Kouroussis C, Androulakis N, Kakolyris S, Souglakos J, Kotsakis T, Mavroudis D, Katsogridakis K, Vardakis N, Hatzidaki D, Samonis G, Vlachonikolis J, Georgoulias V
Department of Medical Oncology, School of Medicine, University of Crete, Heraklion, Greece.
J Clin Oncol. 1999 Mar;17(3):862-9. doi: 10.1200/JCO.1999.17.3.862.
To define the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of docetaxel in combination with mitoxantrone in patients with metastatic breast cancer (MBC).
Forty-one chemotherapy-naive patients with MBC (median age, 61 years) were enrolled. Thirty-eight (93%) had performance status (World Health Organization [WHO]) 0, 29 (71%) were postmenopausal, and 21 (51%) had estrogen receptor-negative tumors. Patients received escalated doses of docetaxel (75 to 100 mg/m2) on day 1 and mitoxantrone (8 to 22 mg/m2) on day 8. Treatment was repeated every 3 weeks.
A total of 217 chemotherapy cycles were administered. Without recombinant human granulocyte colony-stimulating factor (rhG-CSF) support, the MTD1 occurred at the first dose level (docetaxel 75 mg/m2 and mitoxantrone 8 mg/m2); DLTs were febrile neutropenia, grade 4 neutropenia lasting more than 5 days, and grade 3 diarrhea. With prophylactic rhG-CSF, the MTD2 was docetaxel 100 mg/m2 and mitoxantrone 20 mg/m2; DLTs were febrile neutropenia and grade 4 neutropenia. Nine (22%) patients developed neutropenia after the first cycle of treatment. A total of 19 episodes of febrile neutropenia (9% of the cycles) occurred during the whole period of the study; there were no toxic deaths. At high docetaxel (100 mg/m2) and mitoxantrone (> 12 mg/m2) dose levels, a significant decrease of the absolute lymphocyte number was observed; immunophenotyping revealed that all lymphocyte subpopulations were reduced. Grades 2 and 3 neurosensory toxicity occurred in six patients (15%) and one patient (2%), respectively. No cardiac toxicity was observed. Nine complete responses (22%) and 23 partial responses (56%) were achieved (overall response rate, 78%; 95% confidence interval, 62.5% to 88.8%). The median duration of response was 12.5 months, and the median time to tumor progression was 14.5 months.
The reported combination of docetaxel and mitoxantrone with G-CSF support is a safe, intensified, well-tolerated, and effective regimen as first-line treatment in patients with MBC.
确定多西他赛联合米托蒽醌治疗转移性乳腺癌（MBC）患者的最大耐受剂量（MTD）和剂量限制性毒性（DLT）。
纳入41例初治MBC患者（中位年龄61岁）。38例（93%）患者的体能状态（世界卫生组织[WHO]标准）为0，29例（71%）为绝经后女性，21例（51%）患者的肿瘤雌激素受体为阴性。患者于第1天接受递增剂量的多西他赛（75至100mg/m²），第8天接受米托蒽醌（8至22mg/m²）。每3周重复治疗。
共进行了217个化疗周期。在无重组人粒细胞集落刺激因子（rhG-CSF）支持的情况下，MTD1出现在第一个剂量水平（多西他赛75mg/m²和米托蒽醌8mg/m²）；DLT为发热性中性粒细胞减少、持续超过5天的4级中性粒细胞减少和3级腹泻。在预防性使用rhG-CSF的情况下，MTD2为多西他赛100mg/m²和米托蒽醌20mg/m²；DLT为发热性中性粒细胞减少和4级中性粒细胞减少。9例（22%）患者在第一个治疗周期后出现中性粒细胞减少。在研究全过程中共发生19次发热性中性粒细胞减少事件（占周期数的9%）；无毒性死亡病例。在高剂量多西他赛（100mg/m²）和米托蒽醌（>12mg/m²）水平时，观察到绝对淋巴细胞数显著减少；免疫表型分析显示所有淋巴细胞亚群均减少。6例（15%）患者发生2级神经感觉毒性，1例（2%）患者发生3级神经感觉毒性。未观察到心脏毒性。获得9例完全缓解（22%）和23例部分缓解（56%）（总缓解率78%；95%置信区间，62.5%至88.8%）。中位缓解持续时间为12.5个月，中位肿瘤进展时间为14.5个月。
报道的多西他赛联合米托蒽醌并给予G-CSF支持的方案，作为MBC患者的一线治疗，是一种安全、强化、耐受性良好且有效的方案。
