晚期结直肠癌内科治疗进展

会计学1晚期结直肠癌内科治疗进展晚期结直肠癌内科治疗进展F 5FU 已经应用于临床治疗胃肠道肿瘤近已经应用于临床治疗胃肠道肿瘤近40年年5-FU开发5060708090 20005-FU针剂非选择性口服非选择性口服5FUFT207UFT肿瘤选择性肿瘤选择性口服口服5FU前体药前体药Futulon新一代口服经三步活化5-FU药物希罗达1957 1980s 1990s 2000-2002 2003 20045FU 单药单药开普拓开普拓 (盐酸伊立替康注射液盐酸伊立替康注射液) 2线线 开普拓开普拓+艾比特思艾比特思(cetuximab) 2线线希罗达希罗达 (卡培他滨卡培他滨 ) 1线线乐沙定乐沙定 (奥沙利铂奥沙利铂) 2线线 5-FU/LV开普拓开普拓1线线批准奥沙批准奥沙利铂线利铂线开普拓开普拓+阿瓦斯丁阿瓦斯丁 (bevacizumab) 1线线L-OHP,CPT-11,靶向治疗 XeliRi (46%50%) 5-FU治疗大肠癌的方案治疗大肠癌的方案欧洲欧洲(滴注滴注)方案方案 AIO方案方案：5-FU 23002600mg/m2/24h d1.8.15.22.29.36 FA 500mg/m2/2h d1.8.15.22.29.36 DGM方案方案：5-FU 400mg/m2/推注 600mg/m2/22h d1.2 FA200mg/m2/2h d1.2/2W 6W美国美国(推注推注)方案方案 Mayo方案方案：5-FU 425mg/m2/d d1.2.3.4.5 FA 20mg/m2/d d1.2.3.4.5 4W RegimenResponse rate(%)TTP(months)Median survival(months)AIO20.5/11.56.4/4.1*13.2/12.0Schmoll et al. 2000De Gramont32.6/14.4*6.3/5.0*14.2/13.0De Gramont et al. 1997Roswell Park30.3/12.1*N/A12.6/10.6Petrelli et al. 1989Raltitrexed19.3/16.74.7/3.610.3/10.3Cunningham et al. 1996Raltitrexed18.6/18.13.9*/5.110.9/12.3Cocconi et al. 1998UFT/LV11.7/14.53.5*/3.812.4/13.4Pazdur et al. 1999Xeloda25.7/16.7*4.6/4.712.9/12.8Hoff 2000Study regimen/Mayo Clinic regimen; *p 0.01Response rate reported for measurable patients only (79% of ITT population)Comparator arm: i.v. bolus 5-FU 500mg/m2, days 15 every 28 days, without LVComparator arm: LV 200mg/m2 plus 5-FU 400mg/m2, days 15 every 28 days希罗达希罗达 (n=603) 5-FU/LV (n=604) PR + CR (%) 25.7 16.7 p0.0002 病情稳定 (%)47.8 52.2 IRC* PR + CR (%) 22.4 13.2 p0.0001 病情稳定 (%)52.9 57.6 *IRC =独立审查委员会Integrated CRC观察者Integrated CRC希罗达 (n=603)5-FU/LV (n=604)中位生存期 (CI)5-FU/LV: 13.1 (11.914.2)13.113.1051015202530时间 (月)估计可能性1.00.80.60.40.20 病例病例(%) 95%CI 总有效率总有效率 RR* 55 45-65疾病稳定疾病稳定 32 23-43疾病进展疾病进展 6 2-13早期停药早期停药 6 2-131. D. Cunningham et al, ASCO 98 and Lancet 19982. E. Van Cutsem et al, ASCO 98 and Ph. Rougier, Lancet 1998 开普拓开普拓 + 5FU/FA 5FU/FA 开普拓开普拓 + 5FU/FA 的优势的优势总有效率总有效率 49% 31% +18% (p 0.001)经证实的有效率经证实的有效率 41% 23% +18% (p 0.001)(可评价病人：可评价病人：4周后周后) (33.3-48.6) (17.0-30.2)中位有效及稳定时间中位有效及稳定时间(月月) 8.6 6.2 +2.4 (p 0.001) 中位进展时间中位进展时间 (月月) 6.7 4.4 +2.3 (p 0.001)中位生存期中位生存期(月月) 17.4 14.1 +3.3 (p = 0.031)1. Douillard J.Y., et al. The Lancet 2000; 355: 1041-1047.Saltz L.B. N Engl J Med 2000; 343: 905-14剂量：剂量：130mg/m2 2小时静点小时静点,每每3周重复周重复随机化随机化, 多中心多中心, 开放性开放性, 前瞻性前瞻性, III期临床研究期临床研究直至进展直至进展R直至进展直至进展直至进展直至进展直至进展直至进展L-OHP 100 mg/m2 IV+ 简化的简化的 LV5FUA组组B组组 A组组 B组组 FOLFIRI FOLFOX FOLFOX FOLFIRI P 109 81 111 69RR(CR)% 56(3) 15 54(5) 4 0.68RR+SD% 79 63 81 35MTTP(M) 14.4 11.5 0.65MST(M) 20.4 21.5 0.9PFS(15M) 49 40 治疗晚期大肠癌新的联合化疗方案治疗晚期大肠癌新的联合化疗方案Irinotecan+XelpdaOxaliplatin+XelodaIrinotecan+OxaliplatinIrinotecan+Oxaliplatin+Xeloda、matrix metalloprotein inhibitors (金属蛋白酶抑制剂)-临床上未证实美国FDA批准日期3.抑制表皮生长受体因子信号传道J Clin Oncol, Vol 21, Issue 14 (July), 2003: 2787-2799 Mode of action of EGFR inhibitorsEGF/TGFRRAntibodyDNAKK SignallingEGFR-TKsEGFR-TKsExtracellularIntracellularMembraneCell survival (anti-apoptosis) Angiogenesis Metastasis ProliferationGrowth factors Chemotherapy/ radiotherapy sensitivityExpert Opin Pharmacother. 2004 Jul;5(7):1621-33. Cetuximab 用法用法J Clin Oncol. 2004 Apr 1;22(7):1201-8Phase II, open-label clinical trialThe 29th ESMO Congress 29 Oct. 2 Nov.2004N Engl J Med. 2004 Jul 22;351(4):337-45SD 26.7% 35.1%DC(PR+SD) 45.9% 45.6%MRD(m) 6.0 5.5MOS(m) 7.8 7.7 The 29th ESMO Congress 29 Oct. 2 Nov.2004The 29th ESMO Congress 29 Oct. 2 Nov.2004Sprouting capillary4. Appearance of new tumour vasculatureTumour3. Endothelial cell proliferation and migration2. Proteolyticdestruction of extracellular matrix1. Secretion ofangiogenicfactors Tumour angiogenesisDrugs Today (Barc). 2005 Jan;41(1):23-6(P=0.06)(P0 .001)(P0.001)The 29th ESMO Congress 29 Oct. 2 Nov.2004Copyright 2005 AlphaMed PressVenook, A. Oncologist 2005;10:250-261Figure 2. Survival benefit of bevacizumab plus first-line chemotherapy relative to other treatment strategies in patients with mCRC A组组 B组组 FOLFIRI FOLFOX FOLFOX FOLFIRI P 109 81 111 69RR(CR)% 56(3) 15 54(5) 4 0.68RR+SD% 79 63 81 35MTTP(M) 14.4 11.5 0.65MST(M) 20.4 21.5 0.9PFS(15M) 49 40 SD 26.7% 35.1%DC(PR+SD) 45.9% 45.6%MRD(m) 6.0 5.5MOS(m) 7.8 7.7 The 29th ESMO Congress 29 Oct. 2 Nov.2004Copyright 2005 AlphaMed PressVenook, A. Oncologist 2005;10:250-261Figure 2. Survival benefit of bevacizumab plus first-line chemotherapy relative to other treatment strategies in patients with mCRC