Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over 3 hours: A regimen with high activity and low cardiotoxicity in advanced breast cancer
Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over 3 hours: A regimen with high activity and low cardiotoxicity in advanced breast cancer
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DOI：
10.1200/jco.1997.15.7.2510
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发表时间：
1997-07-01
影响因子：
45.3
通讯作者：
DelTacca, M
中科院分区：
文献类型：
--
作者：
Conte, PF;Baldini, E;DelTacca, M
目的：测定紫杉醇固定剂量表柔比星静脉滴注3h以上的最大耐受量(MTD)，研究表柔比星与表阿霉素联合用药的血药动力学，并评价其在初治转移性乳腺癌患者中的毒性和活性。患者和方法：50例转移性乳腺癌、可测量疾病、左心室射血分数(LVEF)正常的患者，在紫杉醇静脉滴注3h以上前，表阿霉素90 mg/m(2)静注，紫杉醇的初始剂量为135 mg/m(2)，在随后的队列中增加20 mg/m(2)，直到剂量限制毒性(DLT)，每剂量水平(175~225 mg/m(2))至少有2名患者在第1周期进行紫杉醇和表阿霉素的血浆药代动力学研究。结果：在8例接受紫杉醇225 mg/m(2)剂量的患者中，2例为发热性中性粒细胞减少症，紫杉醇的平均血药浓度峰值在5.1~6.2mU/L之间，剂量为175~225 mg/m(2)，紫杉醇175和225 mg/m(2)组的表阿霉素浓度由47.3+/-9.4降至37.9+/-7.5 ng/m L。最相关的毒性是4级中性粒细胞减少(占所有疗程的61%)，紫杉醇的药代动力学数据，特别是阈值水平以上的紫杉醇，与骨髓抑制无关，心脏毒性轻微：3例(6%)患者出现轻度充血性心力衰竭，治疗有效，在49例可评估的患者中，41例有效(84%；结果显示：(1)表阿霉素为90 mg/m(2)，紫杉醇为200 mg/m(2)；(2)紫杉醇的药代动力学数据与骨髓抑制无明显关系，而紫杉醇剂量的增加与表柔比星血浆浓度的降低有关；(3)在转移性乳腺癌中，这种关联是可行的，心脏毒性低，活性高。(C)1997年，由美国临床肿瘤学会主办。
Purpose: To determine the maximum-tolerated dose (MTD) of paclitaxel over 3 hours with a fixed dose of epirubicin, to investigate the plasma pharmacokinetics of this combination, and to evaluate the toxicity and the activity in previously untreated metastatic breast cancer patients.Patients and Methods: Fifty patients with metastatic breast cancer, measurable disease, and normal left ventricular ejection fraction (LVEF) were eligible, Epirubicin was administered as an intravenous (IV) bolus at the fixed dose of 90 mg/m(2) before the infusion of paclitaxel over 3 hours, The initial dose of paclitaxel was 135 mg/m(2) and was increased by 20 mg/m(2) in subsequent cohorts of six patients until dose-limiting toxicity (DLT), plasma pharmacokinetics of paclitaxel and epirubicin was performed at cycle 1 in at least two patients per dose level of paclitaxel (175 up to 225 mg/m(2)),Results: The DLT of this combination was febrile neutropenia two of eight patients who received paclitaxel at 225 mg/m(2), The mean peak plasma concentration of paclitaxel ranged between 5.1 and 6.2 mu mol/L at doses of 175 to 225 mg/m(2), The concentration of epirubicinol decreased from 47.3 +/- 9.4 to 37.9 +/- 7.5 ng/mL in patients treated with paclitaxel 175 and 225 mg/m(2). The most relevant toxicity was grade 4 neutropenia (61% of all courses), The pharmacokinetic data of paclitaxel, in particular the rime above the threshold level of 0.05 mu mol/L, were not significantly related to myelosuppression, Cardiac toxicity was mild: three patients (6%) developed mild congestive heart failure that was responsive to therapy, Among 49 assessable patients, 41 responses (84%; 95% confidence interval [CI], 70% to 92%) were observed, and nine (18%) of these were complete,Conclusion: Our study demonstrates that (1) the MTD is epirubicin 90 mg/m(2) and paclitaxel 200 mg/m(2); (2) no clear relationship exists between pharmacokinetic data of paclitaxel and myelosuppression, while the increase in the dose of paclitaxel is associated with a reduction in epirubicinol plasma levels; and (3) the association is feasible, with low cardiotoxicity, and has a high activity in metastatic breast cancer. (C) 1997 by American Society of Clinical Oncology.