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1、1晚期结直肠癌晚期结直肠癌内科治疗进展内科治疗进展 2晚期大肠癌内科治疗现状晚期大肠癌内科治疗现状-可选择的药物和方案较少可选择的药物和方案较少IFL，FOLFIRI，FOLFOX，XELOX，XELIRI,IROX，FOLFOXIRI 3晚期结直肠癌治疗晚期结直肠癌治疗 几几 个个 问问 题题4联合方案的比较联合方案的比较5CPT-11 or Oxaliplatin+5-Fu/CF 一 线 治 疗6L-OHP 100 mg/m2 IV+LV5FU2RPDPDPDArm AArm BPDTournigand C,de Gramont,et al.J Clin Oncol.2004V 308 D
2、esignA Randomized GERCOR Study7Arm AArm BSequential treatment allows to reach 20 month survivalTTP 1st+2ndlineTournigand C,de Gramont,et al.J Clin Oncol.20048Additional Studies FOLFOX vs FOLFIRI360 patients with Stage IV colon cancerFOLFIRIFOLFOX 4RR 31%TTP 7 monthsOS 14 monthsRR 34%TTP 7 monthsOS 1
3、5 monthsColucci et al JCO Aug 1 20059FOLFOXIRI phase III studySouglakos J.et al.Br J Cancer 200610FOLFOXIRI vs FOFIRI:phase IIIFalcone A.2006 GI Symposium11有最佳联合方案吗有最佳联合方案吗?12Adapted from Grothey A,et al.J Clin Oncol.2004;22:1209-1214;Grothey A,Sargent D.J Clin Oncol.2005;23:9441-9442.Number of Cyto
4、toxic Drugs Received Demonstrates Correlation With Survival2221201918171615141312Median OS(mo)Patients treated with 3 drugs(%)P=.00010 10 20 30 40 50 60 70 80Infusional 5-FU/LV+irinotecanInfusional 5-FU/LV+oxaliplatinBolus 5-FU/LV+irinotecanIrinotecan+oxaliplatinBolus 5-FU/LV LV5FU2Initial Line of T
5、herapyUpdated Analysis13N engl j med 2004,350:2335-2342贝伐单抗联合贝伐单抗联合IFL方案与单用方案与单用IFL 方案的对比方案的对比*：14 ASCO 2008FOLFOX6+cetuximab versus FOLFIRI+cetuximab as first-line therapy in metastatic CRC1.Response rates,PFS and OS were similar 2.Safety profiles were similar to those for chemotherapy alone,with e
6、xception of skin reactions15 Impact of Kras mutation on Phase III Trial of Cetuximab First-Line Metastatic CRC:CRYSTALFOLFIRI+cetuximabFOLFIRIPreviously untreated CRC patientsN=1221Primary endpoint:PFS16KRAS evaluable population587 subjects analyzed for KRAS mutation status540(45%)subjects:KRAS eval
7、uable population348(64.4%)KRAS wild-type192(35.6%)KRAS mutant171 subjects with events(49.1%)Group A:105(54.7%)Group B:87(45.3%)101 subjects with events(52.6%)1198 subjects(ITT)Group A:172(49.4%)Group B:176(50.6%)FOLFIRICetuximab+FOLFIRIVan Cutsem et al:ASCO 200817CRYSTAL Study -Relating KRAS status
8、to efficacy:PFSCetuximab+FOLFIRI HR=0.63;p=0.007 mPFS wild-type(n=172):9.9 monthsmPFS mutant(n=105):7.6 monthsFOLFIRI HR=0.97;p=0.87 mPFS wild-type(n=176):8.7 monthsmPFS mutant(n=87):8.1 months0.51.00.40.30.20.10.00.60.70.80.9802461016Progression-free survival estimateMonthsCetuximab+FOLFIRI WTCetux
9、imab+FOLFIRI mutant12140.51.00.40.30.20.10.00.60.70.80.9MonthsFOLFIRI WTFOLFIRI mutant8024610161214Van Cutsem et al:ASCO 200818Summary of KRas Crystal efficacyaCochran-Mantel-Haenszel(CMH)testVan Cutsem et al:ASCO 200819Phase II OPUS:FOLFOX4 CetuximabRANDOMIZECetuximab 400 mg/m2 initial IV infusion(
10、day 1)then 250 mg/m2 weekly+oxaliplatin 85 mg/m2+5-FU/LV every 2 weeks EGFR detectable mCRCOxaliplatin 85 mg/m2+5-FU/LV every 2 weeksTreatment until progression,symptomatic deterioration,or unacceptable toxicity.Bokemeyer C,et al.ASCO 2008.Abstract 4000.Cetuximab+FOLFOX4FOLFOX420Phase II OPUS:Impact
11、 of KRas on FOLFOX+/-CetuximabBokemeyer et al:ASCO,#4000,200821These results suggest a negative interaction between anti-VEGF and anti-EGFR antibodies ASCO 2008CAIRO2 study2223晚期结直肠癌治疗晚期结直肠癌治疗 几几 个个 问问 题题24晚期大肠癌化疗的现状晚期大肠癌化疗的现状25FOLFIRI-FOLFOX6 VS FOLFOX6-FOLFIRIA Randomized GERCOR StudyTournigand et
12、 al.,JCO 2004 26晚期结直肠癌治疗的新观念晚期结直肠癌治疗的新观念 是一种是一种“慢性病慢性病”，难以治愈；，难以治愈；重点不是治愈，而是控制发展，重点不是治愈，而是控制发展，提高生活质量提高生活质量 “患者与肿瘤共存患者与肿瘤共存”；以化疗严重毒副作用和长期较差生活质量，换取以化疗严重毒副作用和长期较差生活质量，换取 生存期有限延长不合适；生存期有限延长不合适；为了避免或减轻毒副作用，保证生活质量，牺牲较为了避免或减轻毒副作用，保证生活质量，牺牲较 长生存期也是不明智。长生存期也是不明智。27晚期大肠癌治疗的新观念晚期大肠癌治疗的新观念 治疗策略：开始就要综合考虑整体规划治疗，
13、治疗策略：开始就要综合考虑整体规划治疗，权衡各个治疗阶段疗效和毒性的利弊。权衡各个治疗阶段疗效和毒性的利弊。从单药到多种选择从单药到多种选择-整体规划治疗之路整体规划治疗之路28整体规划治疗整体规划治疗29L-OHP 100 mg/m2 IV+LV5FU2RPDPDPDArm AArm BPDTournigand C,de Gramont,et al.J Clin Oncol.2004V 308 DesignA Randomized GERCOR Study 晚期大肠癌化疗的现状晚期大肠癌化疗的现状-序贯使用含三种药物的化疗延长生存序贯使用含三种药物的化疗延长生存30FOLFIRI-FOLFO
14、X6 VS FOLFOX6-FOLFIRIFOLFIRI FOLFOX6 FOLFOX6 FOLFIRI (N=109)(N=81)(N=111)(N=69)二线治疗后二线治疗后PSF 14.2 10.9 (中位中位 月月)P=0.64OS 21.5 20.6(中位中位 月月)P=0.99PFS 8.5 4.2 8.0 2.5(中位中位 月月)有效率（）有效率（）56 15 54 4 31Adapted from Grothey A,et al.J Clin Oncol.2004;22:1209-1214;Grothey A,Sargent D.J Clin Oncol.2005;23:944
15、1-9442.Number of Cytotoxic Drugs Received Demonstrates Correlation With Survival2221201918171615141312Median OS(mo)Patients treated with 3 drugs(%)P=.00010 10 20 30 40 50 60 70 80Infusional 5-FU/LV+irinotecanInfusional 5-FU/LV+oxaliplatinBolus 5-FU/LV+irinotecanIrinotecan+oxaliplatinBolus 5-FU/LV LV
16、5FU2Initial Line of TherapyUpdated Analysis32TournigandTournigand序贯试验毒性分析序贯试验毒性分析*P=.001 vs Arm A.33NCCN.Clinical Practice Guidelines in Oncology:Colon Cancer.Version 2.2006;Grothey A,et al.J Clin Oncol.2004;22:1209-1214;Sun W,Haller DG.Oncology.2005;19:1158-1160;Saltz LB.Oncology.2005;19:1147-1154.转移性结直肠癌有多项治疗选择；转移性结直肠癌有多项治疗选择；正确使用多种治疗可最大延长患者生存；正确使用多种治疗可最大延长患者生存；正确的用药顺序可确保疗效，不良反应最小；正确的用药顺序可确保疗效，不良反应最小；治疗中尽早考虑和使用所有的有效药物及方案，治疗中尽早考虑和使用所有的有效药物及方案，优化治疗顺序，延长生存期，提高生活质量。优化治疗顺序，延长生存期，提高生活质量。Grothey A 和和
