结肠癌的治疗

2020/11/4,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,2020/11/4,*,结肠癌的治疗,之,辅助治疗篇,山大二院 晋刚,2020/11/4,1,结肠癌的术后辅助治疗,2020/11/4,2,2020/11/4,3,结肠癌5年生存率：期93.2%，A期84.7%，B期72.2%，A期83.4%，B期63.1%，C期44.3%，期8.1%,2020/11/4,4,II期病人送检淋巴结数目与生存的关系,（ I NT-0089的再分析）,100,90,80,70,60,50,40,30,20,10,0,生存百分比,0,12,24,36,48,60,72,84,96,108,120,20,个送检淋巴结,11,20,送检淋巴结,1,10,送检淋巴结,87%,80%,73%,79%,73%,59%,术后月,如果,10,个送检淋巴结，则诊断效力降低,2020/11/4,5,2020/11/4,6,Phase III MOSAIC,R,FOLFOX4,LV5FU2,(de Gramont),6 months (12 Cycles),2,236 pts,148 Centers,20 Countries,2020/11/4,7,MOSAIC,2005 ASCO,的,4,年,DFS,结果,0,0,20,40,60,80,100,无疾病生存,(%),HR 95% CI:,0.77 0.650.90,6.6%,FOLFOX4,279/1123 (24.8%),LV5FU2,345/1123 (30.7%),月,6,12,18,24,30,36,42,48,54,60,66,p0.001,2020/11/4,8,4,年无疾病生存,(2005 ASCO),II,期与,III,期病人,HR (95% CI): 0.82 (0.601.13) Stage II,0.75 (0.620.89) Stage III,1.0,0.9,0.8,0.7,0.6,0.5,0.3,0.4,0.2,0.1,0.0,0,FOLFOX4:,LV5FU2:,66,6,12,18,24,30,36,42,48,54,60,4-yr: 8.6%,4-yr: 3.5%,3-yr: 7.2%,672,Stage III,675,Stage III,451,Stage II,448,Stage II,FOLFOX4:,LV5FU2:,无疾病生存,2020/11/4,9,QUASAR: Adjuvant vs. Observation in Stage II CRC,150 centers in 17 countires, 3239 pts.,Uncertain Indication,Observation 1617,5-FU (370 mg/m2) with,low dose FA, 1622,-,Large randomized trial,-Pragmatic trial,2020/11/4,10,Chemo,Observation,P value,Relative risk,5-yrs recurrence,22.3%,26.2%,0.001,0.78,5-yrs survival,80.3,77.4,0.02,0.83,2020/11/4,11,QUASAR临床试验,单药5-Fu治疗期结肠癌术后患者，生存期的分析显示：生存率改善小（p=0.04）但有统计学意义。,只有少部分病人获益，如果能选出从辅助化疗获益的病人，那么大部分病人就避免了不必要的化疗。,2020/11/4,12,高危的II期病人指至少含以下一项,T4,组织学分级差（3或4级）,肠梗阻,T3伴有局部穿孔或封闭,切缘不确定或阳性,脉管侵犯,淋巴结活检数量不足12个,2020/11/4,13,含奥沙利铂方案,2020/11/4,14,NSABP C-07,FU 500+LV 500,weekly x 6,every 8 weeks x 3,FU 500+LV 500,weekly x 6,every 8 weeks x 3,+,Oxaliplatin 85 weeks 1, 3 & 5,of each 8 week cycle,R,N = 2492,Primary endpoint:,3-year DFS,2020/11/4,15,NSABP C-07 Trial (FLOX vs. FU/LV) 3-year Disease-free Survival,p, 0.004,HR: 0.79 0.67 0.93,21% Risk Reduction,0.5,0.6,0.7,0.8,0.9,1,0,1,2,3,4,Ev # 3-yr DFS,FLOX 272 76.5%,FU/LV 332 71.6%,2020/11/4,16,C-07 and MOSAIC 3-yr DFS: Stage II and III,3-yr DFS,HR,C-07,76.5 %,4.9 %,0.79,MOSAIC,77.9 %,5.1 %,0.77,2020/11/4,17,含卡培他滨方案,2020/11/4,18,X-ACT研究是一项非劣效性研究，纳入的期结肠癌患者随机分配到口服希罗达组(1004例)和静注5-FU/LV组(983例,Mayo方案)。研究的主要目的是验证在结肠癌辅助治疗中,希罗达组治疗的无疾病生存(DFS)至少与推注5-FU/LV相当。次要终点包括无复发生存(RFS)、OS和安全性。,由此证明,，,希罗达,改善无病生存率和总体生存率与5-FU/LV相似。,2020/11/4,19,ITT 人群,5,年,DFS,卡培他滨,60.8%,5-FU/LV 56.7%,HR=0.88,(95% CI: 0.771.01),NI margin 1.20,优效性检验 p=0.0682,0,1,2,3,4,5,6,7,8,0.4,0.6,0.8,1.0,概率,年,5年绝对差异 4.1%,X-ACT研究7年数据更新：希罗达,改善无病生存率和总体生存率,Twelves C, et al. ASCO GI 2008. Abstract 274.,0,1,2,3,4,5,6,7,8,0.4,0.6,0.8,1.0,年,概率,5年绝对差异3.0%,HR=0.86 (95% CI: 0.741.01),优效性检验 p=0.06,5,年,OS,卡培他滨,(n=1 004)71.4%,5-FU/LV(n=983)68.4%,2020/11/4,20,NO16968,研究是一项评价XELOX（口服希罗达联合静脉滴注奥沙利铂）与5-FU/LV（常规静脉内注射化疗药物5-氟尿嘧啶/亚叶酸）作为期（早期）结肠癌患者术后辅助治疗疗效的开放性、随机临床研究。,该研究共招募1886名期结肠癌患者，在29个国家的226个研究中心同时开展。,该研究的主要终点是证明XELOX相对于5-FU/LV在无病生存率方面显示出的优效性。次要终点包括对不同治疗组总体生存期、无复发生存期、安全性。,2020/11/4,21,未化疗或放疗,III 期结肠癌,切除术后,8 周N=1886,n=944,n=942,随,机,化,辅助,XELOX vs 5-FU/LV: NO16968 (XELOXA) III 期试验研究设计,主要研究终点t: 优效性检验DFS,次要研究终点: RFS, OS, 耐受性,推注 5-FU/LV,(6 月),Mayo Clinic n=664或Roswell Park n=278,XELOX,(6 月),希罗达,1000mg/m,2,bid d1,14奥沙利铂d1,q3w8 个周期,Schmoll et al.,JCO 2007Haller et al. ESMO/ECCO 2009,2020/11/4,22,XELOX显著提高5年DFS,XELOX,5-FU/LV,1.0,0.0,0.2,0.4,0.6,0.8,0,1,2,3,4,5,6,年,ITT人群,4年差异,:,6.1%,5年差异,:,6.3%,3年差异,: 4.5%,70.9% 68.4%,3年,DFS,66.5% 62.3%,4年DFS,5年DFS,59.8%,66.1%,生存概率,Haller et al. Eur J Cancer Suppl 2009;7:4(Abst 5LBA),HR=0.80(95%CI:0.69-0.93),P=0.0045,2020/11/4,23,XELOX显著提高 RFS,ITT 人群,1.0,0.0,0.2,0.4,0.6,0.8,0,1,2,3,4,5,6,XELOX,5-FU/LV,72.1% 69.7%,3年RFS,67.5% 63.3%,4年RFS,5年RFS,60.9%,67.8%,HR=0.78 (95% CI: 0.670.92)p=0.0024,4年差异,:,6.4%,5年差异,:,6.9%,3年差异：,4.6%,年,生存概率,Haller et al. Eur J Cancer Suppl 2009;7:4(Abst 5LBA),2020/11/4,24,XELOX具有提高 OS 的趋势,ITT population,1.0,0.0,0.2,0.4,0.6,0.8,0,1,2,3,4,5,6,XELOX,5-FU/LV,5年差异,:,3.4%,HR=0.87 (95% CI: 0.721.05)p=0.1486,年,77.6%,5年OS,74.2%,生存概率,Haller et al. Eur J Cancer Suppl 2009;7:4(Abst 5LBA),2020/11/4,25,最佳辅助化疗方案,FOLFOX,XELOX,LV/5-Fu,卡培他滨,对于辅助化疗，目前没有任何证据显示可以联合任何分子靶向药物。,2020/11/4,26,1、术后分期的判断,2、根据分期选择最佳治疗方法,3、选择最佳化疗方案,2020/11/4,27,复发转移结肠癌治疗,2020/11/4,28,2020/11/4,29,2020/11/4,30,分子靶向治疗的选择,2020/11/4,31,Crystal,：无进展生存期分析,Progression-free survival time (months),PFS estimate,1.0,0.8,0.9,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0,2,4,6,8,10,12,14,16,18,20,HR = 0.851; 95% CI = 0.726-0.998,Stratified log-rank p-value = 0.0479,8.9 mo,8.0 mo,FOLFIRI, n=599,Cetuximab + FOLFIRI, n=599,1-year PFS rate,23% vs 34%,Subjects at risk,FOLFIRI alone,599,492,402,293,178,83,35,16,7,4,1,Cetuximab +,FOLFIRI,599,499,392,298,196,103,58,29,12,5,1,2007.ASCO annual meeting .Abstract No.4000,2020/11/4,32,总生存的分层分析(wK-ras),2020/11/4,33,有七个月的差距！,2020/11/4,34,OPUS,研究,(II,期,),: K-,ras,野生型数据更新,西妥昔加,FOLFOX4,对照,FOLFOX4(n=179),OS,月,22.8 vs 18.5 (HR=0.855; p=0.3854),PFS,月,8.3 vs 7.2 (HR=0.567; p=0.0064),ORR, %,57.3 vs 34.0(OR=2.5512; p=0.0027),Bokemeyer et al. ECCO-ESMO 2009 (abstract No. 6079),2020/11/4,35,转移性结直肠癌一线治疗 COIN研究(III期)： 西妥昔,XELOX/FOLFOX,Continuous* XELOX 或 FOLFOX,Arm A,R,一线治疗 mCRC( 2445例),Arm B,Continuous XELOX or FOLFOX + 西妥昔,Arm C,Intermittent*XELOX 或 FOLFOX,65% XELOX; 35% FOLFOX(根据患者或医生的选择),主要终点,:,OS优效性（K-ras 野生型患者）,Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA),2020/11/4,36,K-,ras,野生型患者疗效,Outcome,XELOX/FOLFOX +,西妥昔,(n=362),XELOX/FOLFOX(n=367),HR (95% CI),PFS,月,8.6,8.6,0.959 (0.841.09)p=0.60,OS, 月,17.0,17.9,1.038 (0.901.20)p=0.68,12周ORR%,59,50,1.44* p=0.015,*Odds ratio,Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA),2020/11/4,37,1.00,0.75,0.50,0.25,0,生存,时间,(,月,),野生型患者,PFS,ITT analysis,No. at riskArm A Arm B,0,6,12,18,24,30,36,42,367,361,245,249,92,103,41,42,18,22,11,9,6,6,1,0,Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA),Arm A (XELOX/FOLFOX),Arm B (XELOX/FOLFOX +,西妥昔,),Arm A,Arm B,Diff.,中位 PFS,8.6,8.6,+0.07,HR point estimate = 0.95995% CI 0.841.09p=0.60,2020/11/4,38,生存曲线,1.00,0.75,0.50,0.25,0,生存概率,Time (months),0,6,12,18,24,30,36,42,No. at riskArm AArm B,367,362,316,306,250,238,154,149,83,80,44,42,19,17,1,3,ITT analysis,Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA),Arm A (XELOX/FOLFOX),Arm B (XELOX/FOLFOX +,西妥昔,),Arm A,Arm B,Diff.,中位 OS,17.9,17.0,0.92,2-,年生存, %,36.1,34.4,-1.66,HR point estimate = 1.03895% CI 0.901.20p=0.68,2020/11/4,39,AVF2107g,贝伐单抗,的,III,期研究,IFL,推注 5-FU 500 mg/m,2,亚叶酸钙 20 mg/m,2,依立替康 125 mg/m,2,用药 4/6 周,疾病进展后,不接受贝伐单抗治疗,Hurwitz H, et al. N Engl J Med 2004;350:233542,5-FU/LV,推注,5-FU 500 mg/m,2,亚叶酸钙,500 mg/m,2,用药,6/8,周,贝伐单抗,5 mg/kg 每2周1次,先前未曾治疗的转移性 CRC,PD,PD,PD,推注IFL + 安慰剂（n=412）,推注IFL + 贝伐单抗（n=403）,5-FU/LV +贝伐单抗 （n=110）,疾病进展后,可接受贝伐单抗治疗,疾病进展后,可接受贝伐单抗治疗,2020/11/4,40,无进展生存,0.2,0,10,20,30,0,0.8,1.0,0.4,0.6,Progression-free survival (mo),Proportion progression-free,Treatment Group,IFL + placebo,IFL + bevacizumab,Hurwitz et al.,Proc Am Soc Clin Oncol.,2003;22. Abstract 3646 and oral presentation.,Avastin PI.,HR=0.54,P,12;,III期与高危II期患者需要辅助化疗;,奥沙利铂在辅助化疗中有重要地位;,K-ras检测是西妥昔用药的前提;,贝伐推荐在一、二线使用,西妥昔可任意线使用;,2020/11/4,43,人生就像开飞机，飞多高不是关键，关键是落地一定要稳当安全！,2020/11/4,44,谢谢,2020/11/4,45,