转移性肠癌的后线治疗

CRC化疗进展,中位生存时间,35302520151050,月,1980 1985 1990 1995 2000,5-FU,最佳支持治疗,依立替康,卡培他滨,奥沙利铂,mCRC治疗方案的进步改变了患者的预后,199019911992199419951997199820002001200320042006*,OS estimate,01224364860,1.00.20,Months,Kopetz, et al. JCO 2009,不能手术mCRC 患者分组,第3类患者转移瘤不可切除，无症状，疾病进展缓慢,强化治疗,轻度强化治疗,(Schmoll H-J, Sargent D. Lancet 2007;370:105107),第1类患者转移瘤潜在可能切除,第2类患者转移瘤不可切除，肿瘤负荷大或肿瘤相关症状明显,PFS & OS“生存更长时间”,EGFR靶点的重要作用,*抑制细胞凋亡*促进细胞增殖*促进细胞的低分化*促进血管生成*促进细胞的转移和侵袭,Baselga. Eur J Cancer 2001: 37 Suppl 4:S16-S22.,EGFR 在特定人类癌症中的表达情况,Salomon (1995); Chow (1997),31-48%,膀胱癌,Salomon (1995); Watanabe (1996);Rieske (1998),40-63%,神经胶质瘤,Bartlett (1996); Fischer-Colbrie (1997),35-70%,卵巢癌,Klijn (1992); Bucci (1997);Walker (1999),14-91%,乳腺癌,Salomon (1995); Yoshida (1997),50-90%,肾癌,Fujino (1996); Fontanini (1998),40-90%,非小细胞肺癌,Salomon (1995); Uegaki (1997),30-95%,胰腺癌,Salomon (1995); Grandis (1996),95-100%,头颈部肿瘤,Salomon (1995); Messa (1998),72-82%,结直肠癌,参考文献,肿瘤的 EGFR 表达百分比,肿瘤类型,EGFR 表达的临床意义,Neal (1985),差,膀胱癌,Sainsbury (1985),差,乳腺癌,Volm (1998)Veale (1993)Ohsaki (2000)Pavelic (1993),增加,降低OS,差差,非小细胞肺癌,Dong (1998)Yamanaka (1993),降低OS,差,胰腺癌,Grandis (1998)Maurizi (1996),降低 DFS降低OS,差,头颈部癌,Mayer (1993)Hemming (1992),增加,差,结直肠癌,参考文献,转移风险,生存,预后,肿瘤类型,DFS = disease-free survival; OS = overall survival;,爱必妥 (西妥昔单抗),爱必妥 是靶向EGFR的嵌合性IgG1 单克隆抗体 爱必妥与 EGFR结合，阻断信号传导，抑制细胞增殖、转移、血管生成以及细胞刺激凋亡,在HT29人结肠癌细胞模型中，爱必妥 增强了伊立替康的抗肿瘤效应,Prewett et al. Clin Cancer Res 2002;8:994-1003.,Mean tumor volume (mm3),Days,0,安慰剂爱必妥伊立替康爱必妥 + 伊立替康,Initiation of treatment,10,20,30,40,50,0,1000,2000,3000,4000,爱必妥单药提高mCRC三线患者的生存,爱必妥单药用于化疗失败mCRC的 II期临床研究 与BOND研究的结果一致,在EGFR 表达阳性 mCRC患者中进行的非随机II期临床研究,Saltz et al. J Clin Oncol 2004;22:1201-1208; Lenz et al. J Clin Oncol 2005;23(16S):Abstract 3536 Updated information presented at ASCO 2005,西妥昔单抗单药治疗晚期CRC患者的III期临床研究 (NCIC CTG and AGITG CO.17),H. Au, C. Karapetis, D. Jonker, C. OCallaghan, H. Kennecke, J. Shapiro, D. Tu, R. Wierzbicki, J. Zalcberg, M. Moore,A trial of the National Cancer Institute of Canada Clinical Trials Group(NCIC CTG) and the Australasian Gastro-Intestinal Trials Group (AGITG),Abstract# 4002 2007 ASCO annual meeting,NCIC CTG CO.17: mCRC 的随机III 期临床研究,EGFR 检测( IHC ),* Cetuximab 400 mg/m2 IV week 1 then 250 mg/m2 IV weekly,疾病进展 或毒性不可耐受,分层: 中心 ECOG PS (0 or 1 vs. 2),REGISTER,随机分组,1:1,Cetuximab* + BSC,BSC alone,所有推荐的治疗均失败或不能耐受,Abstract# 4002 2007 ASCO annual meeting,NCIC CTG CO.17 研究: 主要入选标准,入组标准组织学证实的mCRC，EGFR 检测阳性 (IHC) ECOG PS 评分 0, 1,2既往 anti-TS 治疗既往伊立替康或奥沙利铂治疗 转移性疾病治疗失败或 6 个月内复发或 证实不适合当前的治疗排除标准既往使用国 EGFR 抑制剂,Abstract# 4002 2007 ASCO annual meeting,NCIC CTG CO.17研究: 研究终点,主要终点总生存 次要终点PFSORR (RECIST 标准)安全性 QoL成本效益分析 (稍后报道),Abstract# 4002 2007 ASCO annual meeting,NCIC CTG CO.17 研究: 患者特征,Abstract# 4002 2007 ASCO annual meeting,CETUXIMAB + BSC,CENSORED,BSC,CENSORED,NCIC CTG CO.17研究: 总生存(OS),HR 0.77 (95% CI =0.64 0.92) Stratified log rank p-value = 0.0046,Abstract# 4002 2007 ASCO annual meeting,NCIC CTG CO.17研究: PFS,CETUXIMAB + BSC,CENSORED,BSC,CENSORED,Proportion Progression-Free,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,MONTHS,0,3,6,9,12,15,HR 0.68 (95% CI =0.57 0.80) Stratified log rank p-value 70, prior RT, ECOG 2,病理学证实的 mCRC二维可测量病灶EGFR 检测阳性 ( IHC)以奥沙利铂为基础的治疗失败 失败 = 疾病进展或不能耐受最后一次治疗的6个月内,EPIC 研究主要入组标准,EPIC 研究患者的基线特征,EPIC 研究既往化疗方案,EPIC 研究有效率和疾病控制率,p-value = 0.0001,p-value = 0.0001,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 = 0.0001,EPIC 研究 PFS,PROPORTION ALIVE,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,MONTHS,0,3,6,9,12,15,18,21,24,27,30,33,36,39,HR = 0.975 (95.03% CI = 0.854 1.114),STRATIFIED LOGRANK P-VALUE = 0.7115,Overall Survival,* 大部分患者接受了伊立替康 + 西妥昔单抗治疗,EPIC 研究： 研究的后续治疗,Survival Probability,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,Survival Time Months,0,3,6,9,12,15,18,21,24,27,30,10.2 mo,6.2 mo,IRINOTECAN; N = 345,Cetuximab+ IRINOTECAN; N = 575,EPIC 研究：未接受后续治疗患者的OS,*Goldberg, AACR 2007,奥沙利铂治疗失败后mCRC二线治疗的疗效 与历史数据的对比,EPIC 研究 安全性,与伊立替康单用相比，西妥昔单抗联合伊立替康组：RR显著提高(16.4% vs. 4.2%, P0.0001) PFS 显著提高(4.0月 vs. 2.6月, P0.0001)西妥昔单抗联合伊立替康是奥沙利铂一线治疗失败患者的标准二线治疗方案。,EPIC 研究 结论,45,2012 NCCN 指南推荐爱必妥,National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology v3 2012; colon cancer. Accessed at: /professionals/physician_gls/PDF/colon.pdf,爱必妥是mCRC二线治疗的标准 NCCI Guideline ( 2007 ),一线FOLFOX治疗失败后 爱必妥FOLFIRI 爱必妥伊立替康一线FOLFIRI治疗失败后 爱必妥伊立替康 爱必妥单药,谢 谢,依立替康治疗晚期转移性结直肠癌,一线Saltz研究和Douillard研究（V303研究）比较CF/5-FUCPT-11作为一线治疗晚期结直肠癌的疗效，结果显示，两组有效率（ORR）、中位无进展生存期（PFS）和总生存期（OS）均存在显著差异。EORTC 40986 比较了CPT-11CF/5-FU和CF/5-FU，中位PFS分别为8.5个月和6.4个月，中位OS分别为20.1个月和16.9个月，,5-FU 治疗CRC,J Clin Oncol. 1998 16(1):301-308,6 RCT, 1219 pts,静脉输注5-FU可显著提高缓解率，对生存期有轻微影响，更好的安全性,依立替康 一线治疗CRC的III期临床研究,31490.001,21390.001,31,01,FU/ LV inf.FU/ LV inf. + Irinotecanp-value,Douillard,Lancet 3/2000#338,12.614.80.04,4.37.00.004,FU/ LV bolus (Mayo)FU/ LV bolus + Irinotecan (IFL)p-value,Saltz,NEJM 9/2000 #457,31.554.20.0001,16.920.1n.s.,001,FU/ LV inf.FU/ LV inf. + Irinotecanp-value,Koehne,ASCO 2003#430,RR(%),OS(mos),PFS (mos),Protocol,Author,PFS 2.7月，OS 2.2月,PFS 2.3月，OS 3.3月,PFS 2.1月，OS ns,奥沙利铂 一线治疗CRC的III期临床研究,22.350.70.0001,16530.0001,14.716.2n.s.,6.29.00.0001,FU/LV inf.FU/LV inf. + Oxalipl. FOLFOX4p-value,De Gramont,JCO 8/ 2000#420,19.919.4n.s.,48,FU/LV inf.FU/LV inf. + Oxaliplatinp-value,Giacchetti,JCO 1/ 2000#200,22.649.10.0001,16.119.7n.s.,001,FU/ LV Bolus (Mayo)FU/ LV inf. + Oxaliplatinp-value,Grothey,ASCO 2002#252,RR(%),OS(mos),PFS (mos),Protocol,Author,PFS 2.6PFS 2.8PFS 2.5,统 计 学 无 差 异,FOLFOX 与 IFL 的对照,Goldberg RM, et al. J Clin Oncol. 2004;22:23.,15,19.5(P = .0001),6.9,8.7(P = .0014),0,5,10,15,20,25,IFL,FOLFOX,IFL,FOLFOX,Median Months,Overall Survival,Progression-Free Survival,缓解率: IFL 31