Journal of Clinical Oncology, Vol 15, 2510-2517, Copyright © 1997 by American Society of Clinical Oncology
Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over 3 hours: a regimen with high activity and low cardiotoxicity in advanced breast cancer
PF Conte, E Baldini, A Gennari, A Michelotti, B Salvadori, C Tibaldi, R Danesi, F Innocenti, A Gentile, R Dell'Anna, O Biadi, M Mariani and M Del Tacca
Division of Medical Oncology, Oncologia Medica, Ospedale S. Chiara, Pisa, Italy.
PURPOSE: 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.
PATIENTS AND METHODS: 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). RESULTS: 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.
CONCLUSION: 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.
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