Clinical and pharmacologic study of the epirubicin and paclitaxel combination in women with metastatic breast cancer

nPurpose: A pharmacokinetic interaction may cause increased cardiotoxicity of paclitaxel (PTX) and high cumulative dose of doxorubicin. We tested anti tumor activity, tolerability, and pharmacokinetics of the lesser cardiotoxi c epirubicin (EPI) and PTX (ET combination). patients and Methods: Twenty-seven women with untreated metastatic breast c ancer, median age of 56 years, and prominent visceral involvement (74%) wer e studied. Three-weekly EPI (90 mg/m(2)) and PTX (200 mg/m(2) over 3 hours) were given for a maximum nine cycles. EPI was administered 24 hours before PTX (E --> T) in cycle I,and 15 minutes before PTX (ET) thereafter. EPI, e pirubicinol (EOL), EPI-glucuronide (EPI-SIV), EOL-glucuronide (EOL-glu), PT X, and 6 alpha -OH-PTX were measured in plasma and urine in 14 women. Results: Patients received 205 cycles of ET and a median EPI dose of 720 mg /m(2). Grade 4 neutropenia (49% of cycles) was the most frequent toxicity. Cardiac contractility was decreased in five patients. Mild congestive heart failure occurred in two (7.4%). Response rate was 76% (28% complete). Medi an overall survival was 29 months. On the basis of intrapatient comparison in the first 24 hours of E --> T and ET cycles, PTX did not affect EPI disp osition, but significantly increased plasma exposure ta EOL (by 137%), EPI- glu (threefold) and EOL-glu (twofold). Urinary excretion af EPI dose went f rom 8.2% in E --> T to 11.8% in FT cycles. Clearance of PTX wets 30% slower in ET than E --> T. ET cycles caused lower neutrophil nadir than E --> T ( 644 +/- 327 v 195 +/- 91, P < .05). Conclusion: ET is feasible, devoid of excessive cardiac toxicity, and activ e. A reciprocal pharmacokinetic interference between the two drugs has phar macodynamic consequences, and suggests a direct effect of PTX on EPI metabo lism requiring ad hoc investigation. <(c)> 2001 by American Society of Clin ical Oncology.