ASCO--Anthracycline-based chemotherapy should join tamoxifen(Drug information on tamoxifen) (Nolvadex) as standard therapy for postmenopausal breast cancer patients who have positive lymph nodes and are estrogen-receptor positive.
The assessment came from the lead author of a study that showed significant improvement in disease-free survival in patients treated with tamoxifen plus an anthracycline-containing chemotherapy regimen, as opposed to tamoxifen alone.
"CAF plus tamoxifen significantly delays the time to failure, compared to tamoxifen alone in postmenopausal women with node-positive, receptor-positive disease," said Kathy Albain, MD, of the Cardinal Bernadin Cancer Center of Loyola University Medical Center.
No major subset could be identified that was not impacted favorably by the addition of CAF to tamoxifen, and the benefit remained significant after adjustment for important prognostic factors.
The findings came from a multicenter randomized trial that involved almost 1,500 postmenopausal breast cancer patients. In each patient, the cancer had spread to one or more lymph nodes. All the patients were positive for estrogen receptors, and about 80% were proges-terone-receptor positive.
"In 1988, when this trial was designed, standard treatment for this subset of patients was tamoxifen for 2 to 5 years," Dr. Albain said. "CMF-like regimens added to tamoxifen did no better than tamoxifen alone in most individual trials."
Three different trials had suggested a benefit of adding anthracycline-based chemotherapy for receptor-negative postmenopausal women or for subsets with four or more positive nodes, she said. However, in 1988, no data were available on the potential survival benefit of adding anthracyclines to treatment of a pure hormone-responsive, node-positive subset. Furthermore, some investigators have been reluctant to use anthracyclines in postmenopausal women who might be more susceptible to their cardiac effects.
The study included patients who had undergone mastectomy for T1-3 cancer or breast conservation for T1-2. None had distant metastases. Patients with cardiac disease were excluded.
The Three Treatment Arms
The trial comprised three treatment arms: 361 patients were randomized to receive tamoxifen at a dose of 20 mg daily for five years, and 1,109 were randomized to chemotherapy with either concurrent or sequential tamoxifen.
Chemotherapy consisted of cyclophosphamide(Drug information on cyclophosphamide) (100 mg/m² PO × 14 days), doxorubicin(Drug information on doxorubicin) (30 mg/m² IV on days 1 and 8), and fluorouracil(Drug information on fluorouracil) (500 mg/m² IV on days 1 and 8) for six cycles. Radiation therapy was initiated either before or at the completion of chemotherapy or before the start of tamoxifen in patients who did not receive chemotherapy.
The primary objectives of the trial were to determine whether the addition of anthracycline-based chemotherapy improves survival; whether CAF followed by tamoxifen is superior to CAF and concurrent tamoxifen; and whether toxicity differed among the treatment groups.
At a second interim analysis, the trial was approved for early reporting because one of the major objectives (tamoxifen alone vs tamoxifen plus chemo) had reached a significant difference. The chemotherapy arms were combined for analysis, since the data to answer the sequential tamoxifen question were not mature.
Four-Year Disease-Free Survival
Patients randomized to chemotherapy plus tamoxifen had an estimated four-year disease-free survival of 79% vs 72% for tamoxifen alone (P = .001). The superiority of combined treatment persisted in the major stratification subsets: number of positive nodes, age, and PR status. Overall survival did not differ (about 85% in both groups). "It's too early to tell whether there will be an overall survival benefit because there have been too few events to date," she said.
As expected, the addition of chemotherapy was associated with increased toxicity. However, the incidences of cardiotoxicity and thromboembolic events were low, and no increased risk of endometrial cancer was observed.
Asked if she would now recommend anthracycline-based chemotherapy for this subset, Dr. Albain responded, "I would as long as they meet the same eligibility criteria as in this study."