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=
17、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 4,31,Adapted 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 Cytotoxic Drugs Received Demonstrates Correlat
18、ion With Survival,Please see full prescribing information, including black box warning for CAMPTOSAR, available at this presentation.,Updated Analysis,32,Tournigand序贯试验毒性分析,* P = .001 vs Arm A.,33,NCCN. Clinical Practice Guidelines in Oncology: Colon Cancer. Version 2. 2006; Grothey A, et al. J Clin
19、 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; 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; 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。,Grothey A 和 Tournigand C 研 究 提 示,34,FOCUS Trial: Single agents in sequence vs. combinatio
20、n therapy,Seymour MT. ASCO 2005. Abstract 3518.,35,治疗的整体规划,治疗前后,根据病灶部位、大小和数目,决定可手术切除;根据患者体力状况进行个体化治疗,计划好各个治疗期间可能使用的药物;了解药物的相关毒性,主动采取方案干预,以降低毒性;尽可能开始时接受较为强烈的治疗,如化疗联合靶向药物。,36,有治愈可能的大肠癌治疗 选择尽量强烈的治疗,要严密监控治疗,病灶一旦可以切除,应尽快手术;不要过分等待最佳疗效的出现,术前过多的化疗会导致肝损伤,手术的过度推迟,会延误手术时机;,37,晚期大肠癌化疗应注意,手术不能切除的肝转移如果化疗后有可能手术切除,
21、疗效和毒性的衡量标准不同于不能手术切除的患者;手术切除的重要性 化疗潜在的风险一旦根治性切除,可以免遭长期化疗的痛苦。手术能切除的肝转移 可以化疗,避免过度,38,延长晚期大肠癌生存的方案选择,39,化疗的毒性问题,治疗相关毒性的类型、严重程度和持续时间可能影响治疗的选择和延续;5Fu IV : 腹泻、中性粒细胞减少、粘膜炎5Fu CIV: 手足综合症 FOLFIRI: 腹泻FOLFOX: 中性粒细胞减少、血小板减少、周围神经病变,40,41,晚期结直肠癌治疗 几个问题,有最佳联合方案吗 ?含CPT-11或草酸铂为基础的方案 整体规划(continuum of care) 个体化整体考虑 St
22、op and go ?,42,晚期大肠癌的治疗时间 毒性对治疗时间的影响,治疗直至疾病进展 ?达到预定的药物最大剂量 ?看到肿瘤最大程度的缓解 ?,43,化疗后无进展肿瘤 治疗期限多长合适 ?,英国调查190名医生: 30%医生 化疗有效的3个月后会停用化疗;50%医生 化疗有效的6个月后会停用化疗;20%医生 选择不定期的做化疗。,Seymour MT,et al. Clin Oncol, 1997, 9:248-251,44,Continuous vs Intermittent Chemotherapy 单药化疗12个周期获益患者,Maughan et al, Lancet 2003,随机
23、分组 (1)间歇组:终止治疗直至肿瘤进展后,再行相同方案治疗。 (2)连续组:连续化疗直至肿瘤进展。,45,Continuous vs Intermittent Chemotherapy for MCRC,Maughan et al, Lancet 2003,N=354,46,Continuous vs Intermittent Chemotherapy,单药的间歇化疗显示毒副作用明显减少;拓展到联合方案意义更大:费用、毒性、获益等,47,FOLFOX4 until progression,FOLFOX7 x 6 cy sLV5FU2 x 12 cy FOLFOX7 x 6 cy,A,B,R,
24、Tournigand, C. de Gramont et al. J Clin Oncol; 24:394-400 2006,Stop and Go concept: OPTIMOX 1,48,Chemotherapy regimens: (A) FOLFOX4; (B) FOLFOX7; and (C) simplified LV5FU2,Tournigand, C. de Gramont et al. J Clin Oncol; 24:394-400 2006,49,OPTIMOX 1: overview of results,(%) FOLFOX4 FOLFOX7 RR 58.5 58.
25、3 PFS 9.0 9.2 OS 20.0 21.6 Grade 3/4 18.7 13.3 neurotoxicity,Tournigand, C. de Gramont et al. J Clin Oncol; 24:394-400 2006,50,PFS (n = 620),Tournigand, C. de Gramont et al. J Clin Oncol; 24:394-400 2006,OPTIMOX 1: PFS,51,OPTIMOX 1: Survival,Tournigand, C. de Gramont et al. J Clin Oncol; 24:394-400
26、2006,52,OPTIMOX 1: neurotoxicity,Grade 3 neurotoxicity,0,5,10,15,20,25,1,3,5,7,9,11,13,15,17,19,21,23,Cycles,Percentage of patients,FOLFOX4,FOLFOX7,Tournigand, C. de Gramont et al. J Clin Oncol; 24:394-400 2006,53,maintenance therapy vs chemotherapy-free interval,mFOLFOX7 x 6 cy sLV5FU2 until baseli
27、ne progression mFOLFOX7 reintroduction,mFOLFOX7 x 6 cy No maintenance until baseline progression mFOLFOX7 reintroduction,OPTIMOX 2 Study design,A,B,OPTIMOX2 : chemotherapy-free interval (CFI),OPTIMOX1 : maintenance therapy,Maindrault-Goebel et al., ASCO 2006,54,OPTIMOX-2: Design,mFOLFOX7: no bolus 5
28、-FU, 100 mg/m2 oxaliplatin Comparison: maintenance therapy vs chemotherapy-free intervals (CFI) Primary endpoint DDC Planned trial size N=600, after bevacizumab approved downsized to a randomized phase II trial (N=200) no formal hypotheses between the two arms but sample size was enough to detect a
29、20% difference in 2-year survival (30 vs 50%) ,55,DDC (duration of disease control) ?,OPTIMOX-1/-2 序贯维持或间隙治疗以有效率作为研究终点不合适,以时间有关的研究终点合适; OS 受后续治疗的影响大,不能反映研究方案效应; PFS 能准确反映某个方案的疗效,但不适合维 持治疗或间隙化疗的总体疗效评价; DDC 能较为客观的反映维持治疗或间隙化疗的总体疗效。,56,DDC计算方法,Tournigand C, et al JCO 2006,24:394-400,57,OPTIMOX-2: Effica
30、cy,Maindrault-Goebel F, et al. 2007 ASCO,Maintenance LV5FU therapy prolongs PFS and OS, especially in patients with poor prognosis.,58,GISCAD-Trial: Design,Primary endpoint: OS Non-inferiority: 4 months difference accepted!,R,FOLFIRI,Evaluation,4 mos,N=336,Labianca et al., ASCO 2006,59,GISCAD: Summa
31、ry,No difference in efficacy No difference in toxicity (surprisingly!),Labianca et al., ASCO 2006,60,n=600,OPTIMOX 3 VEGF + EGFR inhibition,+/- Erlotinib,+/- Erlotinib,R,61,Stop and Go Strategy in Practice,Available data supports a stop and go strategy in MCRC without adverse prognostic factor Enoug
32、h chemotherapy before Stop,62,phase III CONcePT trial (FOLFOX7 + BEV),2008 ASCO,63,phase III CONcePT trial (FOLFOX7 + BEV),Intermittent oxaliplatin significantly increased TTF vs continuous oxaliplatin without compromising PFS Continuous oxaliplatin caused more discontinuations due to peripheral sen
33、sory neuropathy than intermittent oxaliplatin Activity of FOLFOX + bevacizumab was not affected by Ca/Mg; suggestion of neuroprotection by Ca/Mg (PNQ),64,晚期大肠癌的治疗新理念,化疗能获益,而不能治愈;无明确的一线和二线化疗方案;根据个体情况安排三类化疗药物, 有序应用几个方案;处理好化疗与分子靶向药物的关系;避免过度化疗stop and go 对预后好的患者个体化,65,中国人群UGT1A基因SNP分布 与CPT-11毒性的关系,解放军30
34、7医院 北京肿瘤医院 浙江大学第一附属医院 中国医学科学院肿瘤医院 解放军301医院,66,CPT-11二线用于大肠癌的研究对比,1.本研究 2.ASCO.2005;23(124s):abstr 3686 3. 中华肿瘤杂志.2003;25(6):607-609,4.Br J Cancer.2006;94(9):1287-1292 5.Clin Transl Oncol.2005;7(6):244-249 6. Med Oncol.2003;20(1):37-43,67,CPT11代谢相关通路,UGT1A 作为重要的药物代谢酶,其基因多态性 能够显著影响药物的疗效和毒性,68,UGT1A基因复
35、合物及SNP分布,M Saeki .Haplotype structures of the UGT1A complex in a Japanese population. The Pharmacogenomics Journal .2006;6:6375.,UGT1A1 肝内 UGT1A7 上消化道 UGT1A9 肝内和结肠,69,基因型与酶活性的关系,70,中国人与白种人大肠癌患者 UGT1A基因型分布比较,* Fisehers exact test #Clinical cancer res 2005,11:1226-1236,71,中国人与白种人大肠癌患者 UGT1A基因型分布比较(续),
36、72,健康中国人群与大肠癌患者 UGT1A基因型分布比较,* Fisehers exact test,73,健康中国人群与大肠癌患者 UGT1A基因型分布比较(续),74,UGT1A基因型与CPT-11毒性的关系,75,UGT1A基因型与CPT-11毒性的关系,76,小 结,中国人CPT-11的严重腹泻相对较轻(5); 严重腹泻与白种人相比降低十个百分点; 可能与UGT1A酶基因型分布不同有关; 中国人群中酶活性较高的基因型UGT1A1* (TA) 6/6 分布相对较高; 酶活性较高的基因型的患者,其腹泻相对轻。,77,肿瘤内科医生需要把握,治疗目的要明确:可能治愈 ?姑息性 ?FOLFIRI
37、 和 FOLFOX 主要方案,RR、PFS、OS相等, Cet,Bev 显著提高效果;初步个体化治疗NCCN guideline 和 Continuum of care 两手抓;,78,肠 癌 组 织, 外周血细胞,TS 高表达, DPD 缺乏,肿瘤TS 低表达,血液 DPD 正常、 UGT1A1纯合,ERCC1高,CPT-11 减量 或 Oxaliplatin,氟脲嘧啶类或其他 TS 抑制剂,临床的个体化治疗,ERCC1高,UGT1A1纯合,UGT1A1杂合,ERCC1低,CPT-11,Oxaliplatin,79,肿瘤内科医生面临的问题,理想模式:量体裁衣,最大获益,最小毒性真正实现的个体化 ?KRas 突变患者的最佳治疗方案 ?Cet+Bev 无增效, 了解 VEGF 和 EGFR 通道不够,80,谢 谢,