Tatsuya Ioka1, Makoto Ueno2, Hideki Ueno3, Joon Oh Park4, Heung-Moon Chang5, Naoki Sasahira6, Masashi Kanai7, Ik Joo Chung8, Masafumi Ikeda9, Shoji Nakamori10, Nobumasa Mizuno11, Yasushi Omuro12, Taketo Yamaguchi13, Hiroki Hara14, Kazuya Sugimori15, Junji Furuse16, Hiroyuki Maguchi17, Masayuki Furukawa18, Kengo Fukuzawa19, Jun-Suk Kim20, Seigo Yukisawa21, Masahiro Takeuchi22, Takuji Okusaka3, Narikazu Boku23, Ichinosuke Hyodo24. 1. Department of Cancer Survey and Gastrointestinal Oncology, Osaka International Cancer Institute, Osaka, Japan. 2. Department of Gastroenterology, Hepatobiliary and Pancreatic Medical Oncology Division, Kanagawa Cancer Center, Yokohama, Japan. 3. Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. 4. Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 5. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 6. Department of Gastroenterology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan. 7. Department of Clinical Oncology, Kyoto University Hospital, Kyoto, Japan. 8. Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, South Korea. 9. Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan. 10. Department of Hepatobiliary and Pancreatic Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan. 11. Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan. 12. Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan. 13. Department of Gastroenterology, Chiba Cancer Center, Chiba, Japan. 14. Department of Gastroenterology, Saitama Cancer Center Hospital, Saitama, Japan. 15. Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan. 16. Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan. 17. Center of Gastroenterology, Teine-Keijinkai Hospital, Sapporo, Japan. 18. Department of Hepato-Biliary-Pancreatology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan. 19. Department of Surgery, Oita Red Cross Hospital, Oita, Japan. 20. Department of Oncology and Hematology, Korea University Guro Hospital, Seoul, South Korea. 21. Department of Medical Oncology, Tochigi Cancer Center, Utsunomiya, Japan. 22. Department of Clinical Medicine, School of Pharmacy (Biostatistics), Kitasato University, Tokyo, Japan. 23. Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan. 24. Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. Electronic address: ihyodo@md.tsukuba.ac.jp.
Abstract
BACKGROUND: In our previous randomised phase 2 study for patients with gemcitabine-refractory advanced pancreatic cancer, S-1 plus leucovorin improved progression-free survival compared with S-1 alone. Here, we evaluated the efficacy of TAS-118 (S-1 plus leucovorin) versus S-1 in overall survival (OS). PATIENTS AND METHODS: This randomised, open-label, phase 3 study was conducted at 58 centres in Japan and Korea. Patients with metastatic pancreatic cancer that progressed during first-line gemcitabine-based chemotherapy or recurred during or after post-operative gemcitabine-based adjuvant treatment were randomly assigned (1:1) to receive either S-1 (40-60 mg, twice daily for 4 weeks in a 6-week cycle) or TAS-118 (S-1 40-60 mg plus leucovorin 25 mg, twice daily for 1 week in a 2-week cycle). The primary end-point was OS. RESULTS: A total of 603 patients were randomised, and 300 and 301 patients receivedTAS-118 and S-1, respectively. There was no difference in OS between groups (median OS for TAS-118 versus S-1, 7.6 months versus 7.9 months; hazard ratio [HR], 0.98 [95% confidence interval (CI), 0.82-1.16]; P = 0.756). Progression-free survival was significantly longer with TAS-118 than S-1 (median, 3.9 months versus 2.8 months; HR, 0.80 [95% CI, 0.67-0.95]; P = 0.009). There were interactions between Japan and Korea (P = 0.004) and between unresectable and recurrent disease (P = 0.025) in OS. Incidence, profile and severity of adverse events were similar between groups. CONCLUSION:TAS-118 did not improve OS in patients with gemcitabine-refractory advanced pancreatic cancer compared to S-1. Further studies are needed to find patients who have benefit from adding leucovorin to S-1.
RCT Entities:
BACKGROUND: In our previous randomised phase 2 study for patients with gemcitabine-refractory advanced pancreatic cancer, S-1 plus leucovorin improved progression-free survival compared with S-1 alone. Here, we evaluated the efficacy of TAS-118 (S-1 plus leucovorin) versus S-1 in overall survival (OS). PATIENTS AND METHODS: This randomised, open-label, phase 3 study was conducted at 58 centres in Japan and Korea. Patients with metastatic pancreatic cancer that progressed during first-line gemcitabine-based chemotherapy or recurred during or after post-operative gemcitabine-based adjuvant treatment were randomly assigned (1:1) to receive either S-1 (40-60 mg, twice daily for 4 weeks in a 6-week cycle) or TAS-118 (S-1 40-60 mg plus leucovorin 25 mg, twice daily for 1 week in a 2-week cycle). The primary end-point was OS. RESULTS: A total of 603 patients were randomised, and 300 and 301 patients received TAS-118 and S-1, respectively. There was no difference in OS between groups (median OS for TAS-118 versus S-1, 7.6 months versus 7.9 months; hazard ratio [HR], 0.98 [95% confidence interval (CI), 0.82-1.16]; P = 0.756). Progression-free survival was significantly longer with TAS-118 than S-1 (median, 3.9 months versus 2.8 months; HR, 0.80 [95% CI, 0.67-0.95]; P = 0.009). There were interactions between Japan and Korea (P = 0.004) and between unresectable and recurrent disease (P = 0.025) in OS. Incidence, profile and severity of adverse events were similar between groups. CONCLUSION:TAS-118 did not improve OS in patients with gemcitabine-refractory advanced pancreatic cancer compared to S-1. Further studies are needed to find patients who have benefit from adding leucovorin to S-1.