Conte P F, Baldini E, Gennari A, Michelotti A, Salvadori B, Tibaldi C, Danesi R, Innocenti F, Gentile A, Dell'Anna R, Biadi O, Mariani M, Del Tacca M
Division of Medical Oncology, Oncologia Medica, Ospedale S. Chiara, Pisa, Italy.
J Clin Oncol. 1997 Jul;15(7):2510-7. doi: 10.1200/JCO.1997.15.7.2510.
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.
Fifty patients with metastatic breast cancer, measurable disease, and normal left ventricular ejection fraction (LVEF) were eligible. Epirubicin was administered as an intravenous (I.V.) bolus at the fixed dose of 90 mg/m2 before the infusion of paclitaxel over 3 hours. The initial dose of paclitaxel was 135 mg/m2 and was increased by 20 mg/m2 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/m2).
The DLT of this combination was febrile neutropenia in two of eight patients who received paclitaxel at 225 mg/m2. The mean peak plasma concentration of paclitaxel ranged between 5.1 and 6.2 micromol/L at doses of 175 to 225 mg/m2. 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/m2. The most relevant toxicity was grade 4 neutropenia (61% of all courses). The pharmacokinetic data of paclitaxel, in particular the time above the threshold level of 0.05 micromol/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.
Our study demonstrates that (1) the MTD is epirubicin 90 mg/m2 and paclitaxel 200 mg/m2; (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.
确定在给予固定剂量表柔比星的情况下，3小时内紫杉醇的最大耐受剂量（MTD），研究该联合用药方案的血浆药代动力学，并评估其在既往未接受治疗的转移性乳腺癌患者中的毒性和活性。
50例转移性乳腺癌患者符合条件，其疾病可测量，左心室射血分数（LVEF）正常。在3小时内输注紫杉醇前，以90mg/m²的固定剂量静脉推注表柔比星。紫杉醇的初始剂量为135mg/m²，随后每组6例患者剂量增加20mg/m²，直至出现剂量限制性毒性（DLT）。在每个紫杉醇剂量水平（175至225mg/m²）的至少2例患者中，于第1周期进行紫杉醇和表柔比星的血浆药代动力学研究。
在接受225mg/m²紫杉醇治疗的8例患者中，有2例出现发热性中性粒细胞减少，这是该联合用药方案的DLT。在175至225mg/m²剂量下，紫杉醇的平均血浆峰浓度在5.1至6.2μmol/L之间。在接受175mg/m²和225mg/m²紫杉醇治疗的患者中，表柔比星醇的浓度从47.3±9.4ng/mL降至37.9±7.5ng/mL。最主要的毒性是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，特别是高于0.05μmol/L阈值水平的时间，与骨髓抑制无显著相关性。心脏毒性较轻：3例患者（6%）出现轻度充血性心力衰竭，对治疗有反应。在49例可评估患者中，观察到41例缓解（84%；95%置信区间[CI]，70%至92%），其中9例（18%）为完全缓解。
我们的研究表明，（1）MTD为表柔比星90mg/m²和紫杉醇200mg/m²；（2）紫杉醇的药代动力学数据与骨髓抑制之间无明确关系，而紫杉醇剂量增加与表柔比星醇血浆水平降低相关；（3）该联合用药方案可行，心脏毒性低，在转移性乳腺癌中具有高活性。
