CEF Maintains Advantage Over CMF at 10 Years

SAN ANTONIO—A 10-year update of Canada’s MA.5 trial has found a continuing survival advantage for node-positive premenopausal breast cancer patients treated with adjuvant cyclophosphamide/epirubicin (Ellence)/fluorouracil (5-FU) (CEF) vs those given classic cyclophosphamide/methotrexate/5-FU (CMF).

Kathleen I. Pritchard, MD, head of Clinical Trials and Epidemiology at Toronto-Sunnybrook Regional Cancer Centre, reported the 10-year results at the 25th Annual San Antonio Breast Cancer Symposium (abstract 17).

710 Patients

The National Cancer Institute of Canada Clinical Trials Group MA.5 trial, which began in 1989, involves 710 pre- or perimenopausal women with early-stage breast cancer who had undergone radical mastectomy or lumpectomy with axillary dissection and who had one or more positive nodes.

The patients were randomized to classic CMF (cyclophosphamide, 100 mg/m2 orally days 1 to 14; methotrexate, 40 mg/m² IV days 1 and 8; and 5-FU, 600 mg/m² IV days 1 and 8) or CEF (cyclophosphamide, 75 mg/m² orally days 1 to 14; epirubicin, 60 mg/m² IV days 1 and 8; and 5-FU, 500 mg/m2 IV days 1 and 8). The CEF arm included antibiotic prophylaxis with daily cotrimoxazole. Both regimens were administered over six 4-week cycles.

Patients who had undergone lumpec-tomy received breast irradiation at the completion of chemotherapy; locore-gional radiation was not permitted. Tamoxifen (Nolvadex) was not part of the study protocol, Dr. Pritchard said, and the vast majority of patients did not receive it.

Study Results

At a median follow-up of 59 months, the researchers found a statistically significant improvement in disease-free survival and in overall survival for CEF, compared with CMF.

The 5-year disease-free survival rates were 63% for patients treated with CEF vs 53% for those treated with CMF. Overall 5-year survival was 77% for CEF vs 70% for CMF (J Clin Oncol 16:2651-2658, 1998).

At the 5-year mark, five patients in the CEF group had developed acute leukemia, and one patient in the CMF group had experienced congestive heart failure.

Ten-Year Results

At a median follow-up of 106 months, 162 CEF patients had experienced a breast cancer recurrence, compared with 201 patients in the CMF group. There had been 131 deaths in the CEF arm vs 153 in the CMF arm.

"The 10-year disease-free survival for CEF is 52% vs 45% for CMF—a statistically significant difference," Dr. Pritchard reported. "The hazard ratio for CMF compared to CEF is 1.31."

The researchers also analyzed the data according to lymph node status, Dr. Pritchard said. Among women with one to three positive nodes, the 10-year disease-free survival was 60% in the CEF group vs 56% in the CMF group. For patients with four or more positive nodes, 10-year disease-free survival rates were 40% and 28%, respectively.

Dr. Pritchard noted that the benefits of CEF were seen in both estrogen-receptor (ER)-positive and ER-negative tumors. Among the ER-negative patients, 10-year disease-free survival rates were 55% with CEF and 47% with CMF. In the ER-positive subgroup, 10-year disease-free survival rates were 50% and 42%, respectively. She added that perhaps because tamoxifen was not required in this study, these results are somewhat different from what may be seen in other trials of adjuvant therapy. Overall 10-year survival rates for women treated with CEF vs CMF were 62% vs 58%, respectively, with a hazard ratio of 1.18.

At the 10-year mark, one patient in the CMF group had developed leukemia (total of one patient), and no additional cases of leukemia had developed in the CEF group (total of five patients). Four cases of congestive heart failure had developed among the CEF-treated patients (total of 4 patients), and no additional cases had arisen in the CMF-treated group (total of one patient).

"In conclusion, the previously demonstrated benefits of CEF over CMF adjuvant chemotherapy have been maintained with longer follow-up," Dr. Pritchard said. "Benefits are seen and appear to be similar in the one-to-three and four-plus nodal subgroups and in women with ER-positive and ER-negative tumors."