Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial
Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial
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DOI：
10.1016/s1470-2045(13)70490-x
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发表时间：
2013-12-01
期刊：
影响因子：
51.1
通讯作者：
Sugihara, Kenichi
中科院分区：
文献类型：
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作者：
Yamada, Yasuhide;Takahari, Daisuke;Sugihara, Kenichi
背景在亚洲进行的研究表明，S-1加奥沙利铂（SOX）方案在转移性结直肠癌患者中具有良好的疗效和安全性。我们的目的是建立SOX加贝伐单抗是否非劣效于mFOLFOX 6（改良方案的甲酰四氢叶酸，氟尿嘧啶，奥沙利铂）加贝伐单抗作为一线化疗转移性结直肠cancer.Methods我们进行了一项开放标签，非劣效性，随机3期临床试验在日本的82个网站。我们招募了年龄在20-80岁之间的转移性结直肠癌患者，东部肿瘤协作组体能状态为0或1，有可评估的病变，既往未接受过化疗或放疗，可以口服药物，并且有足够的器官功能。合格患者被随机分配（1：1）接受mFOLFOX 6+贝伐珠单抗治疗（在每个2周周期的第1天，5 mg/kg贝伐珠单抗静脉输注，同时静脉输注85 mg/m2奥沙利铂、200 mg/m2左旋四氢叶酸、400 mg/m2推注氟尿嘧啶和2400 mg/m2输注氟尿嘧啶）或SOX加贝伐珠单抗（每3周周期第1天，贝伐单抗7.5 mg/kg静脉输注，奥沙利铂130 mg/m2静脉输注;从第1天晚餐后至第15天早餐后，每天两次给予指定剂量的S-1，随后停药7天）。采用最小化方法集中进行随机化，并按机构和是否给予术后辅助化疗进行分层。参与者、研究者和数据分析员不对治疗分配设盲。主要终点是无进展生存期（PFS），定义为入组与疾病进展（靶病灶最长尺寸总和较基线增加>= 20%，或出现新病灶）或死亡（以先发生者为准）之间的间隔。主要分析采用改良意向治疗法。该试验在日本药物信息中心注册，编号为JapicCTI-090699。结果2009年2月1日至2011年3月31日，512例患者接受随机分组。256例分配接受SOX+贝伐珠单抗治疗的患者和255例分配接受mFOLFOX 6+贝伐珠单抗治疗的患者被纳入主要分析。mFOLFOX 6+贝伐珠单抗组的中位PFS为11.5个月（95% CI 10.7-13.2），SOX+贝伐珠单抗组为11.7个月（10.7-12.9）（HR 1.04，95% CI 0.86-1.27;小于非劣效性界值1.33，p（非劣效性）= 0.014）。最常见的3级或3级以上血液学不良事件为白细胞减少症（安全性分析中249例接受mFOLFOX 6+贝伐珠单抗治疗的患者中21例[8%]，250例接受SOX+贝伐珠单抗治疗的患者中6例[2%]; p=0.0029）和中性粒细胞减少症（84例[34%] vs 22例[9%]; p
Background Studies done in Asia have shown that a regimen of S-1 plus oxaliplatin (SOX) has promising efficacy and safety in patients with metastatic colorectal cancer. We aimed to establish whether SOX plus bevacizumab is non-inferior to mFOLFOX6 (modified regimen of leucovorin, fluorouracil, and oxaliplatin) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer.Methods We undertook an open-label, non-inferiority, randomised phase 3 trial in 82 sites in Japan. We enrolled individuals aged 20-80 years who had metastatic colorectal cancer, had an Eastern Cooperative Oncology Group performance status of 0 or 1, had assessable lesions, had received no previous chemotherapy or radiotherapy, could take drugs orally, and had adequate organ function. Eligible patients were randomly assigned (1:1) to receive either mFOLFOX6 plus bevacizumab (on day 1 of each 2-week cycle, 5 mg/kg intravenous infusion of bevacizumab and a simultaneous intravenous infusion of 85 mg/m(2) oxaliplatin, 200 mg/m(2) l-leucovorin, 400 mg/m(2) bolus fluorouracil, and 2400 mg/m(2) infusional fluorouracil) or SOX plus bevacizumab (on day 1 of each 3-week cycle, 7.5 mg/kg intravenous infusion of bevacizumab and 130 mg/m(2) intravenous infusion of oxaliplatin; assigned dose of S-1 twice a day from after dinner on day 1 to after breakfast on day 15, followed by 7-day break). Randomisation was done centrally with the minimisation method, with stratification by institution and whether postoperative adjuvant chemotherapy had been given. Participants, investigators, and data analysts were not masked to treatment assignment. The primary endpoint was progression-free survival (PFS), which was defined as the interval between enrolment and progressive disease (>= 20% increase in sum of longest dimensions of target lesions from baseline, or appearance of new lesions) or death, whichever came first. The primary analysis was done by modified intention to treat. This trial is registered with the Japan Pharmaceutical Information Center, number JapicCTI-090699.Findings Between Feb 1, 2009, and March 31, 2011, 512 patients underwent randomisation. 256 patients assigned to receive SOX plus bevacizumab and 255 assigned to receive mFOLFOX6 plus bevacizumab were included in the primary analysis. Median PFS was 11.5 months (95% CI 10.7-13.2) in the group assigned to mFOLFOX6 plus bevacizumab and 11.7 months (10.7-12.9) in the group assigned to SOX plus bevacizumab (HR 1.04, 95% CI 0.86-1.27; less than non-inferiority margin of 1.33, p(non-inferiority) = 0.014). The most common haematological adverse events of grade 3 or higher were leucopenia (21 [8%] of 249 patients given mFOLFOX6 plus bevacizumab included in safety analysis vs six [2%] of 250 given SOX plus bevacizumab; p=0.0029) and neutropenia (84 [34%] vs 22 [9%]; p