一项关于连续口服卡培他滨治疗恶性实体瘤患者的日本I期研究。

A Japanese phase I study of continuous oral capecitabine in patients with malignant solid tumors.

作者信息

Saeki Toshiaki, Takashima Shigemitsu, Terashima Masanori, Satoh Atsushi, Toi Masakazu, Osaki Akihiko, Toge Tetsuya, Ohno Shinji, Nomura Naohiro, Fukuyama Yoshio, Koizumi Wasaburo, Taguchi Tetsuo

机构信息

Department of Clinical Research and Surgery, National Hospital Organization Shikoku Cancer Center, Ehime, Japan.

出版信息

Int J Clin Oncol. 2005 Feb;10(1):51-7. doi: 10.1007/s10147-004-0460-y.

DOI:10.1007/s10147-004-0460-y

PMID:15729602

Abstract

BACKGROUND

This study aimed to evaluate the tolerability and pharmacokinetics of capecitabine, given twice daily for 6 weeks without interruption, and to identify the maximum tolerated dose (MTD) and the suggested phase II schedule.

METHODS

The initial dose of capecitabine was 251 mg/m2 twice daily, without interruption, and a dose escalation schedule was planned according to a modified Fibonacci scheme. Patients received oral capecitabine twice daily for at least 6 weeks unless grade 3 or 4 toxicity was observed. Blood and urine samples were collected for pharmocokinetic analysis on days 1 and 15.

RESULTS

Sixteen patients with malignant solid tumors (seven breast, seven colorectal, and two gastric) were enrolled, all of whom were evaluable. Among 4 patients treated with capecitabine 1255 mg/m2 twice daily, one experienced grade 4 hemorrhagic gastric ulcer and one experienced grade 3 skin toxicity. Consequently, this dose was defined as the MTD, and gastrointestinal and cutaneous effects were identified as dose-limiting toxicities. There was no grade 3/4 diarrhea at any dose level. There was also no grade 4 hematologic toxicity at doses below the MTD, and there were no treatment-related deaths. Two patients with breast cancer had partial responses, at capecitabine doses of 502 mg/m2 and 1255 mg/m2, twice daily. Pharmacokinetic data show that high concentrations of doxifluridine (5'-DFUR) occur in tumor cells within 2 h after administration of capecitabine.

CONCLUSION

The MTD of continuous oral capecitabine over 6 weeks was 1255 mg/m2 twice daily. Because of the higher occurrence of skin disorders reported in this study with a continuous treatment regimen, an intermittent treatment regimen of 828 mg/m2, administered twice daily for 3 weeks, followed by a 1-week rest period, was recommended for phase II studies. This regimen is being evaluated in phase II studies in Japanese patients with gastric, colorectal, and breast cancers.

摘要

背景

本研究旨在评估卡培他滨每日两次、连续6周不间断给药的耐受性和药代动力学，并确定最大耐受剂量（MTD）和推荐的II期给药方案。

方法

卡培他滨的初始剂量为每日两次、每次251 mg/m²，不间断给药，并根据改良的斐波那契方案制定剂量递增计划。患者每日口服卡培他滨两次，持续至少6周，除非观察到3级或4级毒性。在第1天和第15天采集血液和尿液样本进行药代动力学分析。

结果

招募了16例恶性实体瘤患者（7例乳腺癌、7例结直肠癌和2例胃癌），所有患者均可评估。在4例接受每日两次、每次1255 mg/m²卡培他滨治疗的患者中，1例出现4级出血性胃溃疡，1例出现3级皮肤毒性。因此，该剂量被定义为MTD，胃肠道和皮肤反应被确定为剂量限制性毒性。在任何剂量水平均未出现3/4级腹泻。在低于MTD的剂量下也未出现4级血液学毒性，且无治疗相关死亡。2例乳腺癌患者在每日两次、每次502 mg/m²和1255 mg/m²的卡培他滨剂量下出现部分缓解。药代动力学数据显示，在给予卡培他滨后2小时内，肿瘤细胞内出现高浓度的多西氟尿苷（5'-DFUR）。