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A Detailed Evaluation of Cardiac Toxicity

A Phase II Study of Doxorubicin and One- or Three-Hour-Infusion Paclitaxel in Patients with Metastatic Breast Cancer¹

Departments of Breast Medical Oncology [S. H. G., D. J. B., N. K. I., Z. U. R., V. V., R. L. T., M. F. R., E. R., D. F., A. U. B., G. N. H.], Bioimmunotherapy [J. L. M.], Internal Medicine Specialties [M. E.], and Pathology [N. G. O.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Purpose: This Phase II study was designed to determine the efficacy and toxicityof 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.

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