Tadamichi Denda1, Mitsuro Kanda2, Yoshitaka Morita3, Ho Min Kim4, Tomomi Kashiwada5, Chu Matsuda6, Shinji Fujieda7, Ken Nakata8, Kenta Murotani9, Koji Oba10,11, Junichi Sakamoto12, Hideyuki Mishima13. 1. Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan. 2. Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. m-kanda@med.nagoya-u.ac.jp. 3. Department of Radiology, Kobe Medical Center, Kobe, Japan. 4. Department of Surgery, Rinku General Medical Center, Izumisano, Japan. 5. Division of Cancer Center, Saga University Hospital, Saga, Japan. 6. Department of Surgery, Osaka General Medical Center, Osaka, Japan. 7. Division of Gastroenterology, Ibaraki Prefectural Hospital, Kasama, Japan. 8. Department of Surgery, Sakai City Hospital, Sakai, Japan. 9. Clinical Research Center, Aichi Medical University Hospital, Nagakute, Japan. 10. Department of Biostatistics, School of Public Health, Tokyo University Graduate School of Medicine, Tokyo, Japan. 11. Interfaculty Initiative in Information Studies, Tokyo University, Tokyo, Japan. 12. Tokai Central Hospital, Gifu, Japan. 13. Cancer Center, Aichi Medical University, Nagakute, Japan.
Abstract
PURPOSE: Dose adjustment of 5-fluorouracil (FU) based on pharmacokinetic monitoring has been shown to reduce toxicities and increase efficacy compared with dosing based on body surface area in patients with metastatic colorectal cancer (mCRC). We evaluated the efficacy and safety of pharmacokinetic dose adjustment of FU in a modified FOLFOX7 (mFOLFOX7) plus bevacizumab regimen in Japanese patients with previously untreated mCRC. METHODS: This single-arm, multicenter phase II trial enrolled 48 patients with mCRC. Treatment consisted of 5 mg/kg intravenous bevacizumab followed by mFOLFOX7 (oxaliplatin 85 mg/m2 on day 1, infused leucovorin 200 mg/m2, followed by a 2400 mg/m2 infusion of FU for 46 h starting on day 1), repeated every 2 weeks. FU concentrations were measured by immunoassay between 18 and 36 h after the start of continuous FU infusion, and the FU dose was then adjusted if required in subsequent cycles. The primary endpoint was response rate. RESULTS: The median initial area under the concentration-time curve for FU was 23 mg h/L. Twenty-nine patients (60%) achieved the target concentration at the first cycle, and all 48 achieved it within the fourth cycle. The overall frequency of grade 3/4 adverse effects was 38%, with no significant difference between patients who did and not require dose adjustments. The overall response rate was 48% (95% confidence intervals = 34-62%). The median progression-free and overall survival rates were 11.3 and 24.1 months, respectively. CONCLUSIONS: Pharmacokinetic dose adjustment of FU in mFOLFOX7 plus bevacizumab can optimize FU concentrations promptly and is safe in Japanese patients with mCRC.
RCT Entities:
PURPOSE: Dose adjustment of 5-fluorouracil (FU) based on pharmacokinetic monitoring has been shown to reduce toxicities and increase efficacy compared with dosing based on body surface area in patients with metastatic colorectal cancer (mCRC). We evaluated the efficacy and safety of pharmacokinetic dose adjustment of FU in a modified FOLFOX7 (mFOLFOX7) plus bevacizumab regimen in Japanese patients with previously untreated mCRC. METHODS: This single-arm, multicenter phase II trial enrolled 48 patients with mCRC. Treatment consisted of 5 mg/kg intravenous bevacizumab followed by mFOLFOX7 (oxaliplatin 85 mg/m2 on day 1, infused leucovorin 200 mg/m2, followed by a 2400 mg/m2 infusion of FU for 46 h starting on day 1), repeated every 2 weeks. FU concentrations were measured by immunoassay between 18 and 36 h after the start of continuous FU infusion, and the FU dose was then adjusted if required in subsequent cycles. The primary endpoint was response rate. RESULTS: The median initial area under the concentration-time curve for FU was 23 mg h/L. Twenty-nine patients (60%) achieved the target concentration at the first cycle, and all 48 achieved it within the fourth cycle. The overall frequency of grade 3/4 adverse effects was 38%, with no significant difference between patients who did and not require dose adjustments. The overall response rate was 48% (95% confidence intervals = 34-62%). The median progression-free and overall survival rates were 11.3 and 24.1 months, respectively. CONCLUSIONS: Pharmacokinetic dose adjustment of FU in mFOLFOX7 plus bevacizumab can optimize FU concentrations promptly and is safe in Japanese patients with mCRC.
Authors: Jan H Beumer; Edward Chu; Carmen Allegra; Yusuke Tanigawara; Gerard Milano; Robert Diasio; Tae Won Kim; Ron H Mathijssen; Li Zhang; Dirk Arnold; Katsuki Muneoka; Narikazu Boku; Markus Joerger Journal: Clin Pharmacol Ther Date: 2018-09-11 Impact factor: 6.875
Authors: Victor Hugo Fonseca de Jesus; Marcos Pedro Guedes Camandaroba; Mauro Daniel Spina Donadio; Audrey Cabral; Thiago Pimentel Muniz; Luciana de Moura Leite; Lucas Ferreira Sant'Ana Journal: J Gastrointest Oncol Date: 2018-08