A randomized phase II study of combination, alternating and sequential regimens of doxorubicin and docetaxel as first-line chemotherapy for women with metastatic breast cancer

Background: This randomized phase II study was conducted to evaluate the efficacy of doxorubicin and docetaxel (DOC) administered either as a combination, an alternating or a sequential regimen in women with metastatic breast cancer. Secondary objectives included overall response, time to progression, survival and safety. Patients and methods: Patients with breast cancer (n = 123) were randomized to receive doxorubicin and DOC either in combination (60 mg/m2 of each drug), or by alternated or sequential schedule (100 mg/m2 DOC and 75 mg/m2 doxorubicin) every 3 weeks for a maximum of eight cycles as first chemotherapy for stage IV disease. A second randomization allocated patients from each arm to receive prophylactic oral ciprofloxacin or no therapy to prevent febrile neutropenia. Results: Patients received a median of eight cycles. In an intention-to-treat analysis, the overall response was 63%, 52% and 61% in the combination, alternating and sequential schedules, respectively. Corresponding rates of complete response were 15%, 14% and 11%. Grade 4 neutropenia was common in all arms (81%) and, together with febrile neutropenia, was significantly more frequent with the combination. Prophylaxis with ciprofloxacin did not reduce the incidence of febrile neutropenia or infection. Other frequent non-hematological adverse events included alopecia, nausea, vomiting, stomatitis and asthenia. Congestive heart failure only occurred in the combination arm (10%). Conclusion: All three schedules are feasible and endowed of good therapeutic activity. In view of the more pronounced toxicity and the risk of cardiac events because of the higher exposure to doxorubicin, the combination should be least favored when treating women with metastatic breast cancer. Prophylaxis with ciprofloxacin was ineffective and is not recommended.