A detailed evaluation of cardiac toxicity: A phase II study of doxorubicin and one- or three-hour-infusion paclitaxel in patients with metastatic breast cancer

Purpose: This Phase II study was designed to determine the efficacy and toxicity of combination doxorubicin and paclitaxel as front-line treatment for metastatic breast cancer. Experimental Design: Eligible patients had no prior anthracycline or taxane therapy and normal cardiac function. They were treated with bolus doxorubicin 60 mg/m², followed by paclitaxel 200 mg/m², as either 1- or 3-h infusions for six to seven cycles. Single-agent paclitaxel was continued thereafter. Serial multiple gated acquisition scans were performed, and endomyocardial biopsies were performed for consenting patients. Results: Eighty-two patients were enrolled with a median age of 53 years (range, 32-78 years). Of 79 evaluable patients, 58.2% had an objective response (3.8% complete response + 54.4% partial response), 34.2% had stable disease, and 7.6% had progressive disease. With median follow-up of 37.5 months, median time to progression was 7 months; median survival was 31 months. Multiple gated acquisition scans were performed in 82 of 82 patients at baseline, 75 of 82 patients at a total doxorubicin dose of 60-180 mg/m², 62 of 68 patients at 200-300 mg/m², 18 of 52 patients at 310-360 mg/m², and 4 of 8 patients at 420 mg/m². Median ejection fractions were 62.5, 60, 57.5, 52.5, and 32%, respectively. Fifteen of 82 (18.3%) patients had a decrease in ejection fraction ≥15% to an absolute ejection fraction ≤50%. Eight of these 15 patients (53%) developed clinical congestive heart failure: 4 of 8 (50%) who received a total doxorubicin dose of 420 mg/m² versus 4 of 74 (5.4%) who received a dose ≤360 mg/m² (P = 0.002). Conclusions: When the doxorubicin dose exceeds 360 mg/m², the combination of bolus doxorubicin and paclitaxel presents unacceptable cardiac risk.