Han Kwang Yang1, Jiafu Ji2, Sang Uk Han3, Masanori Terashima4, Guoxin Li5, Hyung Ho Kim6, Simon Law7, Asim Shabbir8, Kyo Young Song9, Woo Jin Hyung10, Nik Ritza Kosai11, Koji Kono12, Kazunari Misawa13, Hiroshi Yabusaki14, Takahiro Kinoshita15, Peng Choong Lau16, Young Woo Kim17, Jaideep Raj Rao18, Enders Ng19, Takanobu Yamada20, Kazuhiro Yoshida21, Do Joong Park1, Bee Choo Tai22, Jimmy Bok Yan So23. 1. Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea. 2. Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China. 3. Department of Surgery, Ajou University School of Medicine, Suwon, South Korea. 4. Department of Gastric Surgery, Shizuoka Cancer Centre, Shizuoka, Japan. 5. Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China. 6. Department of Surgery, Seoul National Bundang Hospital, Seongnam, South Korea. 7. Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region of China. 8. Department of Surgery, National University Hospital, Singapore. 9. Department of Surgery, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea. 10. Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea. 11. Department of Surgery, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia. 12. Department of Gastrointestinal Tract Surgery, Fukushima Medical University, Fukushima, Japan. 13. Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Japan. 14. Department of Surgery, Niigata Cancer Center Hospital, Niigata, Japan. 15. Gastric Surgery Division, National Cancer Center Hospital East, Chiba, Japan. 16. Department of Surgery, University Malaya Medical Centre, Kuala Lumpur Malaysia. 17. Department of Surgery, National Cancer Centre, Seoul, South Korea. 18. Department of General Surgery, Tan Tock Seng Hospital, Singapore. 19. Department of Surgery, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China. 20. Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan. 21. Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu, Japan. 22. Saw Swee Hock School of Public Health, National University of Singapore, Singapore. 23. Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address: jimmyso@nus.edu.sg.
Abstract
BACKGROUND: Peritoneal recurrence of gastric cancer after curative surgical resection is common and portends a poor prognosis. Early studies suggest that extensive intraoperative peritoneal lavage (EIPL) might reduce the risk of peritoneal recurrence and improve survival. We aimed to evaluate the survival benefit of EIPL in patients with gastric cancer undergoing curative gastrectomy. METHODS: In this open-label, phase 3, multicentre randomised trial, patients aged 21-80 years with cT3 or cT4 gastric cancer undergoing curative resection were enrolled at 22 centres from South Korea, China, Japan, Malaysia, Hong Kong, and Singapore. Patients were randomly assigned to receive surgery and EIPL (EIPL group) or surgery alone (standard surgery group) via a web-based programme in random permuted blocks in varying block sizes of four and six, assuming equal allocation between treatment groups. Randomisation was stratified according to study site and the sequence was generated using a computer program and concealed until the interventions were assigned. After surgery in the EIPL group, peritoneal lavage was done with 1 L of warm (42°C) normal 0·9% saline followed by complete aspiration; this procedure was repeated ten times. The primary endpoint was overall survival. All analyses were done assuming intention to treat. This trial is registered with ClinicalTrials.gov, NCT02140034. FINDINGS:Between Sept 16, 2012, and Aug 3, 2018, 800 patients were randomly assigned to the EIPL group (n=398) or the standard surgery group (n=402). Two patients in the EIPL group and one in the standard surgery group withdrew from the trial immediately after randomisation and were excluded from the intention-to-treat analysis. At the third interim analysis on Aug 28, 2019, the predictive probability of overall survival being significantly higher in the EIPL group was less than 0·5%; therefore, the trial was terminated on the basis of futility. With a median follow-up of 2·4 years (IQR 1·5-3·0), the two groups were similar in terms of overall survival (hazard ratio 1·09 [95% CI 0·78-1·52; p=0·62). 3-year overall survival was 77·0% (95% CI 71·4-81·6) for the EIPL group and 76·7% (71·0-81·5) for the standard surgery group. 60 adverse events were reported in the EIPL group and 41 were reported in the standard surgery group. The most common adverse events included anastomotic leak (ten [3%] of 346 patients in the EIPL group vs six [2%] of 362 patients in the standard surgery group), bleeding (six [2%] vs six [2%]), intra-abdominal abscess (four [1%] vs five [1%]), superficial wound infection (seven [2%] vs one [<1%]), and abnormal liver function (six [2%] vs one [<1%]). Ten of the reported adverse events (eight in the EIPL group and two in the standard surgery group) resulted in death. INTERPRETATION:EIPL and surgery did not have a survival benefit compared with surgery alone and is not recommended for patients undergoing curative gastrectomy for gastric cancer. FUNDING: National Medical Research Council, Singapore.
RCT Entities:
BACKGROUND: Peritoneal recurrence of gastric cancer after curative surgical resection is common and portends a poor prognosis. Early studies suggest that extensive intraoperative peritoneal lavage (EIPL) might reduce the risk of peritoneal recurrence and improve survival. We aimed to evaluate the survival benefit of EIPL in patients with gastric cancer undergoing curative gastrectomy. METHODS: In this open-label, phase 3, multicentre randomised trial, patients aged 21-80 years with cT3 or cT4 gastric cancer undergoing curative resection were enrolled at 22 centres from South Korea, China, Japan, Malaysia, Hong Kong, and Singapore. Patients were randomly assigned to receive surgery and EIPL (EIPL group) or surgery alone (standard surgery group) via a web-based programme in random permuted blocks in varying block sizes of four and six, assuming equal allocation between treatment groups. Randomisation was stratified according to study site and the sequence was generated using a computer program and concealed until the interventions were assigned. After surgery in the EIPL group, peritoneal lavage was done with 1 L of warm (42°C) normal 0·9% saline followed by complete aspiration; this procedure was repeated ten times. The primary endpoint was overall survival. All analyses were done assuming intention to treat. This trial is registered with ClinicalTrials.gov, NCT02140034. FINDINGS: Between Sept 16, 2012, and Aug 3, 2018, 800 patients were randomly assigned to the EIPL group (n=398) or the standard surgery group (n=402). Two patients in the EIPL group and one in the standard surgery group withdrew from the trial immediately after randomisation and were excluded from the intention-to-treat analysis. At the third interim analysis on Aug 28, 2019, the predictive probability of overall survival being significantly higher in the EIPL group was less than 0·5%; therefore, the trial was terminated on the basis of futility. With a median follow-up of 2·4 years (IQR 1·5-3·0), the two groups were similar in terms of overall survival (hazard ratio 1·09 [95% CI 0·78-1·52; p=0·62). 3-year overall survival was 77·0% (95% CI 71·4-81·6) for the EIPL group and 76·7% (71·0-81·5) for the standard surgery group. 60 adverse events were reported in the EIPL group and 41 were reported in the standard surgery group. The most common adverse events included anastomotic leak (ten [3%] of 346 patients in the EIPL group vs six [2%] of 362 patients in the standard surgery group), bleeding (six [2%] vs six [2%]), intra-abdominal abscess (four [1%] vs five [1%]), superficial wound infection (seven [2%] vs one [<1%]), and abnormal liver function (six [2%] vs one [<1%]). Ten of the reported adverse events (eight in the EIPL group and two in the standard surgery group) resulted in death. INTERPRETATION: EIPL and surgery did not have a survival benefit compared with surgery alone and is not recommended for patients undergoing curative gastrectomy for gastric cancer. FUNDING: National Medical Research Council, Singapore.
Authors: Beate Rau; Linda Feldbrügge; Felix Gronau; Miguel Enrique Alberto Vilchez; Peter Thuss-Patience; Pierre Emmanuel Bonnot; Olivier Glehen Journal: Visc Med Date: 2022-02-23