Phase I and pharmacokinetic study of two sequences of gemcitabine and docetaxel administered weekly to patients with advanced cancer
Phase I and pharmacokinetic study of two sequences of gemcitabine and docetaxel administered weekly to patients with advanced cancer
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DOI：
10.1007/s002800100317
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发表时间：
2001-08-01
影响因子：
3
通讯作者：
Rizvi, NA
中科院分区：
文献类型：
--
作者：
Bhargava, P;Marshall, JL;Rizvi, NA
目的：确定吉西他滨和多西他赛联合用药的最大耐受剂量（MTD）、剂量限制毒性（DLT）以及药物序列对毒性和药代动力学的影响。方法：共有 34 名晚期癌症患者按照以下剂量递增方案，在每个 21 天周期的第 1 天和第 8 天接受吉西他滨和多西紫杉醇治疗：分别为 1 级、800 和 30 mg/m(2)； 2 级、800 和 40 mg/m(2)； 3级、1000和40 mg/m(2)；以及 4 级、1250 和 40 mg/m(2)。在每个剂量水平，至少三名患者被分配到两种给药顺序之一：吉西他滨->多西他赛或多西他赛->吉西他滨。一旦达到 MTD，另外 6 名接受不超过一种化疗方案的患者被纳入剂量水平 3 和 4（吉西他滨 --> 多西他赛），以确定最低限度预处理患者的 MTD。结果：中性粒细胞减少症是最常见的 DLT，总发生率为 23.5%。接受过两种或多种既往化疗方案的患者中有 62% (8/13) 发生 3/4 级中性粒细胞减少症，但接受过不超过一种既往化疗方案的患者则完全没有 (0/15) (P < 0.001)。其他 DLT 包括一名患者的 4 级腹泻和 4 级口腔炎。对于既往接受过两种或多种化疗方案的患者，MTD 确定为吉西他滨 800 mg/m(2) 和多西他赛 40 mg/m(2)。然而，经过最低限度预处理的患者（之前不超过一种化疗方案）能够耐受较高剂量的吉西他滨 1250 mg/m(2) 和多西他赛 40 mg/m(2) 的 MTD。两种给药顺序之间的毒性或药代动力学没有显着差异。 23.5% 的患者观察到部分和轻微反应：非小细胞肺癌（八分之二）、胃癌（三分之二）、头颈癌（二分之一）、膀胱癌（四分之二）和肝细胞癌（一分之一）。结论：每 21 天在第 1 天和第 8 天联合使用吉西他滨和多西他赛对于晚期恶性肿瘤患者是可行的且耐受性良好。给药顺序对两种药物的毒性或药代动力学没有显着影响。最低限度预处理的患者可以耐受较高剂量的这种组合，而没有明显的毒性。该方案和组合在多种实体瘤中表现出活性，值得进一步评估。
Purpose: To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and effect of drug sequence on toxicities and pharmacokinetics of the combination of gemcitabine and docetaxel. Methods: A total of 34 patients with advanced cancers were treated with gemcitabine and docetaxel on days 1 and 8 of each 21-day cycle according to the following dose escalation schedule: level 1, 800 and 30 mg/m(2), respectively; level 2, 800 and 40 mg/m(2); level 3, 1000 and 40 mg/m(2); and level 4, 1250 and 40 mg/m(2). At each dose level, at least three patients were assigned to one of the two sequences of drug administration: gemcitabine --> docetaxel or docetaxel --> gemcitabine. Once the MTD had been reached, six additional patients, who had received no more than one chemotherapy regimen, were enrolled to dose levels 3 and 4 (gemcitabine --> docetaxel) to determine the MTD in minimally pretreated patients. Results: Neutropenia was the most frequent DLT with an overall incidence of 23.5%. Grade 3/4 neutropenia occurred in 62% of patients (8/13) who had received two or more prior chemotherapy regimens, but not at all (0/15) in patients who had received no more than one prior chemotherapy regimens (P < 0.001). Additional DLTs included grade 4 diarrhea and grade 4 stomatitis in one patient each. The MTD was determined to be gemcitabine 800 mg/m(2) and docetaxel 40 mg/m(2) in patients who had received two or more prior chemotherapy regimens. However, minimally pretreated patients (no more than one prior chemotherapy regimen) were able to tolerate higher doses with an MTD of gemcitabine 1250 mg/m(2) and docetaxel 40 mg/m(2). There were no significant differences in toxicities or pharmacokinetics between the two sequences of administration. Partial and minor responses were observed in 23.5% of patients: non-small-cell lung (two of eight), gastric (two of three), head and neck (one of two), bladder (two of four) and hepatocellular cancer (one of one). Conclusions: The combination of gemcitabine and docetaxel administered on days 1 and 8 every 21 days was feasible and well tolerated in patients with advanced malignancies. The sequence of administration had no significant effect on the toxicity or pharmacokinetics of either drug. Minimally pretreated patients tolerated higher doses of this combination without significant toxicities. This schedule and combination demonstrated activity in a variety of solid tumors, and merits further evaluation.