Sequential administration of epirubicin and paclitaxel for advanced breast cancer. A phase I randomised trial.

Forty-six previously untreated patients with advanced breast cancer were eligible for the present randomised phase I study. It aimed to evaluate the toxicity and activity of a therapeutic sequence with epirubicin on day 1 followed by paclitaxel on day 2 (sequence A) or the reverse sequence, ie., paclitaxel on day 1 followed by epirubicin on day 2 (sequence B). The starting doses of epirubicin and paclitaxel, administered either according to sequence A or B, (level 1 cohort) were 90 mg/m2 and 175 mg/m2, respectively. Per cohort of 3 patients, the dose of paclitaxel was increased by 25 mg/m2 (levels 2 and 4) and of epirubicin by 10 mg/m2 (levels 3 and 5). Treatment was repeated with 3-week intervals. The maximal tolerated dose (MTD) was achieved at level 1 in sequence B (paclitaxel first) and level 3 (epirubicin 100 mg/m2 followed by paclitaxel 200 mg m2) in sequence A. Dose limiting toxicity (DLT) was neutropenia (+/- febrile) in both sequences. Cardiac events occurred in 28% of the patients; significant decrease in left ventricular ejection function (LVEF) was observed in 8/33 and in 2/13 patients in sequence A and B, respectively. This was associated with 5 and 1 cardiac heart failure (CHF), respectively. In 43 evaluable patients, 10 CR and 25 PR were observed (overall response rate 81%). In the 20 patients with locally advanced disease (LABC), the respective numbers were 7 CR and 11 PR; in the 23 metastatic (MBC) patients, 3 CR and 14 PR were recorded. The median survival of the both groups was not reached at 33 + months. In conclusion , the combination of epirubicin and paclitaxel has significant activity in breast cancer. The recommended sequence of both drugs in combination therapy, mainly to avoid neutropenia, is epirubicin day 1 followed by paclitaxel on day 2. Cardiac toxicity remains problematic in either sequence of administration.