Dombernowsky P, Gehl J, Boesgaard M, Jensen T P, Jensen B V
Department of Oncology, Herlev Hospital and Righospitalet, University of Copenhagen, Denmark.
Semin Oncol. 1996 Feb;23(1 Suppl 1):13-8.
The activity of single-agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been documented in untreated and previously treated metastatic breast cancer, including both patients with anthracycline-resistant disease and those with extensive pretreatment. Such activity has prompted investigations of the optimal doses and schedules of paclitaxel/doxorubicin combinations. With one exception, paclitaxel has been administered as either a 24- or a 3-hour infusion, while the administration times for doxorubicin vary from bolus injection to 72-hour infusion. Results of these completed phase I and II trials are reviewed. Also reported are two European trials that have achieved promising results. In Milan, a phase I/II trial has shown a preliminary response rate exceeding 90% in 32 chemotherapy-naive patients treated with an alternating schedule of paclitaxel given over 3 hours and intravenous bolus doxorubicin. At doses of paclitaxel 200 mg/m2 and doxorubicin 60 mg/m2, the dose-limiting toxicities were neutropenia, oral mucositis, myalgias, and peripheral neuropathy. Congestive heart failure occurred in six patients. A phase I/II study of a 30-minute doxorubicin infusion preceding a 3-hour paclitaxel infusion every 3 weeks in minimally pretreated patients also is reported. Of 29 patients evaluable for response, 17 have achieved partial responses and seven complete responses, for an overall response rate of 83% (95% confidence interval, 79% to 99%). Toxicities observed were grades 3 to 4 neutropenia and moderate paresthesias, nausea/vomiting, alopecia, myalgia, and mucositis. Cardiotoxicity also occurred, as 15 patients had a significant decrease in left ventricular ejection fraction measured by isotope cardiography. Six of these developed congestive heart failure. This effect has been observed only in studies using short infusions of both drugs, and it is now being investigated whether lowering the peak doxorubicin concentration will preclude it.
单药紫杉醇（泰素；百时美施贵宝公司，新泽西州普林斯顿）在未经治疗和先前接受过治疗的转移性乳腺癌中均显示出活性，包括对蒽环类耐药的患者以及接受过广泛预处理的患者。这种活性促使人们对紫杉醇/阿霉素联合用药的最佳剂量和给药方案进行研究。除一项研究外，紫杉醇的给药方式为24小时或3小时静脉滴注，而阿霉素的给药时间则从大剂量注射到72小时静脉滴注不等。本文回顾了这些已完成的I期和II期试验的结果。还报告了两项取得了有前景结果的欧洲试验。在米兰，一项I/II期试验显示，32例未接受过化疗的患者采用3小时静脉滴注紫杉醇和静脉推注阿霉素交替给药方案，初步缓解率超过90%。在紫杉醇剂量为200mg/m²和阿霉素剂量为60mg/m²时，剂量限制性毒性为中性粒细胞减少、口腔黏膜炎、肌痛和周围神经病变。6例患者发生充血性心力衰竭。还报告了一项I/II期研究，在轻度预处理的患者中，每3周在3小时紫杉醇静脉滴注前先进行30分钟阿霉素静脉滴注。在可评估缓解情况的29例患者中，17例达到部分缓解，7例达到完全缓解，总缓解率为83%（95%置信区间，79%至99%）。观察到的毒性为3至4级中性粒细胞减少以及中度感觉异常、恶心/呕吐、脱发、肌痛和黏膜炎。也发生了心脏毒性，15例患者经同位素心动图测量左心室射血分数显著下降。其中6例发展为充血性心力衰竭。这种效应仅在两种药物均采用短时间静脉滴注的研究中观察到，目前正在研究降低阿霉素的峰值浓度是否能避免这种情况。
