Kurita Nobuhiro, Shimada Mitsuo, Iwata Takashi, Nishioka Masanori, Morimoto Shinya, Yoshikawa Kozo, Higashijima Jun, Miyatani Tomohiko, Nakao Toshihiro
Department of Digestive Surgery and Transplantation, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
J Med Invest. 2011 Feb;58(1-2):134-9. doi: 10.2152/jmi.58.134.
Intraperitoneal administration of taxanes revealed excellent anti-tumor effect for peritoneal metastasis of gastric cancer in some experimental models. The aim of this study is to determine maximum tolerated dose (MTD), dose limiting toxicity (DLT) and recommended dose (RD) of intraperitoneally infused paclitaxel (PTX) with S-1 as a phase I study.
Eighteen patients with advanced gastric cancer in addition to confirmed peritoneal metastasis using laparoscopy were enrolled in this study. The regimen consists of oral administration of S-1 (Dose 80 mg: BSA<1.25 m(2), 100 mg: 1.25<BSA<1.5 m(2), 120 mg: BSA>1.5 m(2)) for 14 days and intraperitoneal infusion of PTX (Dose escalation: level I: 40, II: 60, III: 80, level IV: 90, V: 100 mg/m(2)) at day 1 and 14. PTX concentrations in serum and ascites were determined at 4, 8, 12, 24, 48 hours after the infusion, which was repeated twice every 4 weeks.
The number of patients were as follows: Level I: 3, Level II: 6, Level III: 3, Level IV: 3, Level V: 3. Grade 3 leukocytopenia was confirmed in 1 (Level II) and 2 (Level V). MTD is 90 mg/m(2), RD is 80 mg/m(2) and DLT is Grade 3 leukocytopenia. The average serum PTX concentrations remained in optimal range except for all 3 of level V patients. In all cohorts, the PTX concentrations in the ascites were approximately 1000 folds higher than those in serum for 48 hours after the infusion.
MTD and RD were PTX 90 mg/m(2), 80 mg/m(2), respectively. These findings were supported by pharmocokinetics of PTX.
在一些实验模型中，腹腔内给予紫杉烷类药物对胃癌腹膜转移显示出优异的抗肿瘤效果。本研究的目的是作为一项I期研究确定腹腔内输注紫杉醇（PTX）联合S-1的最大耐受剂量（MTD）、剂量限制毒性（DLT）和推荐剂量（RD）。
本研究纳入了18例经腹腔镜检查确诊有腹膜转移的晚期胃癌患者。该方案包括口服S-1（剂量：体表面积<1.25 m²为80 mg，1.25<体表面积<1.5 m²为100 mg，体表面积>1.5 m²为120 mg）14天，并在第1天和第14天腹腔内输注PTX（剂量递增：I级：40，II级：60，III级：80，IV级：90，V级：100 mg/m²）。在输注后4、8、12、24、48小时测定血清和腹水中的PTX浓度，每4周重复两次。
各剂量组患者数量如下：I级：3例，II级：6例，III级：3例，IV级：3例，V级：3例。1例（II级）和2例（V级）出现3级白细胞减少。MTD为90 mg/m²，RD为80 mg/m²，DLT为3级白细胞减少。除所有3例V级患者外，平均血清PTX浓度保持在最佳范围内。在所有队列中，输注后48小时腹水中的PTX浓度比血清中的高约1000倍。
PTX的MTD和RD分别为90 mg/m²、80 mg/m²。这些结果得到了PTX药代动力学的支持。
