Eisuke Booka1, Chiyo K Imamura2, Masashi Takeuchi3, Hirofumi Kawakubo3, Hiroya Takeuchi1, Yusuke Tanigawara4, Yuko Kitagawa3, Narikazu Boku5. 1. Department of Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan. 2. Advanced Cancer Translational Research Institute, Showa University, Tokyo, Japan. 3. Department of Surgery, Keio University School of Medicine, Tokyo, Japan. 4. Laboratory of Pharmacometrics and Systems Pharmacology, Keio Frontier Research & Education Collaborative Square at Tonomachi, Keio University, Kanagawa, Japan. 5. Department of Medical Oncology and General Medicine, IMSUT Hospital, Institute of Medical Science, University of Tokyo, 4-6-1Minato-ku, Shiroganedai, Tokyo, 108-8639, Japan. nboku@ims.u-tokyo.ac.jp.
Abstract
BACKGROUND: The aim of this study was to evaluate clinical validity of the S-1 dosage formula based on body surface area (BSA) and creatinine clearance (CLcr) to achieve the target area under the concentration-time curve of 5-FU, which we had developed and refined in each prospective pharmacokinetic study. METHODS: The recommended dose determined by the refined formula was assessed using data of the SPIRITS (S-1 vs. S-1 plus cisplatin [SP]) and the G-SOX (SP vs. S-1 plus oxaliplatin [SOX]) trials. Nine hundred and thirty-eight patients in these trials were classified into three groups according to their actual S-1 starting doses compared with the recommended doses (under-dosed, <recommended dose; equal-dosed, =recommended dose; over-dosed, >recommended dose). RESULTS: The patients in the under-dosed group in both trials showed similar tendencies: male, younger, higher BSA, and higher CLcr. The incidence of any grade neutropenia was significantly greater in the over-dosed group compared with the equal-dosed group in the S-1 and the SOX arms. The hazard ratios (HR) of overall survival (OS) (under-dosed vs. equal-dosed) were 1.361 (S-1 arm), 1.259 (SP arm) in the SPIRITS trial, and 1.381 (SOX arm), 0.999 (SP arm) in the G-SOX trial. Multivariate analysis in all the patients demonstrated that OS of the over-dosed group was equivalent (HR 1.002, 95% confidence interval [CI] 0.850-1.182, p = 0.980) and that of the under-dosed group was inferior (HR 1.267, 95% CI 1.005-1.597, p = 0.045) to the equal-dosed group. CONCLUSIONS: It is suggested that the refined S-1 dosage formula can recommend optimal dose in terms of safety and efficacy.
BACKGROUND: The aim of this study was to evaluate clinical validity of the S-1 dosage formula based on body surface area (BSA) and creatinine clearance (CLcr) to achieve the target area under the concentration-time curve of 5-FU, which we had developed and refined in each prospective pharmacokinetic study. METHODS: The recommended dose determined by the refined formula was assessed using data of the SPIRITS (S-1 vs. S-1 plus cisplatin [SP]) and the G-SOX (SP vs. S-1 plus oxaliplatin [SOX]) trials. Nine hundred and thirty-eight patients in these trials were classified into three groups according to their actual S-1 starting doses compared with the recommended doses (under-dosed, <recommended dose; equal-dosed, =recommended dose; over-dosed, >recommended dose). RESULTS: The patients in the under-dosed group in both trials showed similar tendencies: male, younger, higher BSA, and higher CLcr. The incidence of any grade neutropenia was significantly greater in the over-dosed group compared with the equal-dosed group in the S-1 and the SOX arms. The hazard ratios (HR) of overall survival (OS) (under-dosed vs. equal-dosed) were 1.361 (S-1 arm), 1.259 (SP arm) in the SPIRITS trial, and 1.381 (SOX arm), 0.999 (SP arm) in the G-SOX trial. Multivariate analysis in all the patients demonstrated that OS of the over-dosed group was equivalent (HR 1.002, 95% confidence interval [CI] 0.850-1.182, p = 0.980) and that of the under-dosed group was inferior (HR 1.267, 95% CI 1.005-1.597, p = 0.045) to the equal-dosed group. CONCLUSIONS: It is suggested that the refined S-1 dosage formula can recommend optimal dose in terms of safety and efficacy.
Authors: T Shirasaka; K Nakano; T Takechi; H Satake; J Uchida; A Fujioka; H Saito; H Okabe; K Oyama; S Takeda; N Unemi; M Fukushima Journal: Cancer Res Date: 1996-06-01 Impact factor: 12.701
Authors: K Hirata; N Horikoshi; K Aiba; M Okazaki; R Denno; K Sasaki; Y Nakano; H Ishizuka; Y Yamada; S Uno; T Taguchi; T Shirasaka Journal: Clin Cancer Res Date: 1999-08 Impact factor: 12.531