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1、1,晚期结直肠癌 内科治疗进展 徐建明 军事医学科学院307医院肿瘤中心,2,晚期大肠癌内科治疗现状 -可选择的药物和方案较少,化疗药物: 5-Fu, 希罗达，S1，雷替曲塞，草酸铂，CPT-11靶向药物：贝伐单抗，西妥昔单抗，帕尼单抗方 案：IFL，FOLFIRI，FOLFOX， XELOX，XELIRI, IROX， FOLFOXIRI 化疗“三类药物， 两个方案”靶向药物expensive ！,3,晚期结直肠癌治疗 几 个 问 题,有最佳联合方案吗 ？ 整体规划（continuum of care） Stop and go ？,4,联合方案的比较,IFL FOLFOX FOLFIRI I
2、ROX FOLFOXIRI, 单抗,5,CPT-11 or Oxaliplatin + 5-Fu/CF 一 线 治 疗,6,CPT-11 180 mg/m2 IV + LV5FU2,FOLFIRI,FOLFOX6,L-OHP 100 mg/m2 IV+ LV5FU2,R,FOLFOX6,FOLFIRI,PD,PD,PD,Arm A,Arm B,PD,Tournigand C, de Gramont, et al. J Clin Oncol. 2004,V 308 DesignA Randomized GERCOR Study,7,56%,0.99,0.26,4%,15%,FOLFIRI (n=
3、69),FOLFOX (n=81),20.6,21.5,OS (months),PFS 1st line (months),54%,Response rate,FOLFOX (n=111),FOLFIRI (n=109),Arm A,Arm B,p value,ns,8.5,8.0,0.003,PFS 2nd line (months),2.5,4.2,Sequential treatment allows to reach 20 month survival,TTP 1st+ 2ndline,14.2,11.8,0.64,Tournigand C, de Gramont, et al. J
4、Clin Oncol. 2004,8,Additional Studies FOLFOX vs FOLFIRI,360 patients with Stage IV colon cancer,FOLFIRI,FOLFOX 4,RR 31% TTP 7 months OS 14 months,RR 34% TTP 7 months OS 15 months,Colucci et al JCO Aug 1 2005,9,FOLFOXIRI phase III study,Souglakos J. et al. Br J Cancer 2006,10,FOLFOXIRI vs FOFIRI: pha
5、se III,Falcone A. 2006 GI Symposium,11,有最佳联合方案吗 ?,IFL and IROX are not optimal doublets FOLFOX or FOLFIRI recommended as 1st line treatment, and crossed over as 2nd line chemo Triplet of FOLFOXIRI is not clearly better than doublets yet,12,Adapted from Grothey A, et al. J Clin Oncol. 2004;22:1209-12
6、14; Grothey A, Sargent D. J Clin Oncol. 2005;23:9441-9442.,Number of Cytotoxic Drugs Received Demonstrates Correlation With Survival,Please see full prescribing information, including black box warning for CAMPTOSAR, available at this presentation.,Updated Analysis,13,N engl j med 2004,350:2335-2342
7、,贝伐单抗联合IFL方案与单用IFL 方案的对比,* IFL ：CPT-11+5FU/LV,14,ASCO 2008,FOLFOX6 + cetuximab versus FOLFIRI + cetuximab as first-line therapy in metastatic CRC,1.Response rates, PFS and OS were similar 2.Safety profiles were similar to those for chemotherapy alone, with exception of skin reactions,15,Impact of Kr
8、as mutation on Phase III Trial of Cetuximab First-Line Metastatic CRC: CRYSTAL,R A N D O M I Z E,FOLFIRI + cetuximab,FOLFIRI,Previously untreated CRC patients N=1221,Primary endpoint: PFS,16,KRAS evaluable population,587 subjects analyzed for KRAS mutation status,540 (45%) subjects: KRAS evaluable p
9、opulation,348 (64.4%) KRAS wild-type,192 (35.6%) KRAS mutant,171 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%),FOLFIRI,Cetuximab + FOLFIRI,Van Cutsem et al: ASCO 2008,17,CRYSTAL Stu
10、dy - Relating KRAS status to efficacy: PFS,Cetuximab + FOLFIRI HR=0.63; p=0.007 mPFS wild-type (n=172): 9.9 months mPFS mutant (n=105): 7.6 months,FOLFIRI HR=0.97; p=0.87 mPFS wild-type (n=176): 8.7 months mPFS mutant (n=87): 8.1 months,0.5,1.0,0.4,0.3,0.2,0.1,0.0,0.6,0.7,0.8,0.9,Months,FOLFIRI WT,F
11、OLFIRI mutant,8,0,2,4,6,10,16,12,14,Van Cutsem et al: ASCO 2008,18,Summary of KRas Crystal efficacy,aCochran-Mantel-Haenszel (CMH) test,Van Cutsem et al: ASCO 2008,19,Phase II OPUS: FOLFOX4 Cetuximab,RANDOMIZE,Cetuximab 400 mg/m2 initial IV infusion (day 1) then 250 mg/m2 weekly + oxaliplatin 85 mg/
12、m2 + 5-FU/LV every 2 weeks,EGFR detectable mCRC,Oxaliplatin 85 mg/m2 + 5-FU/LV every 2 weeks,Treatment until progression, symptomatic deterioration, or unacceptable toxicity. Bokemeyer C, et al. ASCO 2008. Abstract 4000.,Cetuximab + FOLFOX4,FOLFOX4,20,Phase II OPUS: Impact of KRas on FOLFOX +/- Cetu
13、ximab,Bokemeyer et al: ASCO, #4000, 2008,21,These results suggest a negative interaction between anti-VEGF and anti-EGFR antibodiesASCO 2008,CAIRO2 study,22,23,晚期结直肠癌治疗 几 个 问 题,有最佳联合方案吗 ？含CPT-11或草酸铂的方案 Bev, Cet 整体规划（continuum of care） Stop and go ？,24,晚期大肠癌化疗的现状,可选择的药物和有效的方案相对较少；现有模式：“化疗疾病进展更换化疗方案”“
14、肿瘤不息，化疗不止”；化疗提高近期疗效，对生存延长却很有限；即使化疗获益，大部分的缓解时间都是在周而复始的化疗中度过，生活质量极差。,25,FOLFIRI-FOLFOX6 VS FOLFOX6-FOLFIRI A Randomized GERCOR Study,FOLFIRI/FOLFOX6 FOLFOX6/FOLFIRI Median OS 21.5 months 20.6 months,Tournigand et al., JCO 2004,26,晚期结直肠癌治疗的新观念,是一种 “慢性病”，难以治愈；重点不是治愈，而是控制发展，提高生活质量 “患者与肿瘤共存”； 以化疗严重毒副作用和长期
15、较差生活质量，换取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，牺牲较长生存期也是不明智。,27,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，权衡各个治疗阶段疗效和毒性的利弊。,从单药到多种选择 - 整体规划治疗之路,28,整体规划治疗,一线治疗与后续治疗的选择有关，并非独立应用； 各个治疗之间无绝对差别，并非一个方案用到疾 病进展，可以在疾病进展前更换下一个治疗方案 或以后再改回曾用过的方案；实行个体化治疗中，可以在治疗间歇或维持治疗期穿插强烈治疗；对可能切除的肝转移，可以一种或几种方案治疗，以缩小肿瘤，增加根治性切除的机会。,29,CPT-11 180 m
16、g/m2 IV + LV5FU2,FOLFIRI,FOLFOX6,L-OHP 100 mg/m2 IV+ LV5FU2,R,FOLFOX6,FOLFIRI,PD,PD,PD,Arm A,Arm B,PD,Tournigand C, de Gramont, et al. J Clin Oncol. 2004,V 308 DesignA Randomized GERCOR Study,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,30,FOLFIRI-FOLFOX6 VS FOLFOX6-FOLFIRI,FOLFIRI FOLFOX6 FOLFOX6 FOLFIRI(N=109) (N=81) (N=111) (N=69)二线治疗后PSF 14.2 10.9 (中位 月) P=0.64 OS 21.5 20.6 (中位 月) P=0.99 PFS 8.5 4.2 8.0 2.5 (中位 月) 有效率（） 56 15 54 4,
