- 作者：Yasuhide Yamada ; Daisuke Takahari ; Hiroshi Matsumoto ; Hideo Baba ; Masato Nakamura ; Kazuhiro Yoshida ; Motoki Yoshida ; Shigeyoshi Iwamoto ; Ken Shimada ; Yoshito Komatsu ; Yasutsuna Sasaki ; Taroh Satoh ; Keiichi Takahashi ; Hideyuki Mishima ; Kei Muro ; Masahiko Watanabe ; Yuh Sakata ; Satoshi Morita ; Yasuhiro Shimada ; Kenichi Sugihara ; et al.
- 刊名：Lancet Oncology
- 出版年：December, 2013
- 年：2013
- 卷：14
- 期：13
- 页码：1278-1286
- 全文大小：438 K
Summary
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/m2 oxaliplatin, 200 mg/m2 l-leucovorin, 400 mg/m2 bolus fluorouracil, and 2400 mg/m2 infusional fluorouracil) or SOX plus bevacizumab (on day 1 of each 3-week cycle, 7路5 mg/kg intravenous infusion of bevacizumab and 130 mg/m2 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 (鈮?0% 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路5 months (95% CI 10路7-13路2) in the group assigned to mFOLFOX6 plus bevacizumab and 11路7 months (10路7-12路9) in the group assigned to SOX plus bevacizumab (HR 1路04, 95% CI 0路86-1路27; less than non-inferiority margin of 1路33, pnon-inferiority=0路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路0029) and neutropenia (84 [34%] vs 22 [9%]; p<0路0001). Grade 3 or higher anorexia (13 [5%] vs three [1%]; p=0路019) and diarrhoea (23 [9%] vs seven [3%]; p=0路0040) were significantly more common in patients given SOX plus bevacizumab than in those given mFOLFOX6 plus bevacizumab. We recorded seven treatment-related deaths (three in the group given mFOLFOX6 plus bevacizumab; four in that given SOX plus bevacizumab).
Interpretation
SOX plus bevacizumab is non-inferior to mFOLFOX6 plus bevacizumab with respect to PFS as first-line treatment for metastatic colorectal cancer, and could become standard treatment in Asian populations.
Funding
Taiho.