Ecteinascidin-743 (ET-743) for chemotherapy-naive patients with advanced soft tissue sarcomas: Multicenter phase II and pharmacokinetic study
Ecteinascidin-743 (ET-743) for chemotherapy-naive patients with advanced soft tissue sarcomas: Multicenter phase II and pharmacokinetic study
复制标题
DOI：
10.1200/jco.2005.05.028
复制
发表时间：
2005-08-20
影响因子：
45.3
通讯作者：
Demetri, GD
中科院分区：
文献类型：
--
作者：
Garcia-Carbonero, R;Supko, JG;Demetri, GD
目的评价海鞘素-743（ET-743）一线治疗不能切除的晚期软组织肉瘤（STS）的疗效、毒副反应及药代动力学。患者接受1.5 mg/m2的ET-743治疗，24小时连续静脉（IV）输注，每21天一次。结果35例可评价患者中，1例完全缓解，5例部分缓解，总缓解率为17.1%（95%CI为6.6%~ 33.6%）。此外，1例患者有轻微反应，导致20%的总体临床获益。中性粒细胞增多症和转氨酶升高是主要的3 ~ 4级毒性反应，分别占33%和36%。估计的1年无进展生存率和总生存率分别为21%（95% CI，11%至41%）和72%（95% CI，59%至88%）。总体清除率（L/h）与体表面积无显著相关性（r = -0.28; P = 0.21）。轻度肝损害或既往细胞毒性治疗的程度似乎不会显著导致该药物清除率的高患者间变异性（49%）。结论ET-743作为STS的一线治疗药物具有良好的临床疗效，且毒副反应可以接受。可能需要进行额外的研究以建立经验性给药指南，以提高药物在不同程度肝功能障碍患者中的安全性，并明确确立ET-743在这些恶性肿瘤患者中的作用。
Purpose To evaluate the response rate, toxicity profile, and pharmacokinetics of ecteinascidin-743 (ET-743) as first-line therapy in patients with unresectable advanced soft tissue sarcoma (STS).Patients and Methods Thirty-six patients with STS were enrolled onto the study between September 1999 and August 2000. Patients were treated with 1.5 mg/m(2) of ET-743 given as a 24-hour continuous intravenous (IV) infusion every 21 days. Pharmacokinetic sampling was performed in 23 patients.Results One complete and five partial responses were achieved in 35 assessable patients for an overall response rate of 17.1 % (95% CI, 6.6% to 33.6%). In addition, one patient had a minor response, leading to an overall clinical benefit of 20%. Neutropenia and transaminitis were the main grade 3 to 4 toxicities, which occurred in 33% and 36% of the patients. The estimated 1-year progression-free and overall survival rates were 21% (95% CI, 11% to 41%) and 72% (95% CI, 59% to 88%), respectively. Total body clearance (L/h) was not significantly correlated with body-surface area (r = -0.28; P =.21). Mild hepatic impairment or the extent of prior cytotoxic therapy does not seem to contribute significantly to the high interpatient variability (49%) in the clearance of this drug. Severity of treatment-related toxicity was not correlated with pharmacokinetic variables.Conclusion ET-743 demonstrates clinical activity as first-line therapy against STS with acceptable toxicity. Additional studies to establish empirical dosing guidelines may be necessary to improve the safety of the drug in patients with varying degrees of hepatic dysfunction and definitively establish the role of ET-743 for patients with these malignancies.