结肠癌诊治规范

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,*,结肠癌诊治规范,CSCO-2008,结肠癌治疗的焦点,结肠癌手术原则？,结肠癌的复发风险有多大？,什么样的患者需要辅助化疗？,如果要做，什么是最佳方案？,如何制定晚期结肠癌化疗方案？,如何应用单克隆抗体？,结肠癌手术原则,手术仍然占重要地位，甚至更高,手术技巧本身近十年没有重大进步,创造条件进行手术治疗,无瘤技术,注意清扫淋巴结,结肠镜,术前必要的检查和评估（胸腹部盆腔,CT,）,什么患者需要辅助治疗？,手术分期,病人诊断数,（）,5,年生存,（）,I,II,III,IV,15%,20-30%,30-40%,20-25%,85-95%,60-80%,30-60%,5%,系统辅助治疗,辅助治疗效果如何？,19905-FU/lev,优于单纯手术,19945-FU/LV,优于单纯手术,19985-FU/LV,优于,5-FU/lev,19986,个月,=12,个月,1998,大剂量,LV(RPMI)=,低剂量,(Mayo),1998,周方案化疗,=,月方案,(QUASAR),2002FOLFOX,优于,LV5FU2,MOSAIC,2005 ASCO,的,4,年,DFS,结果,de Gramont,et al,ASCO 2005,Abstract 3501,0,0,20,40,60,80,100,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,Data cut off:16 Jan.2005,4,年无疾病生存,(2005 ASCO),II,期与,III,期病人,de Gramont,et al,.ASCO 2005;Abstract 3501,Data cut-off:16 January 2005,月,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,II,期患者较少从辅助治疗中受益。可是，我们能识别高危的,II,期病人吗,?,高危的,II,期病人指至少含以下一项：,T4,肠梗阻,肿瘤穿孔,低分化肿瘤,静脉侵犯,送检淋巴结,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%,如果,10,个送检淋巴结，则诊断效力降低,II,期病人送检淋巴结数目与生存的关系,（,I NT-089,的再分析）,最佳辅助化疗方案,FOLFOX,XELOX,LV/5-Fu(,不能耐受化疗者）,为什么不用伊立替康进行辅助化疗？,伊立替康辅助化疗,PETACC-3:ASCO 2005,3278,例,II,期,/III,期,945/2333,随机,F,LV5FU2:5-FU,静注,400mg/m2,CI:600mg/m2/FA:200mg/m2,N=1050,IF,依立替康,:180mg/m2,+LV5FU2,n=1040,主要终点：,DFS,（,III,期）,次要终点：,RFS,（,III,期）,DFS,（,II,期,&III,期），,OS,Safety,Van Cutsem,et al,ASCO 2005,Abstract LBA8,时间（月）,3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0,0,IF,F,生存率比,无疾病生存,Van Cutsem,et al,ASCO 2005,Abstract LBA8,IF 63.3%,F 60.3%,3,年,DFS,P=0.091,HR:0.89(95%CI:0.77-1.11),伊立替康,一线治疗,p0.05,20.1,16.9,8.5*,6.4,54*,31,5-FU/FA/,伊立替康,5-FU/FA(AIO),EORTC,2003,p0.05,14.8*,12.8,12.0,7.0*,4.3,4.2,39*,21,18,5-FU/FA/,伊立替康,5-FU/FA(Mayo),伊立替康,Saltz,2000,p0.05,17.4*,14.1,6.7*,4.4,41*,23,5-FU/FA/,伊立替康,5-FU/FA(AIO),Douillard,2000,P,中位生存,月,TTP/PFS,月,RR,%,方案,FOLFOX-4 vs LV5FU2,de Gramont,et al,.,J Clin Oncol,.2000;18:2938.,LV5FU2,FOLFOX4,P,值,RR,22.3%,50.7%,0.0001,Median PFS,6.2,9,0.0003,mOS,14.7,16.2,0.12,奥沙利铂,一线治疗,IFL,贝伐单抗,在转移性结直肠癌中的,III,期研究,（,AVF2107g,）,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,IFL,贝伐单抗,III,期试验的生存期,概率,1.0,0.8,0.6,0.4,0.2,0,010203040,生存期（月）,IFL+,安慰剂,IFL+,贝伐单抗,中位生存期（月）,IFL+,安慰剂：,15.6 vs,IFL+,贝伐单抗：,20.3,HR,：,0.66,，,P,=0.00004,HR=,风险比,Hurwitz H,et al.N Engl J Med 2004;350:233542,CPT-11 180 mg/m,2,IV+LV5FU2,FOLFIRI,L-OHP 100 mg/m,2,IV+LV5FU2,R,FOLFIRI,PD,PD,PD,A,组,B,组,PD,Tournigand C,de Gramont,et al.,J Clin Oncol.,2004,V 308,设计,GERCOR,协作组随机对照研究,FOLFOX6,FOLFOX6,56%,0.99,0.26,4%,15%,FOLFIRI,（,n=69,）,FOLFOX,（,n=81,）,20.6,21.5,一线二线治疗的,OS,（月）,一线治疗的,PFS,（月）,54%,缓解率,FOLFOX,（,n=111,）,FOLFIRI,（,n=109,）,A,组,B,组,P,值,NS,8.5,8.0,0.003,二线治疗的,PFS,（月）,2.5,4.2,序贯两个方案的治疗可获得,20,个月生存期,一线二线治疗的,TTP,（月）,14.2,11.8,0.64,Tournigand C,de Gramont,et al.,J Clin Oncol.,2004,药物与生存的关系,11,个,III,临床,共,5768,例病人,Grothey&Sargent,JCO 2005,0 10 20 30 40 50 60 70 80,静滴,5-FU/LV,+,伊立替康,静滴,5-FU/LV,+,奥沙利铂,静注,5-FU/LV,+,伊立替康,依立替康,+,奥沙利铂,静注,5-FU/LV,LV5FU2,22,21,20,19,18,17,16,15,14,13,12,中位生存,(mo),应用,3,药的比率,(%),P,=.0001,一线治疗方案,EPIC,的试验设计,Cetuximab/Irinotecan,Irinotecan,以奥沙利铂为基础的一线治疗失败,Survival,分层因素,:,研究中心,ECOG PS(0-1,2),主要终点,:,总生存,(OS),次要终点,:PFS,RR,DCR,Safety,QoL,样本量,:221,个中心，,1298,例患者,N=648,N=650,Abstract#4003 2007 ASCO annual meeting,PROPORTION PROGRESSION FREE,0.0,0.2,0.4,0.6,0.8,1.0,0,3,6,9,12,15,18,4.0 mo,2.6 mo,MONTHS,HR=0.692,95%CI=0.617 0.776,西妥昔单抗,+,伊立替康,;N=648,伊立替康单用,;N=650,P-value=,3,5,24,以往奥沙利铂用药,有,9,22,无,15,24,Cunningham et al.N Engl J Med 2004;351:337-345,四句高度概括的原则,一线随便挑,二线互换药,三线保证全用到,想用爱必妥，,K-RAS,很重要,EGFR,的传导通路,有效率,(%),59,37,0,10,20,30,40,50,60,70,CRYSTAL,(540,例,),OPUS,(233,例,),43,61,FOLFIRI,FOLFOX,西妥昔,+FOLFIRI,西妥昔,+FOLF0X,CRYSTAL KRAS,野生型,:HR=0.68,p=0.017,进展风险降低,32%,OPUS KRAS,野生型,:HR=0.57,p=0.016,进展风险降低,43%,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,2,4,6,8,10,12,14,16,18,月,无进展生存,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,2,4,6,8,10,12,月,无进展生存,西妥昔,+,化疗（,KRAS,野生型）,如何处理可切除的转移病灶？,以,FOLFOX4,方案行围手术期化疗治疗,可手术的转移性结直肠癌,EORTC Intergroup trial 40983,Nordlinger,et.al.,The Lancet2008;371:1007-1016,研究方案,随机分组,手术,FOLFOX4,FOLFOX4,手术,6,周期,(3,月,),病例数,=364,病人,6,周期,(3,月,),结 果,接受化疗,接受手术,%3-,年,PFS,绝对差异,HazardRatio,(Confidence Interval),P-value,所有患者,182,182,+7.3%,(28.1%to 35.4%),0.79,(0.62-1.02),P=0.058,符合条件患者,171,171,+8.1%,(28.1%to 36.2%),0.77,(0.60-1.00),P=0.041,切除患者,151,152,+9.2%,(33.2%to 42.4%),0.73,(0.55-0.97),P=0.025,FOLFIRI,用于肝手术后辅助治疗,FOLFIRI,对照,LV5FU,主要目标：,DFS,Ychou et al,ASCO 2008,研究方案,随机分组,手术,FOLFIRI,12,周期,病例数,=153,病人,LV/5-FU,12,周期,病例数,=15