PHASE-II CLINICAL AND PHARMACOLOGICAL STUDY OF PIRARUBICIN IN COMBINATION WITH 5-FLUOROURACIL AND CYCLOPHOSPHAMIDE IN METASTATIC BREAST-CANCER

Doxorubicin containing combination chemotherapy regimens are widely us ed for treatment of breast and other cancers, However, these regimens are associated with significant toxicities including myocardial dysfun ction and alopecia. Analogues of doxorubicin are being developed to re duce these side effects, We conducted a Phase II trial of an anthracyc line analogue, pirarubicin, administered in combination with 5-fluorou racil and cyclophosphamide every 3 weeks, as front-line chemotherapy i n women with metastatic breast cancer, Patients who had received prior anthracycline therapy were excluded, The chemotherapy doses were as f ollows: 5-fluorouracil (500 mg/m(2) on days 1 and 8), pirarubicin (50 mg/m(2) on day 1), and cyclophosphamide (500 mg/m(2) on day 1), Among 40 evaluable patients treated on this protocol, a major response (part ial or complete remission) was observed in 26 patients (response rate, 62%; 95% confidence interval, 46-77). The median response duration wa s 8 months, and median survival was 16 months. Grade III/IV myelosuppr ession occurred in 81% of the courses, The median cumulative pirarubic in dose was 410 (range, 90-870) mg/m(2). A significant decrease in lef t ventricular ejection fraction occurred in 12 patients (at a median c umulative pirarubicin dose of 460 mg/m(2)) and led to congestive heart failure in 4 of these patients (cumulative pirarubicin doses of 500, 520, 590, and 730 mg/m(2), respectively). Eleven patients underwent en domyocardial biopsy, either because they experienced a drop in left ve ntricular ejection fraction or because they had received a cumulative pirarubicin dose of 600 mg/m(2) and were still responding to the treat ment, Of these, only one biopsy was found to be more than grade 1.0 (i n an individual who had received a cumulative dose of 705 mg/m(2)), Se vere alopecia occurred in two-thirds of the patients, Pharmacokinetic studies revealed a triphasic elimination of pirarubicin with alpha, be ta, and gamma half-lives of 0.12, 1.44, and 33.9 h, respectively. Tota l clearance of drug was 4.2 liters . h/kg while the cumulative 24-h ur inary excretion was less than 10% of the administered dose, The activi ty of the combination appears to be similar to doxorubicin-containing regimens, while the incidence of alopecia appears to be lower than the historical experience with doxorubicin, However, cardiotoxicity remai ns a significant problem.