Takaki Yoshikawa1, Masanori Terashima2, Junki Mizusawa3, Souya Nunobe4, Yasunori Nishida5, Takanobu Yamada6, Masahide Kaji7, Norimasa Fukushima8, Shinji Hato9, Yasuhiro Choda10, Hiroshi Yabusaki11, Kazuhiro Yoshida12, Seiji Ito13, Atsushi Takeno14, Takashi Yasuda15, Yasuyuki Kawachi16, Hiroshi Katayama3, Haruhiko Fukuda3, Narikazu Boku17, Takeshi Sano4, Mitsuru Sasako18. 1. Department of Gastric Surgery, National Cancer Center Hospital, Chuo-Ku, Tokyo, Japan. Electronic address: tayoshik@ncc.go.jp. 2. Division of Gastric Surgery, Shizuoka Cancer Center, Nagaizumi-cho, Sunto-gun, Shizuoka Prefecture, Japan. 3. JCOG Data Center/Operations Office, National Cancer Center Hospital, Chuo-Ku, Tokyo, Japan. 4. Gastroenterological Surgery, Cancer Institute Ariake Hospital, Koto-Ku, Tokyo, Japan. 5. Department of Surgery, Keiyukai Sapporo Hospital, Siroishi-Ku, Sapporo, Japan. 6. Department of Gastrointestinal Surgery, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-Ku, Japan. 7. Department of Surgery, Toyama Prefectural Central Hospital, Toyama, Japan. 8. Department of Surgery, Yamagata Prefectural Central Hospital, Yamagata, Japan. 9. Department of Surgery, National Hospital Organization, Shikoku Cancer Center, Minami-umemotocho, Matsuyama Japan. 10. Department of Surgery, Hiroshima City Hiroshima Citizens Hospital, Naka-Ku, Hiroshima, Japan. 11. Department of Digestive Surgery, Niigata Cancer Center Hospital, Kawagishimachi, Chuo-Ku, Niigata, Japan. 12. Department of Surgical Oncology, Gifu University, Graduate School of Medicine, Gifu City, Japan. 13. Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Chikusa-ku, Nagoya. 14. Department of Surgery, Kansai Rosai Hospital, Amagasaki, Japan. 15. Department of Gastroenterological Surgery, Hyogo Cancer Center, Akashi, Japan. 16. Department of Surgery, Nagaoka Chuo General Hospital, Nagaoka, Japan. 17. Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Chuo-Ku, Tokyo, Japan. 18. Department of Multidisciplinary Surgical Oncology, Hyogo College of Medicine, Nishinomiya, Japan.
Abstract
BACKGROUND: Postoperative adjuvant chemotherapy with S-1 for 1 year (corresponding to eight courses) is standard care for stage II gastric cancer. Whether the duration of S-1 could be shortened to 6 months (corresponding to four courses) without worsening survival is unclear. The aim of this study was to investigate the non-inferiority of four courses of S-1 compared with eight courses of S-1 for patients with stage II gastric cancer. METHODS: We did a phase 3, open-label, randomised controlled, non-inferiority trial at 59 hospitals in Japan. Patients aged 20-80 years with stage II adenocarcinoma of the stomach were randomly assigned (1:1) to eight courses or four courses of S-1. Randomisation was done by the Japan Clinical Oncology Group Data Center website, using a minimisation method with a random component using institution, stage (IIA vs IIB), age (<70 years vs ≥70 years), and mode of operation (open gastrectomy with bursectomy vs open gastrectomy without bursectomy vs laparoscopic gastrectomy) as adjustment factors. One course was 80 mg/day per m2 of S-1 administered for 4 weeks followed by a rest for 2 weeks. The primary endpoint was relapse-free survival, analysed by intention to treat, with a non-inferiority margin for the hazard ratio (HR) set at 1·37. This study is registered at UMIN-Clinical Trial Registry, number UMIN000007306. FINDINGS:Between Feb 16, 2012, and March 19, 2017, 590 patients were enrolled (295 per group). 528 (89%) patients were analysed at the first planned interim analysis in March, 2017, at which time the point estimate of HR for the four-course group compared with the eight-course group was 2·52 (95% CI 1·11-5·77), which exceeded 1·37 and met the prespecified criteria for early termination. Predictive probability for showing non-inferiority at the final analysis was calculated to be 2·9%. The study was stopped for futility. Updated 3-year relapse-free survival analysed in May, 2017, was 93·1% (95% CI 87·8-96·1) for the eight-course group and 89·8% (84·2-93·5) for the four-course group (HR 1·84, 95% CI 0·93-3·63). The most common grade 3-4 adverse event was neutropenia, observed in 46 (16%) patients in the eight-course group and 51 (17%) patients in the four-course group. INTERPRETATION:S-1 for 1 year should remain as standard adjuvant chemotherapy for stage II gastric cancer. FUNDING: Japan Agency for Medical Research and Development; the Ministry of Health, Labour and Welfare of Japan; the National Cancer Center Research and Development Fund, Japan.
RCT Entities:
BACKGROUND: Postoperative adjuvant chemotherapy with S-1 for 1 year (corresponding to eight courses) is standard care for stage II gastric cancer. Whether the duration of S-1 could be shortened to 6 months (corresponding to four courses) without worsening survival is unclear. The aim of this study was to investigate the non-inferiority of four courses of S-1 compared with eight courses of S-1 for patients with stage II gastric cancer. METHODS: We did a phase 3, open-label, randomised controlled, non-inferiority trial at 59 hospitals in Japan. Patients aged 20-80 years with stage II adenocarcinoma of the stomach were randomly assigned (1:1) to eight courses or four courses of S-1. Randomisation was done by the Japan Clinical Oncology Group Data Center website, using a minimisation method with a random component using institution, stage (IIA vs IIB), age (<70 years vs ≥70 years), and mode of operation (open gastrectomy with bursectomy vs open gastrectomy without bursectomy vs laparoscopic gastrectomy) as adjustment factors. One course was 80 mg/day per m2 of S-1 administered for 4 weeks followed by a rest for 2 weeks. The primary endpoint was relapse-free survival, analysed by intention to treat, with a non-inferiority margin for the hazard ratio (HR) set at 1·37. This study is registered at UMIN-Clinical Trial Registry, number UMIN000007306. FINDINGS: Between Feb 16, 2012, and March 19, 2017, 590 patients were enrolled (295 per group). 528 (89%) patients were analysed at the first planned interim analysis in March, 2017, at which time the point estimate of HR for the four-course group compared with the eight-course group was 2·52 (95% CI 1·11-5·77), which exceeded 1·37 and met the prespecified criteria for early termination. Predictive probability for showing non-inferiority at the final analysis was calculated to be 2·9%. The study was stopped for futility. Updated 3-year relapse-free survival analysed in May, 2017, was 93·1% (95% CI 87·8-96·1) for the eight-course group and 89·8% (84·2-93·5) for the four-course group (HR 1·84, 95% CI 0·93-3·63). The most common grade 3-4 adverse event was neutropenia, observed in 46 (16%) patients in the eight-course group and 51 (17%) patients in the four-course group. INTERPRETATION:S-1 for 1 year should remain as standard adjuvant chemotherapy for stage II gastric cancer. FUNDING: Japan Agency for Medical Research and Development; the Ministry of Health, Labour and Welfare of Japan; the National Cancer Center Research and Development Fund, Japan.
Authors: Tom van den Ende; Frank A Abe Nijenhuis; Héctor G van den Boorn; Emil Ter Veer; Maarten C C M Hulshof; Suzanne S Gisbertz; Martijn G H van Oijen; Hanneke W M van Laarhoven Journal: Front Oncol Date: 2019-07-25 Impact factor: 6.244