Ueda Yuji, Yamagishi Hisakazu, Ichikawa Daisuke, Morii Jun, Koizumi Kinya, Kakihara Naoki, Shimotsuma Masataka, Takenaka Atsushi, Yamashita Tetsuro, Kurioka Hideaki, Nishiyama Masahiko, Morita Satoshi, Nakamura Kanae, Sakamoto Junichi
Department of Surgery, Division of Digestive Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Oncology. 2005;69(3):261-8. doi: 10.1159/000088072. Epub 2005 Sep 1.
A phase I study of weekly intravenous paclitaxel combined with a fixed dose of S-1, a dihydropyrimidine-dehydrogenase-inhibitory oral fluoropyrimidine, was conducted for patients with advanced or recurrent gastric cancer (ARGC). Endpoints of this study were to examine the toxicity profile OF this regimen and to determine the recommended dose (rd) of paclitaxel.
S-1 was fixed at a dose of 80 mg/m(2) per day and was administered for 2 weeks (days 1--14) followed by a 2-week rest. Two dose levels of paclitaxel (level 1: 60 mg/m(2), level 0: 50 mg/m(2)) were studied. Paclitaxel was infused over 1 h on days 1, 8, and 15. Plasma sampling was performed to characterize the pharmacokinetics and pharmacodynamics of paclitaxel in some patients. Fifteen patients were enrolled (6 patients in level 1, and 9 patients in level 0). Dose-limiting toxicities were defined as grade 4 hematological (including grade 3 febrile neutropenia) and grade 3 non-hematological (except anorexia, nausea, vomiting and depilation) toxicities.
Three of 6 patients in level 1 developed grade 4 neutropenia or grade 3 febrile neutropenia, and 1 of them also showed grade 3 diarrhea, which settled the maximum-tolerated dose at this level. At level 0, 2 of 9 patients developed grade 4 neutropenia or grade 3 febrile neutropenia, and the RD of paclitaxel for this protocol was set at this level. Pharmacologic studies demonstrated the persistence of significant serum paclitaxel levels over 24 h after drug administration at both levels. Objective responses according to Response Evaluation Criteria in Solid Tumors were observed in 3 of 6 patients who had measurable disease.
A combination of S-1 and weekly paclitaxel was feasible and well tolerated, and is suggested to produce a worthwhile response in ARGC. These results warrant further investigation, and a phase II study has already been started.
对晚期或复发性胃癌（ARGC）患者进行每周一次静脉注射紫杉醇联合固定剂量的S-1（一种二氢嘧啶脱氢酶抑制性口服氟嘧啶）的I期研究。本研究的终点是检查该方案的毒性特征并确定紫杉醇的推荐剂量（rd）。
S-1固定剂量为每天80mg/m²，给药2周（第1 - 14天），随后休息2周。研究了两个剂量水平的紫杉醇（1级：60mg/m²，0级：50mg/m²）。紫杉醇在第1、8和15天静脉输注1小时。对部分患者进行血浆采样以表征紫杉醇的药代动力学和药效学。共纳入15例患者（1级6例，0级9例）。剂量限制性毒性定义为4级血液学毒性（包括3级发热性中性粒细胞减少）和3级非血液学毒性（厌食、恶心、呕吐和脱发除外）。
1级的6例患者中有3例发生4级中性粒细胞减少或3级发热性中性粒细胞减少，其中1例还出现3级腹泻，确定了该水平的最大耐受剂量。在0级，9例患者中有2例发生4级中性粒细胞减少或3级发热性中性粒细胞减少，本方案中紫杉醇的推荐剂量设定为该水平。药理学研究表明，两个剂量水平给药后24小时内血清紫杉醇水平均持续显著。根据实体瘤疗效评价标准，6例有可测量疾病的患者中有3例观察到客观缓解。
S-1与每周一次紫杉醇联合使用是可行的且耐受性良好，提示对ARGC有值得期待的反应。这些结果值得进一步研究，且一项II期研究已经启动。
