K Yamazaki1, M Nagase2, H Tamagawa3, S Ueda4, T Tamura5, K Murata6, T Eguchi Nakajima7, E Baba8, M Tsuda9, T Moriwaki10, T Esaki11, Y Tsuji12, K Muro13, K Taira14, T Denda15, S Funai16, K Shinozaki17, H Yamashita18, N Sugimoto19, T Okuno20, T Nishina21, M Umeki22, T Kurimoto23, T Takayama24, A Tsuji25, M Yoshida26, A Hosokawa27, Y Shibata28, K Suyama29, M Okabe30, K Suzuki31, N Seki32, K Kawakami33, M Sato34, K Fujikawa35, T Hirashima36, T Shimura37, K Taku38, T Otsuji39, F Tamura40, E Shinozaki41, K Nakashima42, H Hara43, T Tsushima44, M Ando45, S Morita46, N Boku7, I Hyodo10. 1. Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka k.yamazaki@scchr.jp. 2. Department of Clinical Oncology, Jichi Medical University, Shimotsuke. 3. Department of Surgery, Osaka General Medical Center, Osaka. 4. Department of Medical Oncology, Kinki University Faculty of Medicine, Higashiosaka. 5. Department of Medical Oncology, Nara Hospital Kinki University Faculty of Medicine, Ikoma. 6. Department of Surgery, Suita Municipal Hospital, Suita. 7. Department of Clinical Oncology, St Marianna University School of Medicine, Kawasaki. 8. Department of Comprehensive Clinical Oncology, Kyushu University Faculty of Medical Sciences, Fukuoka. 9. Department of Gastroenterological Oncology, Hyogo Cancer Center, Akashi. 10. Division of Gastroenterology, University of Tsukuba, Tsukuba. 11. Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka. 12. Department of Medical Oncology, Tonan Hospital, Sapporo. 13. Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya. 14. Clinical Oncology, Osaka City General Hospital, Osaka. 15. Division of Gastroenterology, Chiba Cancer Center, Chiba. 16. Department of Surgery, Sakai Hospital Kinki University Faculty of Medicine, Sakai. 17. Division of Clinical Oncology, Hiroshima Prefectural Hospital, Hiroshima. 18. Department of Gastroenterology and Hepatology, Okayama Medical Center, Okayama. 19. Department of Clinical Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka. 20. Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe. 21. Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matuyama. 22. Department of Surgery, Hyogo Prefectural Awaji Medical Center, Sumoto. 23. Department of Gastrointestinal Oncology, Nagoya Kyoritsu Hospital, Nagoya. 24. Department of Gastroenterology and Oncology, Tokushima University Graduate School, Tokushima. 25. Department of Medical Oncology, Kochi Health Sciences Center, Kochi. 26. Division of Cancer Chemotherapy Center, Osaka Medical College Hospital, Takatsuki. 27. Department of Gastroenterology and Hematology, Faculty of Medicine, University of Toyama, Toyama. 28. Department of Chemotherapy, Miyazaki Prefectural Miyazaki Hospital, Miyazaki. 29. Department of Medical Oncology, Toranomon Hospital, Tokyo. 30. Department of Surgery, Kurashiki Central Hospital, Kurashiki. 31. Department of gastroenterology, Kushiro City General Hospital, Kushiro. 32. Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo. 33. Department of Gastroenterology, Muroran City General Hospital, Muroran. 34. Department of Gastroenterology and Hepatology, Ryuugasaki Saiseikai Hospital, Ryugasaki. 35. Department of Gastroenterology, Hokkaido Cancer Center, Sapporo. 36. Department of Thoracic Malignancy, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino. 37. Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya. 38. Division of Medical Oncology, Shizuoka General Hospital, Shizuoka. 39. Department of Gastroenterology, Dongo Hospital, Yamatotakada. 40. Department of Gastroenterology, Kumamoto Regional Medical Center, Kumamoto. 41. Department of Gastroenterology, Cancer Institute Hospital of JFCR, Tokyo. 42. First Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki. 43. Department of Gastroenterology, Saitama Cancer Center, Saitama. 44. Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka. 45. Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya. 46. Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Abstract
BACKGROUND:FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS: WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS: Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION:FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER: UMIN000001396.
RCT Entities:
BACKGROUND:FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS: WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS: Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION:FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER: UMIN000001396.