Venturini M, Michelotti A, Papaldo P, Del Mastro L, Bergaglio M, Lionetto R, Lunardi G, Sguotti C, Frevola L, Donati S, Rosso R, Cognetti F
Division of Medical Oncology I, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Ann Oncol. 2001 Aug;12(8):1097-106. doi: 10.1023/a:1011663821703.
To determine the maximum tolerated dose (MTD) and the dose limiting toxicity (DLT) of docetaxel in combination with fixed doses of epirubicin.
Women with locally advanced or metastatic breast cancer were given docetaxel, 60 mg/m2 in escalated doses by steps of 10 mg/m2, in association with two fixed doses of epirubicin (90 mg/m2, and 75 mg/m2). Since neutropenia was foreseen to be the most likely DLT, a third group with prophylactic G-CSF support was planned to define the MTD of docetaxel with 90 mg/m2 of epirubicin. Selected patients underwent pharmacokinetic evaluation of docetaxel.
Fifty-eight patients entered the study. At the first step (90 mg/m2 of epirubicin) the MTD was obtained at 60 mg/m2 of docetaxel. At the second step (75 mg/m2 of epirubicin) the MTD of docetaxel was 80 mg/m2. At the third step (epirubicin 90 mg/m2) G-CSF allowed a safe escalation of docetaxel up to 90 mg/m2. Neutropenia was the most common hematological adverse event. Without G-CSF, grade 4 neutropenia occurred in 69% of cycles, of which 11% was complicated by fever. In G-CSF group, grade 4 neutropenia and neutropenic fever occurred in 31% and 3%, respectively. Most frequent non-hematological adverse effects were asthenia (45%), nausea (39%) and mucositis (36%). No patient developed congestive heart failure. Two toxic deaths occurred. Overall response rate was 73% in 42 out of 58 patients, with no apparent epirubicin dose-related effect. No statistically significant effect of the two doses of epirubicin was observed in docetaxel pharmacokinetics.
On the basis of the toxicity profile, the docetaxel pharmacokinetics and the response rate observed, epirubicin 75 mg/m2 combined with docetaxel 80 mg/m2 can be recommended for further studies.
确定多西他赛与固定剂量表柔比星联合使用时的最大耐受剂量（MTD）和剂量限制性毒性（DLT）。
局部晚期或转移性乳腺癌女性患者接受多西他赛治疗，剂量以10mg/m²的步长递增至60mg/m²，并联合两种固定剂量的表柔比星（90mg/m²和75mg/m²）。由于预计中性粒细胞减少是最可能的DLT，计划设立第三组给予预防性粒细胞集落刺激因子（G-CSF）支持，以确定多西他赛与90mg/m²表柔比星联合使用时的MTD。入选患者接受了多西他赛的药代动力学评估。
58例患者进入研究。在第一步（表柔比星90mg/m²）时，多西他赛的MTD为60mg/m²。在第二步（表柔比星75mg/m²）时，多西他赛的MTD为80mg/m²。在第三步（表柔比星90mg/m²）时，G-CSF使多西他赛安全递增至90mg/m²。中性粒细胞减少是最常见的血液学不良事件。在未使用G-CSF的情况下，4级中性粒细胞减少在69%的周期中出现，其中11%并发发热。在G-CSF组中，4级中性粒细胞减少和中性粒细胞减少性发热分别发生在31%和3%的周期中。最常见的非血液学不良反应为乏力（45%）、恶心（39%）和黏膜炎（36%）。无患者发生充血性心力衰竭。发生了2例毒性死亡。58例患者中的42例总体缓解率为73%，未观察到明显的表柔比星剂量相关效应。在多西他赛药代动力学方面未观察到两种剂量表柔比星的统计学显著效应。
基于所观察到的毒性特征、多西他赛药代动力学和缓解率，可推荐75mg/m²表柔比星与80mg/m²多西他赛联合用于进一步研究。
