Evaluation of clinical validity of an S-1 dosage formula based on renal function using data of the SPIRITS and the G-SOX trials
Evaluation of clinical validity of an S-1 dosage formula based on renal function using data of the SPIRITS and the G-SOX trials
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DOI：
10.1007/s10120-022-01291-z
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发表时间：
2022-03-31
期刊：
影响因子：
7.4
通讯作者：
Boku, Narikazu
中科院分区：
文献类型：
--
作者：
Booka, Eisuke;Imamura, Chiyo K.;Boku, Narikazu
本研究的目的是评价基于体表面积（BSA）和肌酐清除率（CLcr）的S-1剂量公式的临床有效性，以达到我们在每项前瞻性药代动力学研究中开发和完善的5-FU浓度-时间曲线下目标面积。方法使用SPIRITS（S-1 vs. S-1+顺铂[SP]）和G-SOX（SP vs. S-1+奥沙利铂[SOX]）试验的数据，对改良公式确定的推荐剂量进行评估。根据实际S-1起始剂量与推荐剂量（剂量不足、推荐剂量）的比较，将这些试验中的938例患者分为3组。结果两个试验中低剂量组患者均表现为男性、年轻、BSA和CLcr较高的趋势。在S-1和SOX组中，过量给药组中任何级别中性粒细胞减少症的发生率均显著高于等剂量组。SPIRITS试验中总生存期（OS）的风险比（HR）（剂量不足vs.剂量相等）为1.361（S-1组）、1.259（SP组），G-SOX试验中为1.381（SOX组）、0.999（SP组）。所有患者的多变量分析表明，过量给药组的OS与等量给药组相当（HR 1.002，95%置信区间[CI] 0.850-1.182，p = 0.980），剂量不足组的OS劣效于等量给药组（HR 1.267，95% CI 1.005-1.597，p = 0.045）。结论改良后的S-1剂量公式可推荐安全有效的最佳剂量。
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). 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.