晚期大肠癌化疗

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,*,晚期大腸癌的化疗,结直肠癌,肝转移,I,期切除,10-20%,不可切除,80-90%,绝大部分肝转移灶初期不能切除,手术,化疗,/,靶向药物治疗,五年生存率,30-40%,5,年生存率,肝外转移/广泛转移,II,期切除,10-20%,目标,提高结肠癌肝转移灶的切除率,延长晚期结肠癌患者的生存期,改善晚期结肠癌患者的生活质量,1,Therapy for Initially Resectable Liver Metastases,Results of liver surgeryfor metastatic CRC (N,100),N. of patients Operative mort 5-yr survival,Adson, 1984,(1),1412.8%23%,Hughes, 1988,(2),859-33%,Doci, 1991,(3),1005%30%,Scheele, 1991,(4),2196%39%,Rosen, 1992,(5),2804%25%,Nordlinger, 1992,(6),18182.4%26%,Gayowski, 1994,(7),2040%32%,Rees, 1997,(8),1141%37%,1 - MA. Adson,et al.,Arch. Surg., 1984; 119: 647-515 - CB. Rosen,et al.,Ann. Surg., 1992; 216: 493-5052 - KS. Hugues, Surgery, 1988; 103: 278-886 - B. Nordlinger,et coll.,Ed. Paris Springer-Verlag, 1992; 141-59,3 - R. Doci,et al.,Br. J. Surg., 1991; 78: 797-8017 - TJ. Gayowski,et al.,Surgery, 1994; 116: 703-11 4 - J. Scheele,et al.,Surgery, 1991; 110: 13-298 - M. Rees,et al.,Br. J. Surg., 1997; 84: 1136-40,Peri-operative FOLFOX4 chemotherapy and surgery for resectable liver metastases from colorectal cancer,Final efficacy results of the EORTC Intergroup phase III study 40983.,B. Nordlinger, H. Sorbye, B. Glimelius, G.J. Poston, P.M. Schlag, P. Rougier, W.O.Bechstein, J. Primrose, E.T. Walpole, T. Gruenberger,Statistical analysis L. Collette,For the EORTC GI Group, CR UK, ALMCAO, AGITG and FFCD,ALMCAO,AGITG,g,Trial Design and Objectives,R,FOLFOX4 x 6 cycles,Surgery,FOLFOX4 x 6 cycles,Surgery,364 patients,Potentially resectable (1-4) liver metastases,Goal:,Improve,progression-free survival,to demonstrate a 40% increase in median PFS (HR=0.71) with 80% power and 2-sided significance level 5%,Progression-free survival in eligible patients,;,CI:,0.60-1.00,Periop CT,28.1%,36.2%,+8.1%At 3 years,(years),0,1,2,3,4,5,6,0,10,20,30,40,50,60,70,80,90,100,O,N,Number of patients at risk :,125,171,83,57,37,22,8,115,171,115,74,43,21,5,Surgery only,NCCN GUIDELINES 2007,“Patients who have completely resected liver metastases should be offered 4 to 6 months of,adjuvant,chemotherapy observation or a shortened course of chemotherapy is considered for patients who have completed,neoadjuvant,chemotherapy.”,2,Role of Neoadjuvant Systemic Chemotherapy for Liver-only Metastases,化疗对初始不能切除的肝转移患者的影响二次手术切除率,Chemotherapy,Pts,Surgery (%),5-yr OS,Oxaliplatin- based,Adam, 2001,701,14,39%,Giacchetti, 1999,151,51,50%,Alberts, 2003,42,36,-,Tournigand, 2004,111,21,-,Adam, 2004,1439,13,33%,Irinotecan- based,Pozzo, 2004,40,33,-,Ducreux, 2003,55,31,-,Tournigand, 2004,109,9,-,不可切除,开始时不可切除,开始时可切除,乐沙定为主化疗n=701 (80%),14%,86%,Adam R, et al. Ann Surg Oncol 2001;,14,(Suppl 2): iii3,iii6.,患者数,含乐沙定的化疗使结直肠癌肝转移患者获得二次手术机会,法国,Paul Brousse,医院于,19881996,年收治的患者,(n=872),606,95,171,0,100,200,300,400,500,600,700,800,900,95,36%,64%,可切除n=171+95=266,肝转移一次切除及二次,(化疗,后,),切除后,生存,率相似,Adam R, Ann Oncol 2003;14: ii13-ii16,一次切除,(n=425),二次切除（初始时不可切除）,(n=95),生存,(%),54%,50%,34%,34%,27%,29%,19%,0,1,2,3,4,5,6,7,8,9,10,0,0.2,0.4,0.6,0.8,1.0,生存,时间,(年),Collaboration : Oncologists - Surgeons,For Non Resectable Metastases,1- Current chemotherapy allows at least 20% of patients,to be rescued by liver surgery,2- The survival benefit of these patients is substantial,(30% and 20% rate at 5 and 10 years),3- Resectability: a new end point for treatment strategy,全球每年940,000 新发CRC病例,50% 以上伴有肝转移,470,000,超过半数的晚期结直肠癌病人发生肝转移,10%可切除,47，000,30% 以上可切除,141，000,目标,提高结肠癌肝转移灶的切除率,延长晚期结肠癌患者的生存期,改善晚期结肠癌患者的生活质量,结直肠癌治疗十年历程,RR 20%,TTP 56 months OS 1012 months,First-line efficacy,RR,50,%+,TTP 9+ months OS 20+ months,5-FU,5-FU,Oral fluoropyrimidines,Irinotecan,Oxaliplatin,(Eloxatin,),5-FUOral fluoropyrimidines,Irinotecan,Oxaliplatin,(Eloxatin),Cetuximab,Bevacizumab,Low efficacy,1995,One option,2000,More options,2005,Many options,RR, 50,%,TTP 89 months OS 21 months,Issues,Optimal regimens,Optimal regimens,Correct sequencing,1.关于联合化疗,III 期研究: 双药方案的比较,IFL,FOLFOX,FOLFIRI,IROX,FOLFOX和FOLFIRI一线治疗mCRC,Study,Year,Patient numbers,Median PFS/TTP,Median OS,FOLFIRI,Douillard,2000,199,6.7 mo,17.4 mo,Tournigand,2004,113,8.5 mo,20.9 mo,Colucci,2005,164,7.0 mo,14.0 mo,Kohne,2005,214,8.5 mo,20.1 mo,FOLFOX / XELOX,de Gramont,2000,210,9.0 mo,16.2 mo,Goldberg,2004,267,8.7 mo,19.5 mo,Tournigand,2004,111,8.0 mo,21.5 mo,Cassidy FOLFOX,2006,317,7.7 mo,17.7 mo,Cassidy XELOX,2006,317,7.3 mo,18.8 mo,Ducreux FOLFOX,2007,150,9.7 mo,18.4 mo,Ducreux XELOX,2007,150,9.3 mo,19.9 mo,晚期结直肠癌的一线联合化疗,N9741 研究设计,Goldberg et al. J Clin Oncol. 2004;22:23-30.,随机,795 例,IFL:,CPT-11,+5-FU/LV,CPT-11：125 mg/m2; 5FU: 500 mg/m2; LV: 20 mg/m2,d1,8,15,22，每6周重复,FOLFOX:,乐沙定,+5-FU/LV,Eloxatin: 85 mg/m2, d1,; LV: 200 mg/m2，d1,2;,5FU: 400mg/m2 , bolus+600mg/m2 22小时iv，d1,每2周重复,IROX:,乐沙定,+,伊立替康,Eloxatin: 85 mg/m2, d1,; CPT-11: 200 mg/m2, d1;,每3周重复,含乐沙定的FOLFOX方案疗效更优,IFL(n=264),FOLFOX4(n=267),IROX(n=264),缓解率(%),31,45,35,(P=0.002 vs IFL),(P=0.034 vs IFL),中位进展时间(M),6.9,8.7,6.5,(P=0.0014 vs IFL),(P0.05 vs IFL),中位生存时间(,M,),15,19.5,17.4,(P=0.001 vs IFL),(P=0.004 vs IFL),*5年生存率(%),3.8,9.2,5.4,（随访4.3年）,（IFL vs FOLFOX: p,0.002,11%,24%,19%,22%,7%,IROX,三度以上的毒副反应发生率,Goldberg et al.J Clin Oncol. 2004;22:23-30.,V 308,设计方案,FOLFIRI,FOLFOX6,进展,进展,进展,A,组,B,组,进展,Tournigand et al. J Clin Oncol. 2004;22:229-237,R,2 h,CF,200 mg/m,2,5FU CIV 2,400 to 3,000 mg/m,2,Irinotecan,180 mg/m,2,2 h,46 h,FOLFIRI,FOLFOX6,Bolus 5FU 400 mg/m,2,2 h,CF,200 mg/m,2,5FU CIV 2,400 to 3,000 mg/m,2,Eloxatin,100 mg/m2,2 h,46 h,Bolus 5FU 400 mg/m,2,FOLFOX6,FOLFIRI,序贯治疗,获得,20,个月的生存期,Arm A,Arm B,p value,FOLFIRI,FOLFOX,FOLFOX,FOLFIRI,(n=109),(n=81),(n=111),(n=69),中位疗程数（周期）,13 (1-43),8 (2-23),12 (1-38),6 (1-33),缓解率,56%,15%,54%,4%,ns,一线无进展生存期 (月),8.5,8.0,0.26,二线无进展生存期(月),4.2,2.5,0.003,总进展时间（月）,14.2,11.8,0.64,总生存期（月）,21.5,20.6,0.99,可切除率,9%,22%,0.02,Tournigand et al. J Clin Oncol. 2004;22:229-237,3/4级毒性,毒性,FOLFIRI,(n=110)*,FOLFOX6,(n=110)*,P,神经毒性,0,34,0.001,腹泻,14,11,NS,中性粒细胞减少,24,44,0.003,发热性中性粒细胞减少,7,0,0.007,血小板下降,0,5,0.01,贫血,3,3,NS,呕吐,10,3,0.027,粘膜炎,10,1,0.003,恶心,13,3,0.005,皮肤,2,1,NS,疲乏（3度）,4,3,0.028,Tournigand et al. J Clin Oncol. 2004;22:229-237,是否有最佳的联合治疗方案 ?,联合 = 最佳,没有任何一个方案明显最佳，CRC一线治疗,可选用5-FU/LV + 奥沙利铂或伊立替康,IFL 和 IROX 不是最好的联合治疗方案,采用含铂方案治疗，可明显提高二次手术切除率,方案选择需考虑毒性, 短肠: 奥沙利铂更好, 治疗前已有的神经病: 伊立替康,FOLFOX4,治疗老年结肠癌汇总分析,Goldberg R, et al. 2006 ASCO GI,Andre T, et al. N Engl J Med 2004;350:23432351.,Goldberg R, et al,.,J Clin Oncol 2004;22:2330.,de Gramont A, et al. J Clin Oncol 2000;18:29382947,Rothenberg M, et al. J Clin Oncol 2003;21:20592069.,研究名称,研究方案,设置,患者数,(%)(n=3743),MOSAIC,FOLFOX4 vs5-FU/LV,辅助,2246 (60),Goldberg,FOLFOX4 vs IFL,一线进展期,546 (15),de Gramont,FOLFOX4 vs5-FU/LV,一线进展期,420 (11),Rothenberg,FOLFOX4 vs5-FU/LV,二线进展期,531 (14),oxaliplatin 85 mg/m2,FOLFOX4,治疗老年结肠癌汇总分析,Goldberg R, et al. 2006 ASCO GI,Goldberg R, et al. ASCO 2006 Gastro-intestinal Cancers Symposium (Abstract 3502).,27 mo,Group: Mutant (n=78),Group: Wild Type (n=152),Benefit of Avastin is independent of k-RAS status,Bevacizumab,治疗,VEGF,的表达,EGF,Hypoxia,PDGF,IL-8,bFGF,COX-2,NO,Oncogenes,VEGF release,Binding and activation,of VEGFR,Proliferation,Survival,Migration,ANGIOGENESIS,Permeability,Increased expression,(MMP, tPA, uPA, uPAr,eNOS, etc.), P, P,P,P,PDGF = platelet-derived growth factor; IGF-1 = insulin-like growth factor 1IL-8 = insulin-like growth factor 8,IGF-1,VEGF = vascular endothelial growth factor,mFOLFOX,(n=50),FOLFOX+B,evacizumab一线治疗mCRC,Phase II,CapeOx,(n=50),TREE-1,(n=150),mFOLFOX +bevacizumab,(n=75),bFOL +bevacizumab,(n=70),CapeOx(dose reduced)+ bevacizumab,(n=72),TREE-2,(n=223),R,bFOL,(n=50),Nov 2002 Oct 2003,Nov 2003 Apr 2004,R,Efficacy: TREE-1 and TREE-2,FOLFOX,bFOL,CAPEOX,- BEV,N=49,+ BEV,N=71,- BEV,N=50,+ BEV,N=70,- BEV,N=48,+ BEV,N=72,Conf. RR (%)*,43,53,22,41,35,48,TTF (mo),6.5,5.8,4.9,5.5,4.4,5.5,TTP (mo),8.7,9.9,6.9,8.3,5.9,10.3,OS (mo),19.2,26.0,17.9,20.7,17.2,27.0,Hochster et al., ASCO 2006,*per protocol population,B,evacizumab,联合治疗,CRC一线治疗PFS的天花板效应,PFS ( months),sequential data,5.5,6.2,7.4,8.6,7.6,8.7,5.9,3.7,4.4,1.9,0.8,2.3,1.2,4.4,0,2,4,6,8,10,12,Kabbinavar,5-FU/LV,Hurwitz,IFL,Cassidy,XELOX,Cassidy,FOLFOX,Fuchs,FOLFIRI,Hochster,FOLFOX,Hochster,XELOX,PFS + BEV,PFS,If we cannot increase 1st line PFS, why does OS increase?,10 months,17 months,1st PFS,OS 27 Months,More effective use of all active agents?,Continuum of care,Use of EGFR-mAbs?,Use of bevacizumab beyond PD?,Post-1st PD Survival,BEV after 1st Progression in BEV-nave Patients - E3200,FOLFOX + BEV(N=282),FOLFOX (N=279),BEV(N=228),OS (mos),12.9,10.8,10.2,PFS (mos),7.3,4.7,2.7,RR (%),22.7,8.6,3.3,p=N/A,B. Giantonio et al., JCO 2007,BBP(n=642),No BBP(n=531),No Post-PD Treatment(n=253),Evaluablepatients(n=1953),1,st,Progression,(n=1445),BRiTE Registry - Patients with Bevacizumab Beyond Progression (BBP),BRiTE,:,Total N=1953,1445 pts with 1st PD,932 deaths (1/21/07 cut-off),Median follow-up 19.6 mo,Grothey et al. ASCO 2007 #4036,Physician decision - no randomization,BRiTE: Patient Outcome Based on Treatment Post 1st PD,BBP(n=642),No BBP(n=531),No Post-PD Treatment(n=253),# of deaths (%),168(66%),306(58%),260(41%),Median OS (mo),12.6,19.9,31.8,1yr OS rate (%),52.5,77.3,87.7,OS,after,1st PD (mo),3.6,9.5,19.2,Grothey et al. ASCO 2007 #4036,First suggestion of survival benefit associated with using BV beyond 1,st,PD (BBP),Improved OS appears to be due to an increase in survival beyond 1,st,PD in patients treated with BBP,These findings support the evaluation of BBP in the prospective, randomized phase III Intergroup trial,S0600/iBET,BRiTE: Conclusions,评价5-氟尿嘧啶、亚叶酸和奥沙利铂,（FOLFOX）,或卡培他滨和奥沙利铂（,XELOX）,联合,Cediranib （AZD2171, RECENTIN,TM,）,对照FOLFOX 或XELOX 联合安慰剂治疗初治转移性结直肠癌患者的疗效和安全性的一项随机、双盲、III 期临床研究,x,x,x,VEGFR TK,Inhibitor,AZD2171,AZD2171,AZD2171,Avastin,x,x,Ligand Sequestration,Avastin (Genentech/Roche),P,P,P,VEGF-A,VEGF-B,PlGF,VEGF-A,VEGF-C,VEGF-D,VEGF-C,VEGF-D,VEGFR-1,(Flt-1),VEGFR-2,(KDR),VEGFR-3,(Flt-4),Angiogenesis,Lymphangiogenesis,Endothelial,Cell Membrane,Cediranib：,口服、高效的VEGFR阻断剂,抑制VEGFR,抑制肿瘤新血管生成,减少血管密度、直径和渗透性,可以导致新进展肿瘤的毛细血管退化,抑制肿瘤血管生成,Cediranib作用机制,研究设计,FOLFOX,(FOLFOX-4 OR mFOLFOX-6),两周重复一次或,XELOX,三周重复一次,Treatment A: AZD2171,30 mg/day,+ FOLFOX or XELOX,a,Treatment B: AZD2171,20 mg/day,+ FOLFOX or XELOX,a,Treatment C: FOLFOX or XELOX +,placebo,to match AZD2171,a,Randomisation,1,：,1,：,1,目标,提高结肠癌肝转移灶的切除率,延长晚期结肠癌患者的生存期,改善晚期结肠癌患者的生活质量,“STOP and GO”,长期存活的需要,治疗毒性和生活质量的平衡,长期化疗易引起的耐药,持续化疗对缓解率提高有限,复发后再次使用相同的方案仍有效,“Stop and Go”治疗进展期结直肠癌,提高耐受性,停止,奥沙利铂累积应用已达预定剂量,或出现一定级别的感觉神经毒性,当感觉神经毒性已消退或,为阻止肿瘤进展必须应用奥沙利铂治疗,继续,FOLFOX7 x 6 cy,sLV5FU2 x 12 cy,FOLFOX7 x 6 cy,FOLFOX4,直到进展,A,B,R,Tournigand, C. de Gramont et al. J Clin Oncol; 24:394-400 2006,Stop and Go in ACRC,OPTIMOX 1,间歇性,FOLFOX伴维持治疗可保证,疗效,(%) FOLFOX4FOLFOX7,缓解率,无进展生存期,总生存率 20.0 21.6,3/4级神经毒性 18.7 13.3,Tournigand, C. de Gramont et al. J Clin Oncol; 24:394-400 2006,间歇性,FOLFOX伴维持治疗可降低毒性,FOLFOX4,FOLFOX7,sLV5FU2,FOLFOX7,所有,3/4,级毒性,0,5,1,3,5,7,9,11,13,15,17,19,21,23,周期数,患者,（,%,）,10,15,20,25,3,级神经毒性,0,2,1,3,5,7,9,11,13,15,17,19,21,23,周期数,患者,（,%,）,10,4,6,8,12,14,16,18,Tournigand, C. de Gramont et al. J Clin Oncol; 24:394-400 2006,OPTIMOX 1: 结论,对于应用FOLFOX-7方案治疗6个疗程后取得缓解或稳定的病人可以安全地停用奥沙利铂。,再次使用可以对生存产生显著的影响,n=600,OPTIMOX,3 VEGF + EGFR,抑制剂,+/- Erlotinib,+/- Erlotinib,FOLFOX7 x 6,bevacizumab,XELOX4 x 6,bevacizumab,再诱导,再诱导,Bevacizumab,Bevacizumab,巩固,巩固,FOLFOX7 x 6,bevacizumab,XELOX4 x 6,bevacizumab,诱导,诱导,R,卡培他滨，伊利替康和奥沙利铂治疗进展性结直肠癌：比较序贯与联合用药,a study of the Dutch Colorectal Cancer Group (DCCG),CJA Punt et al.,ASCO 2007,CAIRO 方案,Arm A,Arm B,Randomize,capecitabine,N=397,capecitabine +,oxaliplatin,N=143 (36%),irinotecan,N=251 (62%),capecitabine +,oxaliplatin,N=213 (53%),capecitabine +,irinotecan,N=398,1,st,line,2,nd,line,3,rd,line,疗效,End,Point,Singles,N=397,Combo,N=398,P-value,Response rate (%),20%,41%,na,PFS (mos),5.8,7.8,0.0002,OS (mos),16.3,17.4,0.33,晚期结直肠癌治疗的历史进步,5-FU/LV (Saltz),5-FU/LV (Douillard),5-FU/LV (de Gr),IFL (Goldberg),IFL (Saltz),FOLFIRI (Tournigard),FOLFOX (,Tournigard,FOLFOX (Goldberg),IFL+,Bev,FOLFOXIRI,BRITE registry,FOLFOX+CetuX(Acrobat),0,5,10,15,20,25,30,Median OS (months),