2,d1;CPT-11:200mg/m2,d1;每3周重复含奥沙利铂的FOLFOX方案疗效更优IFL(n=264)FOLFOX4(n=267)IROX(n=264)缓解率(%)314535(P=0.002vsIFL)(P=0.034vsIFL)中位进展时间(M)6.98.76.5(P=0.0014vsIFL)(P0.05vsIFL)中位生存时间(M)1519.517.4(P=0.001vsIFL)(P=0.004vsIFL)*5年生存率(%)3.89.25.4（随访4.3年）（IFLvsFOLFOX:p0.001）(IROXvsFOLFOX4:P=0.016)Goldbergetal.JClinOncol.2004;22:23-30.*SanoffHKetal.ASCO2007:Abstract4067.V308设计方案－GERCOR随机试验FOLFIRIFOLFOX6进展进展进展A组B组进展Tournigandetal.JClinOncol.2004;22:229-237R2hCF200mg/m25FUCIV2,400to3,000mg/m2Irinotecan180mg/m22h46hFOLFIRIFOLFOX6Bolus5FU400mg/m22hCF200mg/m25FUCIV2,400to3,000mg/m2Eloxatin®100mg/m22h46hBolus5FU400mg/m2FOLFOX6FOLFIRI序贯治疗获得20个月的生存期ArmAArmBpvalueFOLFIRIFOLFOXFOLFOXFOLFIRI(n=109)(n=81)(n=111)(n=69)中位疗程数（周期）13(1-43)8(2-23)12(1-38)6(1-33)缓解率56%15%54%4%ns一线无进展生存期(月)8.58.00.26二线无进展生存期(月)4.22.50.003总进展时间（月）14.211.80.64总生存期（月）21.520.60.99可切除率9%22%0.02Tournigandetal.JClinOncol.2004;22:229-237NO16966:XELOX方案主要目标满足PFS不劣于对照组危害比HR=1.01(97.5%CI:0.91–1.12)上限1.23(不劣于的边界值)0.00.20.40.60.81.0月评估概率8.08.542363024181260意向治疗人群(ITT人群)XELOX/XELOX+安慰剂/XELOX+贝伐单抗(n=1017)FOLFOX/FOLFOX+安慰剂/FOLFOX+贝伐单抗(n=1017)Cassidyetal.ASCOGI2008NO16966:XELOXvsFOLFOX总生存期（OS）相同XELOX/XELOX+安慰剂/XELOX+贝伐单抗(n=1017)FOLFOX/FOLFOX+安慰剂/FOLFOX+贝伐单抗(n=1017)0.00.20.40.60.81.0月评估概率19.819.6危害比（HR）=0.99(97.5%CI:0.88–1.12)42363024181260Cassidyetal.ASCOGI2008意向治疗人群(ITT人群)XELIRI与FOLFIRI或IFL的比较XELIRI1(n=52)IFL2(n=264)FOLFIRI3(n=145)反应率(%)463133中位TTP(月)7.16.96.5中位OS(月)15.615.017.41PattYZetal.EurJCancer20032GoldbergRetal.JClinOncol20043DouillardJYetal.Lancet2000最佳的联合治疗方案•联合=最佳•FOLFOX，XELOX与FOLFIRI都可选用•IFL，XELIRI和IROX不是最好的联合治疗方案•考虑提高二次手术切除率•需考虑化疗方案的毒性，患者耐受性等3.为什么要检测KRAS？1LièvreA,etal.JClinOncol2008;26:374–379;2VanCutsemE,etal.JClinOncol2008;26(Suppl.abstract2);3BokemeyerC,etal.JClinOncol2008;26(Suppl.abstract4000)潜在的结肠癌疗效预测标志物MeropolNJ,etal.ASCO2008药物标志物FluoropyrimidinesTS,DPD*,TP,MSI,MTHFRexpression/polymorphismsIrinotecanUGTpolymorphisms*,MSI,transporterpolymorphismsOxaliplatinERCC1,GSTP1,XPDexpression,transporterpolymorphismsEGFRantibodiesGeneamplification/polymorphism,RASmutation,BRAFmutation,ligandexpression,PTENexpression,VEGFlevelsVEGFinhibitorsVEGFpolymorphisms,ICAMpolymorphisms/levels,E-selectinlevels,HIF1,Glut-1,VEGFRgeneexpressionGeneralCirculatingtumorcells*FDArecognizedCRYSTALIII期临床试验:研究设计•分层分析:–地区–ECOG评分•入组人群:–随机入组(n=1217)–安全性分析(n=1202)–ITT人群(n=1198)FOLFIRIIrinotecan(180mg/m2)+5-FU(400mg/m2bolus+2400mg/m2as46-hcontinuousinfusion)+LV(every2weeks)爱必妥+FOLFIRI爱必妥(IV400mg/m2onday1,then250mg/m2weekly)+Irinotecan(180mg/m2)+5-FU(400mg/m2bolus+2400mg/m2as46-hcontinuousinfusion)+LV(every2weeks)R表达EGFR的mCRCVanCutsemE,etal.ASCO2007(AbstractNo.4000)1.00.80.90.00.10.20.30.40.50.60.702468101214161820CRYSTAL研究主要终点:PFS(ITT人群)PFSestimateVanCutsemE,etal.ASCO2007(AbstractNo.4000)PFStime(months)1-yearPFSrate:23%vs34%FOLFIRI(n=599)ERBITUX+FOLFIRI(n=599)PFSITT:HR=0.85;p=0.048mPFSERBITUX+FOLFIRI:8.9monthsmPFSFOLFIRI:8.0monthsITT人群KRAS野生型KRAS突变型FOLFIRI爱必妥+FOLFIRIFOLFIRI爱必妥+FOLFIRIFOLFIRI爱必妥+FOLFIRI患者数599599350316183214OS(months)18.619.920.023.516.716.2HR0.930.7961.035p=0.3p=0.0094p=0.7551PFS(months)8.08.98.49.97.77