Shun Ishiyama1, Takeshi Yamada2, Masato Nakamura3, Masanobu Enomoto4, Kiichi Sugimoto1, Hajime Yokomizo5, Chihiro Kosugi6, Ryo Ohta7, Kei Ishimaru8, Hiromichi Sonoda7, Keiichiro Ishibashi9, Hidekazu Kuramochi10, Yoichiro Yoshida11, Daisuke Ichikawa12, Keiji Hirata13, Hiroshi Yoshida7, Yojiro Hashiguchi14, Hideyuki Ishida9, Keiji Koda6, Kenji Katsumata4, Kazuhiro Sakamoto1. 1. Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan. 2. Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan. y-tak@nms.ac.jp. 3. Aizawa Comprehensive Cancer Center, Aizawa Hospital, Nagano, Japan. 4. Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan. 5. Department of Surgery, Tokyo Women's Medical University, Medical Center East, Tokyo, Japan. 6. Department of Surgery, Teikyo University Chiba Medical Center, Chiba, Japan. 7. Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan. 8. Department of Minimally Invasive Gastroenterology, Ehime University Graduate School of Medicine, Ehime, Japan. 9. Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan. 10. Department of Chemotherapy, Tokyo Women's Medical University, Yachiyo Medical Center, Chiba, Japan. 11. Department of Gastroenterological Surgery, Fukuoka University Faculty of Medicine, Fukuoka, Japan. 12. First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan. 13. Department of Surgery 1, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. 14. Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan.
Abstract
BACKGROUND: Regorafenib significantly improves overall survival in previously treated metastatic colorectal cancer patients. However, various toxicities, such as hand-foot skin reaction (HFSR), fatigue, and liver dysfunction have limited the use of regorafenib. These toxicities appear soon after treatment initiation. The ReDOS study demonstrated the effectiveness of a weekly dose-escalation therapy of regorafenib starting with a lower daily dose; however, its usefulness in Asian subjects is unknown. We conducted a phase II study to evaluate the safety and survival benefit of regorafenib dose-escalation therapy for Japanese patients. METHODS: Patients with sufficient organ function, who had previously received more than two lines of chemotherapy were included. Regorafenib was started at 80 mg/day and escalated to 120 mg/day in Week 2 and 160 mg/day in Week 3, if no severe drug-related toxicities were observed. The primary endpoint was cancer progression-free survival (PFS). Tumor response and progression were assessed radiologically every 8 weeks. This study was registered in the University Hospital Medical Information Network (UMIN#UMIN000028933). RESULTS: 57 patients were enrolled and all started regorafenib at 80 mg/day. 32 patients (56.1%) were subsequently escalated to 120 mg/day and 19 (33.3%) to 160 mg/day. Only 8 patients (14.0%) discontinued treatment because of adverse events. Median PFS was 1.9 months. Median overall survival was 8.9 months, the response rate was 0%, and the disease control rate was 31.6%. The most frequent adverse event greater than grade 3 was hypertension (19.3%), followed by HFSR (14.0%). CONCLUSIONS: Regorafenib dose-escalation therapy is well tolerated with PFS-like regorafenib standard therapy.
BACKGROUND: Regorafenib significantly improves overall survival in previously treated metastatic colorectal cancer patients. However, various toxicities, such as hand-foot skin reaction (HFSR), fatigue, and liver dysfunction have limited the use of regorafenib. These toxicities appear soon after treatment initiation. The ReDOS study demonstrated the effectiveness of a weekly dose-escalation therapy of regorafenib starting with a lower daily dose; however, its usefulness in Asian subjects is unknown. We conducted a phase II study to evaluate the safety and survival benefit of regorafenib dose-escalation therapy for Japanese patients. METHODS: Patients with sufficient organ function, who had previously received more than two lines of chemotherapy were included. Regorafenib was started at 80 mg/day and escalated to 120 mg/day in Week 2 and 160 mg/day in Week 3, if no severe drug-related toxicities were observed. The primary endpoint was cancer progression-free survival (PFS). Tumor response and progression were assessed radiologically every 8 weeks. This study was registered in the University Hospital Medical Information Network (UMIN#UMIN000028933). RESULTS: 57 patients were enrolled and all started regorafenib at 80 mg/day. 32 patients (56.1%) were subsequently escalated to 120 mg/day and 19 (33.3%) to 160 mg/day. Only 8 patients (14.0%) discontinued treatment because of adverse events. Median PFS was 1.9 months. Median overall survival was 8.9 months, the response rate was 0%, and the disease control rate was 31.6%. The most frequent adverse event greater than grade 3 was hypertension (19.3%), followed by HFSR (14.0%). CONCLUSIONS: Regorafenib dose-escalation therapy is well tolerated with PFS-like regorafenib standard therapy.
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