Xiaotian Zhang1, Han Liang2, Ziyu Li1, Yingwei Xue3, Yanong Wang4, Zhiwei Zhou5, Jiren Yu6, Zhaode Bu1, Lin Chen7, Yian Du8, Xinbao Wang8, Aiwen Wu1, Guoli Li9, Xiangqian Su1, Gang Xiao10, Ming Cui1, Dan Wu7, Li Chen11, Xiaojiang Wu1, Yanbing Zhou12, Lianhai Zhang1, Chengxue Dang13, Yulong He14, Zhongtao Zhang15, Yihong Sun16, Yong Li17, Huanqiu Chen18, Yuxian Bai19, Changsong Qi1, Peiwu Yu20, Guanbao Zhu21, Jian Suo22, Baoqing Jia11, Leping Li23, Changming Huang24, Fei Li25, Yingjiang Ye26, Huimian Xu27, Xin Wang28, Yannan Yuan1, Jian-Yu E29, Xiangji Ying1, Chen Yao30, Lin Shen31, Jiafu Ji32. 1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China. 2. Department of Gastric Surgery, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China. 3. Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin, China. 4. Department of Gastric Surgery, Fudan University Shanghai Cancer Centre, Shanghai, China. 5. Department of Gastric Surgery, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, China. 6. Department of Gastrointestinal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. 7. Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. 8. Department of Gastric Surgery and Department of Hepatopancreatobiliary Surgery, Zhejiang Cancer Hospital, Hangzhou, China. 9. Department of General surgery, Nanjing Jinling Hospital, Nanjing, China. 10. Department of General Surgery, Beijing Hospital, Beijing, China. 11. Department of General Surgery, Chinese PLA General Hospital, Beijing, China. 12. Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China. 13. Department of Oncology Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. 14. Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. 15. Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China. 16. Department of General Surgery, Zhongshan Hospital, Fudan University, Guangzhou, China. 17. Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China. 18. Department of General Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China. 19. Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, China. 20. Department of General Surgery, The First Hospital Affiliated to Army Medical University, Chongqing, China. 21. Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. 22. Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, China. 23. Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Jinan, China. 24. Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China. 25. Department of General Surgery, Xuanwu Hospital Capital Medical University, Beijing, China. 26. Department of General Surgery, Peking University People's Hospital, Beijing, China. 27. Department of Gastrointestinal Oncology Surgery, The First Hospital of China Medical University, Shenyang, China. 28. Department of General Surgery, Peking University First Hospital, Beijing, China. 29. Wilmer Eye Institute, Johns Hopkins University School of Medicine and Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. 30. Peking University Clinical Research Institute, Peking University First Hospital, Beijing, China. 31. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China. Electronic address: shenlin@bjmu.edu.cn. 32. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China. Electronic address: jijiafu@hsc.pku.edu.cn.
Abstract
BACKGROUND: The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy. METHODS: We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naivepatients aged 18 years or older with historically confirmed cT4aN+ M0 or cT4bNany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral capecitabine 1000 mg/m2 twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral S-1 40-60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m2 on day one of each 21 day plus oral S-1 40-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546. FINDINGS:Between Aug 15, 2012, and Feb 28, 2017, 1094patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5-56·3) in the adjuvant-CapOx group, 56·5% (51·0-61·7) in the adjuvant-SOX group, and 59·4% (53·8-64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61-0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68-1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3-4 adverse events was neutropenia (32 [12%] of 258 patients in the adjuvant-CapOx group, 21 [8%] of 249 patients in the adjuvant-SOX group, and 30 [10%] of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported. INTERPRETATION: Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer. FUNDING: National Key Research and Development Program of China, Beijing Scholars Program 2018-2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
RCT Entities:
BACKGROUND: The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy. METHODS: We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral capecitabine 1000 mg/m2 twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral S-1 40-60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m2 on day one of each 21 day plus oral S-1 40-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546. FINDINGS: Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5-56·3) in the adjuvant-CapOx group, 56·5% (51·0-61·7) in the adjuvant-SOX group, and 59·4% (53·8-64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61-0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68-1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3-4 adverse events was neutropenia (32 [12%] of 258 patients in the adjuvant-CapOx group, 21 [8%] of 249 patients in the adjuvant-SOX group, and 30 [10%] of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported. INTERPRETATION: Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer. FUNDING: National Key Research and Development Program of China, Beijing Scholars Program 2018-2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.