序贯与联合化疗治疗晚期结直肠癌（FFCD 2000-05）：一项开放标签、随机、3 期临床试验。
Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial.
机构信息
Institut Gustave Roussy, Paris, France.
出版信息
Lancet Oncol. 2011 Oct;12(11):1032-44. doi: 10.1016/S1470-2045(11)70199-1. Epub 2011 Sep 6.
BACKGROUND
The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined. Our aim was to investigate whether combination treatment is better than the sequential administration of the same drugs in patients with advanced colorectal cancer.
METHODS
In this open-label, randomised, phase 3 trial, we randomly assigned patients (1:1 ratio) with advanced, measurable, non-resectable colorectal cancer and WHO performance status 0-2 to receive either first-line treatment with bolus (400 mg/m(2)) and infusional (2400 mg/m(2)) fluorouracil plus leucovorin (400 mg/m(2)) (simplified LV5FU2 regimen), second-line LV5FU2 plus oxaliplatin (100 mg/m(2)) (FOLFOX6), and third-line LV5FU2 plus irinotecan (180 mg/m(2)) (FOLFIRI) or first-line FOLFOX6 and second-line FOLFIRI. Chemotherapy was administered every 2 weeks. Randomisation was done centrally using minimisation (minimisation factors were WHO performance status, previous adjuvant chemotherapy, number of disease sites, and centre). The primary endpoint was progression-free survival after two lines of treatment. Analyses were by intention-to-treat. This trial is registered at ClinicalTrials.gov, NCT00126256.
FINDINGS
205 patients were randomly assigned to the sequential group and 205 to the combination group. 161 (79%) patients in the sequential group and 161 (79%) in the combination group died during the study. Median progression-free survival after two lines was 10·5 months (95% CI 9·6-11·5) in the sequential group and 10·3 months (9·0-11·9) in the combination group (hazard ratio 0·95, 95% CI 0·77-1·16; p=0·61). All six deaths caused by toxic effects of treatment occurred in the combination group. During first-line chemotherapy, significantly fewer severe (grade 3-4) haematological adverse events (12 events in 203 patients in sequential group vs 83 events in 203 patients in combination group; p<0·0001) and non-haematological adverse events (26 events vs 186 events; p<0·0001) occurred in the sequential group than in the combination group.
INTERPRETATION
Upfront combination chemotherapy is more toxic and is not more effective than the sequential use of the same cytotoxic drugs in patients with advanced, non-resectable colorectal cancer.
FUNDING
Sanofi-Aventis France.
背景
对于晚期结直肠癌，细胞毒药物的最佳使用方法尚未确定。我们的目的是研究联合治疗是否优于晚期不可切除结直肠癌患者相同药物的序贯给药。
方法
在这项开放标签、随机、3 期临床试验中，我们将晚期、可测量、不可切除的结直肠癌和世界卫生组织体力状态 0-2 的患者按 1:1 的比例随机分配，接受一线治疗：推注（400 mg/m(2)）和输注（2400 mg/m(2)）氟尿嘧啶加亚叶酸（400 mg/m(2)）（简化 LV5FU2 方案），二线 LV5FU2 加奥沙利铂（100 mg/m(2)）（FOLFOX6），三线 LV5FU2 加伊立替康（180 mg/m(2)）（FOLFIRI），或一线 FOLFOX6 和二线 FOLFIRI。每 2 周给予化疗。中央采用最小化进行随机化（最小化因素为世界卫生组织体力状态、辅助化疗史、疾病部位数和中心）。主要终点是二线治疗后的无进展生存期。分析采用意向治疗。该试验在 ClinicalTrials.gov 注册，NCT00126256。
结果
205 例患者被随机分配至序贯组，205 例患者被随机分配至联合组。序贯组 161 例（79%）和联合组 161 例（79%）患者在研究期间死亡。序贯组二线后无进展生存期的中位数为 10.5 个月（95%CI 9.6-11.5），联合组为 10.3 个月（9.0-11.9）（风险比 0.95，95%CI 0.77-1.16；p=0.61）。所有 6 例因治疗毒性导致的死亡均发生在联合组。在一线化疗期间，序贯组严重（3-4 级）血液学不良事件（203 例患者中 12 例 vs 联合组 203 例患者中 83 例；p<0.0001）和非血液学不良事件（26 例 vs 186 例；p<0.0001）的发生率明显低于联合组。
解释
一线联合化疗比晚期不可切除结直肠癌患者相同细胞毒药物的序贯使用毒性更大，且效果并不更佳。
资金
赛诺菲-安万特法国公司。
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