肠癌个体化治疗ESMO更新

个体化治疗-延长转移性结直肠癌患者生存的新标准,转移性结直肠癌的基本状况,有近25%的肠癌患者在确诊时就有转移灶,25%,有近一半的肠癌患者最终会转化为转移性结直肠癌,Parkin DM, et al. CA Cancer J Clin 2005;55:74108; Bilchik AJ, et al. J Clin Oncol 2008;26:53205351,50%,如何使转移性结直肠癌患者治疗的获益最大化?,Determine the optimal strategy and treatment goals for patients with mCRCCure: resection of metastases / conversion of unresectable to resectable diseaseProlongation of survivalSymptom relief / maintenance of quality of life,Optimize conversion treatmentSelect the therapy for maximum tumor reduction with minimum liver toxicityPersonalize treatment in 1st-line mCRCIdentify biomarkers to predict treatment responseIn patients with KRAS wild-type tumors, addition of ERBITUX to chemotherapy improves overall survival in 1st-line mCRCImprove collaboration between medical teamsAdoption of a multidisciplinary approach is important for the optimal treatment of patients with mCRC,如何使转移性结直肠癌患者治疗的获益最大化?,Prognostic markers: tumor characteristics laboratory patient characteristics patients preference,Group 1,2 or 3: Definition of Treatment aim,Choice of 1st line CTx & start treatment (consider starting dose!),Predictive Markers:KRAS,Availability,Revision of treatment aim: - Change treatment according new treatment aim?- Adapt according toxicity,Decision algorithm for advanced CRC,4-8 weeks,对于不可切除转移性结直肠癌患者的分类,Group 3患者转移灶不能切除，肿瘤症状不明显或肿瘤进展速度不快,强烈治疗,非强烈治疗,Schmoll H-J, Sargent D. Lancet 2007;370:105107,Group 1患者的转移灶有切除的可能性,Group 2患者转移灶不能切除并且肿瘤负荷比较大或者有肿瘤相关的症状,mCRC, metastatic colorectal cancer,mCRC: 不同的患者群体，不同的治疗策略,(Schmoll H-J, Sargent D. Lancet 2007;370:105107)Adapted in VanCutsem et al. Annals Oncol 2010,mCRC: 不同的患者群体，不同的治疗策略,(Schmoll H-J, Sargent D. Lancet 2007;370:105107)Adapted in VanCutsem et al. Annals Oncol 2010,提高切除率； 创造治愈可能性,快速缩小肿瘤，控制症状；,延缓进展；（以单药为主）,Non-resected patients are survivinglonger in recent years,Non-resected patients are now experiencing longer OS currently about 2 years,Kopetz S, et al. J Clin Oncol 2009;27:36773683,Demonstrated OS improvement in phase III trials in 1st-line mCRC,BSC,Fluoropyrimidine,Irinotecan,Oxaliplatin,OS (months),BSC, best supportive care,Scheithauer W, et al. Br Med J 1993;306:7525;Saltz et al. N Engl J Med 2000;343:90514;Hoff et al. JCO 2001;19:228292;Van Cutsem et al. JCO 2001;19:4097-4106,Goldberg et al. JCO 2004;22:23-30;Tournigand et al. JCO 2004;22:229-37,Tournigand et al. JCO 2004;22:229-37;Van Cutsem et al. ASCO-GI 2010:abstract 281,Van Cutsem et al. ASCO-GI 2010:abstract 281,Saltz et al. N Engl J Med 2000;343:90514,Hurwitz et al. N Engl J Med 2004;350:233542,Falcone et al. JCO 2007;25:167076,对于不可切除转移性结直肠癌患者的分类,Schmoll H-J, Sargent D. Lancet 2007;370:105107,着重于临床研究获得的有效率及肿瘤缩小数据,mCRC, metastatic colorectal cancer;RR, response rate,Group 3患者转移灶不能切除，肿瘤症状不明显或肿瘤进展速度不快,强烈治疗,非强烈治疗,Group 1患者的转移灶有切除的可能性,Group 2患者转移灶不能切除并且肿瘤负荷比较大或者有肿瘤相关的症状,肿瘤的控制对于方案选择尤为重要,增加转移灶切除的可能性,缓解肿瘤相关症状,影响肿瘤治疗的长期预后,肿瘤缩小,5FU/LV用于晚期结直肠癌化疗,5FU FU/LV P值5FU vs FU/LV RR 11% 21% 0.0001 OS(m) 10.5 11.7 0.04 LV5FU2 LV 200mg/m2 + 5-FU 400mg/m2 iv, 2400mg/m2 civ 46h，两周一次 AIO方案 LV 500mg/m + 5-FU 1500-2000mg/mciv 24h,每周一次Mayo Clinic方案 LV 20mg/m 静推+ 5-FU 425mg/m iv d1-5,每4周一次重复2次，之后每5周一次 Meta-analysis Group in Cancer 1998 : 5-FU持续静滴RR显著高于静推(22%和14%，P0.0002），但对OS没影响持续静脉滴注的血液学毒性低于静脉推注方案（4%和31%， P0.0001），消化道反应也轻，但H-FS和粘膜炎稍高,(From Thirion P ，JCO 2004),N9741: 2004年的结果,Goldberg RM, et al. JCO 2004;22:23-30.,*FOLFOX与IFL比较,美国FDA依据此试验，批准含乐沙定的FOLFOX方案作为晚期肠癌的一线治疗方案,Response rate of CT plus target agents,Response rate (%),0,10,20,30,40,50,60,70,FOLFIRI(n=350),FOLFOX(n=97),ERBITUX + FOLFIRI(n=316),ERBITUX + FOLFOX(n=82),57,34,40,57,p50% tumor reduction,13% of patients had50% tumor reduction,41% of patients had50% tumor reduction,31% of patients had50% tumor reduction,Patients with KRAS wt tumors,Van Cutsem E, et al. ASCO 2010;Bokemeyer C, et al. ASCO GI 2010;Maughan T, et al. ECCO-ESMO 2009,*Independent review confirmed response*Investigator assessed response at 12 weeksCT, chemotherapy; wt, wild-type,Summary of 3 randomized studies: Consistent benefit in response rates,p0.0001,p=0.0027,p=0.015,40,50,34,57,57,59,n=350,n=316,n=97,n=82,n=367,n=362,CRYSTAL,OPUS,COIN,CT,CT + ERBITUX,*,*,*,1st-line treatment results : PFS,CRYSTAL (KRAS wt)1,OPUS (KRAS wt)2,AVF2107g3,NO169664,ERBITUX,Bevacizumab,PFS,Time (months),0.0,0.2,0.4,0.6,0.8,1.0,12,0,4,8,16,20,9.9,8.4,1.0,0.8,0.6,0.4,0.2,0.0,0,4,8,12,16,20,Time (months),PFS,7.2,8.3,0,5,10,15,20,25,0.0,0.2,0.4,0.6,0.8,1.0,PFS,HR= 0.89,Time (months),0.0,0.2,0.4,0.6,0.8,1.0,PFS,0,10,20,30,Time (months),6.2,10.6,9.4,8.6,HR=0.696,HR=0.567,HR=0.54,1Van Cutsem E, et al. ASCO GI 2010 Abstract No. 281; 2Bokemeyer C, et al. ASCO GI 2010 Abstract No. 428; 3Hurwitz H et al. N Eng J Med 2004; 4Saltz LB et al. J Clin Oncol 2008,1st-line treatment: OS,1Van Cutsem E, et al. ASCO GI 2010 Abstract No. 281; 2Bokemeyer C, et al. ASCO GI 2010 Abstract No. 428; 3Hurwitz H et al. N Eng J Med 2004; 4Saltz LB et al. J Clin Oncol 2008,0.8,0.6,0.4,0.2,0,0,12,6,18,24,30,36,Time (months),OS,1.0,0.0,0.2,0.4,0.6,0.8,1.0,OS,0,10,20,30,Time (months),40,20.3,15.6,21.3,19.9,OS,0.0,0.2,0.4,0.6,0.8,1.0,18,0,6,12,24,54,30,36,42,48,Time (months),20,23.5,HR=0.796,0.0,0.2,0.4,0.6,0.8,1.0,0,6,12,18,24,30,36,Time (months),OS,18.5,22.8,HR=0.855,HR=0.89,CRYSTAL (KRAS wt)1,OPUS (KRAS wt)2,NO169664,ERBITUX,Bevacizumab,AVF2107g,IFL + bevacizumab (n=402)IFL + placebo (n=411),HR=0.66,50,OS, PFS and RR benefit in randomized trials using biologics vs CT only in 1st-line mCRC,*Primary endpoint; NR, not reported,Clinical biomarkers: Personalized therapy makes better result,肿瘤预后因子和疗效预测标记物的检测是发展的方向,某些标志物具有预测及预后双重价值,预后标记物能够提供与治疗方案无关的疗效信息,预测标记物能够提供针对特定治疗方案的疗效信息,Identified 60% of patients (KRAS wt) treated with tailored therapy,Van Cutsem E, et al. N Engl J Med 2009;360:14081417;Bokemeyer C, et al. J Clin Oncol 2009;27:663671,使用生物标记物来优化结直肠癌患者的治疗,筛选出占总人群60%的 患者以获得最佳治疗效果治疗未经选择的患者群 (100% 患者) 会降低临床获益并带来部分不必要的毒副反应 对比一种方案针对所有患者而言，个体化治疗将成为更佳的治疗理念并成为未来治疗的趋势。,对于转移性结直肠癌其他潜在的生物标记物,BRAFPTENPI3Kp53 VEGF,COX-2NRAS HeregulinEpiregulinAmphiregulin,CRYSTAL and OPUS pooled analysis: Tumor samples,The number of samples evaluable for KRAS mutations were:1063 (89%) from the CRYSTAL study increased from 45% previously1315 (93%) from the OPUS study increased from 69% previously2In the KRAS wt population, tumor samples were analyzed for BRAF:625/666 (94%) in the CRYSTAL study175/179 (98%) in the OPUS study,1Van Cutsem E, et al. N Engl J Med 2009;360:14081417; 2Bokemeyer C, et al. J Clin Oncol 2009;27:663671; Bokemeyer C, et al. J Clin Oncol 2010;28(Suppl. 15):Abstract No. 3506,CRYSTAL and OPUS analysis, BRAF mutation: Patients seem to benefit from adding ERBITUX to CT,mt, mutant; ORR, overall response rate,BRAF mutations were detected in 8.8% of the KRAS wt population in this pooled analysis,Bokemeyer C, et al. J Clin Oncol 2010;28(Suppl. 15):Abstract No. 3506,Pooled analysis of OS in patients with KRAS wt/BRAF wt tumors,OS estimate,Bokemeyer C, et al. J Clin Oncol 2010;28(Suppl. 15):Abstract No. 3506,Time (months),Pooled analysis of OS in patients with KRAS wt tumors according to BRAF mutation status,OS estimate,Bokemeyer C, et al. J Clin Oncol 2010;28(Suppl. 15):Abstract No. 3506,Time (months),Other potential biomarkers in mCRC,BRAFPTENPI3Kp53 VEGF,COX-2NRAS HeregulinEpiregulinAmphiregulin,BRAF mutation in CRYSTALOPUS pooled analysis: Patients seem to benefit from addition of ERBITUX to CT,Therefore, KRAS is the only validated biomarker predictive of efficacy of anti-EGFR antibodies; use of all other biomarkers is at an exploratory stage,WorkMat Result from European : Patient parameters for intensive/less intensive therapy,Group 3Age 65 yearsPS 2Patients understanding and acceptance of possible treatment side effects,Intensive therapy,Less intensive therapy,Group 1Potential for metastases to become resectableLiver mets onlyPhysically able to undergo major surgery,Group 2PS 0-1Speed of progression of metastasesTumor-related symptoms,WorkMat Result from European : Preferred chemotherapy and targeted therapy options,Intense therapy(Groups1&2),Less intense therapy(Group 3),Percentage of groups selecting each therapy as their first choice,Expert review from ICACT 2009:Optimizing 1st-line treatment for mCRC,Adam R, et al Ann Oncol 2010 (Epub ahead of print),Expert panel members:R Adam (France)DG Haller (USA)G Poston (UK)J-L Raoul (France)J-P Spano (France)J Tabernero (Spain)E Van Cutsem (Belgium),Expert review from ICACT 2009:Optimizing 1st-line treatment for mCRC,Careful analysis of each patient and their tumor characteristics,Adam R, et al Ann Oncol 2010 (Epub ahead of print),Is there a potential for cure?,Aim: Maximum tumor shrinkage without delaying surgery,Choice of initial therapy is key - due to the impact on subsequent options,Is primary or secondary surgery possible?,Consider: 5-FU vs oral fluoropyrimidine; continuous vs intermittent CT;neuroprotective measures when using oxaliplatin,Whats new from ESMO 2010?,Tumor shrinkage impacts long-term outcomes in mCRC,早期肿瘤缩小与患者治疗的预后相关?,早期肿瘤缩小与晚期结直肠癌患者的治疗结果相关 (BOND研究),TTP (mo) median:1.6 (1.51.7) vs 7.4 (5.16.7)HR 0.21 (0.140.31); p0.005,OS (mo) median: 7.3 (6.48.2) vs 13.4 (11.715.0)HR 0.22 (0.140.35); p10% 10%10%,OS estimate,Time (months),x,x,x,x,x,x,x,x,x,x,x,x,x,x,x,x,+,Radiologic tumor response at week 6,Median OS: 74.9 vs 30.6 weeks p9.66%Tumor decrease 9.66% at week 6 had significantly longer median OS compared with all other patients (74.9 vs 30.6 weeks; p=0.0000025),CRYSTAL: 8-week tumor regression according to treatment in patients with KRAS wt tumors,爱必妥+FOLFIRI治疗Kras野生型结直肠癌患者肿瘤控制更佳，更迅速。,CRYSTAL: 早期肿瘤对治疗的反应,早期肿瘤缩小会对爱必妥的一线治疗转移性结直肠癌的疗效起到预测作用么？,CRYSTAL研究：对于爱必妥联合FOLFIRI组早期肿瘤缩小预示患者预后更佳,PFS (kras 野生型）,OS (kras 野生型）,治疗8周时肿瘤缩小超过20%的患者与肿瘤缩小小于20%患者比较,PFS延长4.5个月，进展风险降低63.2%OS延长8.7个月,CRYSTAL研究：对于单独化疗组早期肿瘤缩小未显示显著差异,PFS (kras 野生型）,OS (kras 野生型）,治疗8周时肿瘤缩小超过20%的患者与肿瘤缩小小于20%患者比较,ERBITUX in elderly patients,对于不可切除转移性结直肠癌患者的分类,Group 3患者转移灶不能切除，肿瘤症状不明显或肿瘤进展速度不快,强烈治疗,非强烈治疗,Schmoll H-J, Sargent D. Lancet 2007;370:1