肠癌化疗译稿

C R C辅助疗法新进展,江苏省肿瘤防治研究所江苏省肿瘤医院黄富麟,183,000 新发病例 占新发癌症病人13% 致死率45% 占美国癌症死亡人数15% 绝大多数病人接受化学治疗 转移/复发病例接受辅助性化疗 RT治疗,结肠直肠癌: 2004 年美国发病率,Jemal et al Ca Cancer J clin 2004 54; 8-29,Surgery CT,初诊断结肠癌病理分级,Stage I: 15%,Stage IV: 2025%,Stage II: 2030%,Stage III: 3040%,Hamilton and Grem. Current Cancer Therapeutics (3rd ed.) 1998,Stage I or A,Stage III or C,Stage IV or D,病灶局限,手术 化疗,手术 + 化疗,化疗,手术,已转移,Stage I I or B,美国联合委员会结肠直肠癌病期分类,Macdonald JS. CA Cancer J Clin 1999; 49:202-219,手术加辅助治疗模型5年生存率评价,淋巴结 T 低度恶性 高度恶性 转移状况 stage S S + AT S S + AT 0 T 3 73 77 65 70 T 4 60 66 51 57 T 1-2 62 75 53 68 1 - 4 T 3 49 65 38 56 T 4 33 51 23 40 T 1-2 39 57 28 46 5 T 3 24 43 15 32 T 4 11 27 5 17,CRC预后,Stage II: 高危人群 T4 周围神经侵犯 血道转移 淋巴道转移 低分化肿瘤 大肠梗阻,5年 OS3040%,Van Cutsem E et al. Eur J Cancer 2002 Jul; 38(11): 1429-36,Stage III CRC TNM 校正分类 (n=50042),59.8%,42.0%,27.3%,0,10,20,30,40,50,60,70,III A,III B,III C,Node-positive subgroups,Observed 5-year survival (%),p 死亡率 15-35% Identity CRC families genetic screen Intensified screening 外科预防 钙、硒 预防息肉 COX-2 过表达的息肉状癌 COX-2 抑制剂试验 辅助:预防息肉 佐剂病: 以Celecoxib-C225 + CPT-11为基础 的化疗,大便潜血试验,Pignoneet et al, Ann Inlem Med 2002,137-141,肿瘤学,选择治疗方法和选择病人 联合细胞毒药物和定向生物制剂 攻击多靶点 限制细胞毒药物的使用 将定向生物制剂作为 maintence 治疗,结肠癌治疗进展,细胞毒药物化疗: 适量给药方案结合序贯疗法 新因子 Capecitabine （卡培他滨） 靶向药物: VEGF 抑制剂 Bevacizumab-Avastin PTK-787 EGF抑制剂 Cetuximab-C-225 Iressa COX-2抑制剂 Celecoxib 给药方法: 化疗 标记有效和抵抗 定向 效果评价: Metabolic assessment (PET),CRC: 当前最佳治疗方法,连续静脉注射 (CIV) 5- FU 优于大剂量疗法 一线治疗 FOLFOX or FOLFOX + Bevacizumab-Avastin FOLFIRI + Bevacizumab-Avastin 依立替康抵抗: 加Cetuximab-C225 Cetuximab-C225 as front-line therapy + FOLFIRI /FOLFOX - ACROBAT EMR(Europe) CALGB(US) Bevacizumab - Avastin + FOLFOX - ECOG 3200 TREE 2 SWOG/Roche 新药: Capecitabine CIV 5-FU ( BICC-C TREE 2 SWOG / Roche ) Edotecarin: Noncamptothecin topoisomerase - 1 inhibitor,高危的局灶性进展性结肠癌的辅助治疗,2002,Andre et al. Proc Amsco Clin Oncol 2002,5-FU/Levumisolesuperior toSurgery alone,5-FU/LVsuperior toSurgery alone,LV5FU2andMon thly bolusequivalent,5FU/LV superior 5FU/Lev 6-and-12(m) treatmentcycles equivalent Levumisole unnecessary High-dose and Low-doseLV equivalentMonthly and Weekly treatment,1990,1994,1998,结肠癌辅助治疗主要进展回顾,1990 - 1994 (5-FU+LV 或 levamisole化疗优于不治疗 1998 5-FU+LV 优于 5-FU+levamisole 1998 5-FU+LV化疗6月疗效等同12月 1998 Levamisole 化疗不必联合 LV 1998 大剂量 LV =小剂量 LV 1998 每周 = 每月 方案 2001 中老年 = “青年” 2002 持续静脉注射比大剂量安全 2003 FOLFOX 优于 5-FU+LV 2004 CT + Targeted agents - - - Andr T et al. N Engl J Med 2004; 350:2343-51,新一代结肠直肠癌治疗 : 延长生命和持续治疗,Will the efficacy in metastatic Colorectal cancer translate into cure in the Adjuvant Setting?,关于化疗的问题,什么是最有效的化疗方法? 一种生物制剂应该被加入吗? 如果是? 该加入哪一种? 治疗应该持续多久?,Phase III 试验: IFL 、 Mayo 、 CPT-11方案,Saltz. N Engl J Med 2000.,StratifiationPS ( 0 VS 1. 2. )Age ( 65 VS 65)Time form initialDiagnosis (6 m VS 6 m)Prior adjuvant therapy(yes/No),RANDOMIZATION,Standard USA Schedule N=226Irinotecan 125 mg/wk x 4wq 6 w Rep.,Mayo Clinic N=226(Standard Regimen) 5-FU 425 mg/ LV 20 mg/ q 4 w Rep.,IFL (Saltz) Regimen N=231 Irinotecan 125 5-FU/ LV 500/20 mg/wk X 4 wq 6 w Rep.,D X 5d,30,Phase III 试验: IFL 、 Mayo、 CPT-11结果,Patients(%),0,5,10,45,40,35,30,15,20,25,Comfiremed RR,39,21,18,P0.001,Saltz. N Engl J Med 2000,IFL,CPT-11,LF,Time (m),14.8,7,20,15,5,0,10,4.3,12.6,4.2,12,TTP,MST,P=0.004,P=0.04,Phase III 流程: FOLFOX4 VS LV5-FUSchema,Arm A,Arm B,Cycle: Q2W Rep.,De Gramont. J Clin Oncol 2000,D1,D1,D2,D2,0h,0h,2h,0h,0h,Eloxatin85mg/,LV200mg/,5FU infusion600mg/,LV200mg/,5FU infusion600mg/,LV200mg/,5FU infusion600mg/,LV200mg/,5FU infusion600mg/,5FU bolus400mg/,5FU bolus400mg/,5FU bolus400mg/,5FU bolus400mg/,2h,2h,2h,FOLFOX4,LV5FU2,Phase III Traial: FOLFOX4 VS LV5-FU2 Results,Patients(%),0,5,10,45,40,35,30,15,20,25,Comfiremed RR,Time (m),20,15,5,0,10,TTP,MST,50.7,9.0,16.2,22.3,6.2,14.7,De Gramont. J Clin Oncol 2000,FOLFOX4,LV5-FU2,N9741 试验: 研究记录,n=795 patients (stage IV)RR The imbalance of early deaths led to: Temporary closure of trial IFL dose reduction Recommendation for caution with Irinotecan bolus 5-FU and LV After enrolment of 795 patients 2nd cohort of patients with IFL dose reduction (To be presented at ASCO 04) 1. Sargent 2001. 2. Rothenberg et al. 2001. 3. Goldberg et al. JCD 2004.,RANDOMIZATIO N,IFLIrinotecan5-FU/LV,FOLFOXELOXATION5-FU/LV,IROXIrinotecanELOXATION,N 9741 Trial: Efficacy results,IROX IFL FOLFOX (n=264) (n=264) (n=267) P RR(%) 35 31 45 0.002 PFS(%) 6.5 6.5 8.7 0.0014 OS(%) 17.5 15.0 19.5 0.0001 “improvement in efficacy coupled with a favor- able toxicity profile suggests that FOLFOX should be considered a first-line standard of care for patients with advanced CRC more active and better tolerated than IFL or IROX ” Goldberg et al. JAC 2004,N 9741 Trial : Safety dataToxicity Grade 3,% “The adverse event profile for FOLFOX was favorable in comparison with either IFL or IROX. ELOXATION may cause sensory neuropathy an adverse effect that is cumulative but reversible and dosedepend . it occurs after eight to ten cycies.” Goldberg et al. JCO 2004.,0,10,20,30,15,4,28,6,16,6,14,3,3,18,FOLFOX,IFL,p 0.002 for all coparisons,F.neutropenia,Nausea,Vomiting,Paraesthesia,Diarrhoea,Phase III Multicenter GERCOR trial ofFOFIRI followed by FOLFOX6 or theReverse Sequence in Advanced CRC,R,Arm A,Arm B,FOLFIRI,FOLFIRI,FOLFOX6,FOLFOX6,UntilProgression,UntilProgression,UntilProgression,UntilProgression,Tournigand et al. J Clin Oncol. 2004 22: 229-237,FOLFIRI/FOLFOX6,FOLFOX6/FOLFIRI,GERCOR Phase III Trial: Treatment Schedule,(n=109),(n=111),Arm B,Arm A,Tournigend et al. J Clin Oncol. 2004, 22: 229-237,5-FU CIV 2400 to 3000 mg/,LV200 mg/,LV200 mg/,5-FU CIV 2400 to 3000 mg/,Irinotecan180 mg/,Eloxatin100 mg/,FOLFIRI/FOLFOX6,FOLFOX6/FOLFIRI,1 h 30,2 h,46 h,46 h,2 h,2 h,Bolus 5-FU 400 mg/,Bolus 5-FU 400 mg/,First-line,GERCOR Phase III Trial Efficacy Results,Arm BN=111,Arm AN=109,First-line,Second-line,Median PFS,PFS(m) 8.5 8.0,14.2,10.9,First-line,ORR(%),Second-line,15 4,56 54,ORR(%),Median OS(m),21.5 20.6,PFS(m),4.2 2.5,2-yeas SR(%) 41 45,This study suggests that both sequences have similar efficacy. But only based on 100 patientsarm.,Tournigand et al. JCO 2004,GERCOR Phase III Trial: Safety data,Grade (%) Arm A Arm B P value NO: of patients n = 110 n = 110 Neutropenia 25 44 0.05 F.neutropenia 6 1 n s Diarrhoea 14 11 n s Nausea 13 3 0.05 Stomatitis 10 1 0.05 Alopecia (G 2) 24 9 0.05 Neurotoxicity (G 3) 0 34 3 (%),40 24,50 44,DiarrheaG 3 (%),28 14,12 11,Goldberg et al. J Clin Oncol. 2004. 22: 23-30 To urnigand et al. J Clin Oncol. 2004. 22: 229-237,Eloxatin combinations as first-line therapy in advanced CRC,22.350.70.0001,16530.0001,14.716.2n.s.,6.29.00.0001,FU/LV inf.FOLFOX4 p-value,De Gramont.JCO 8/ 2000#420,19.919.4n.s.,6.18.70.048,FU/LV inf.FOLFOXP value,Giacchetti.JCO 1/ 2000#200,22.649.10.0001,16.119.7n.s.,5.37.80.0001,FU/ LV Bolus (Mayo)FUFOXP value,Grothey.ASCO 2002#252,RR(%),OS(m),PFS (m),Protocol,Author,Irinotecan combinations as first-line therapy in advanced CRC,Comparison of efficacy of 5-FU and LV with or without Eloxatin,Highly efficacious first-line treatment should improve the outcome of patients with earlier stage disease,*p 0.001 p 0.01,14.7,6.0,22,PFS (months),RR (%),8.2*,16.2,50.7*,5.2,23,7.8,19.7*,50,1.De Gramont A et al. J Clin Oncol 2000 18:2938-4 2.Goldberg RM et al. J Cli Oncol 2004 22:23-30,Goldberg 20042 (n=242) FOLFOX IFL,De Gramont 20001 (n=420) FOLFOX LV/5-FU2,OS (months),16.1,Towards the Optimal Use of 5FU/LV Eloxatin and Irinotecan in MCRC,“ We need all three active agents in CRC” ( Saltz ASCO 2003 ) “ Median overall Survival correlates with the % of patients who receive all 3 drugs in the course of their disease ” P = 0.0008 Courtesy of Jean-Yres Douillard MD. PhD. Grothey et al. J Clin Oncol 2004 22:1209-1214,Do the benefits of Eloxatinin advanced colon cancer translate to earlier disease?,高度有效的一线治疗应该提高早期病人的缓解率,MOSAIC trial,MOSAIC: 每个国家病例入选数,477 patients364 patients294 patients249 patients135 patients133 patients107 patients,2246 patients(20 CTY) Oct 98 - Jan 01,103 patients69 patients58 patients51 patients37 patients36 patients,27 patients26 patients22 patients21 patients17 patients17 patients3 patients,Cy,Au,UK,B,Andr T et al. N Engl J Med 2004; 350:2343-51,MOSAIC: 主要纳入标准,Stage II ( Dukes B2: T3 - T4 N0 M0 ) or Stage III ( Dukes C: any T N1 N2 M0 ) 原发性肿瘤完全切除 治疗7周内接着手术 未行化学免疫或放射治疗 年龄 1875 岁 ECOG PS 2 Andr T et al. N Engl J Med 2004; 350:2343-51,MOSAIC: 随机方案,分层 : 中心 原发肿瘤的浸润程度 ( T2 T3 or T4 ) 淋巴结转移的数量 ( N0 N1 N2 ) 肠梗阻或肿瘤穿破 Andr T et al. N Engl J Med 2004; 350:2343-51,MOSAIC Phase III 试验,主要: 无瘤生存率 (DFS) 次要:安全 (including long-term)总生存数 (OS),终点,Andre. T. N Engl J Med 2004 350:2343-51,CRC Stage II (40%) Stage III (60%),R,MOSAIC: treatment arms,D1,D2,0h,0h,2h,LV200mg/,5FU infusion600mg/,LV200mg/,5FU infusion600mg/,5FU bolus400mg/,5FU bolus400mg/,2h,LV5FU2,Andr T et al. N Engl J Med 2004; 350:2343-51,D1,D2,0h,0h,Eloxatin85mg/,LV200mg/,5FU infusion600mg/,LV200mg/,5FU infusion600mg/,5FU bolus400mg/,5FU bolus400mg/,2h,2h,FOLFOX4: LV5FU2 + Eloxatin,Every 2 weeks 12 cycles of treatment,Every 2 weeks 12 cycles of treatment,MOSAIC: 病人特征,Andr T et al. N Engl J Med 2004; 350:2343-51,Safety resultsGrade 3-4 Toxicities (per patient),NCI Gr 3 % FOLFOX4 LV5FU2 (n=1108) (n=1111) Thrombocytopenia 1.7 0.4Neutropenia 4