A Randomized Trial of Adjuvant Chemotherapy and Tamoxifen Timing in Postmenopausal, Endocrine-Responsive, Node- Positive Breast Cancer

The most common presentation of breast cancer is an estrogen receptor-positive (ER+) tumor in postmenopausal women, for whom tamoxifen is the gold standard against which other systemic adjuvant treatments are compared.(1–4) Whether to add chemotherapy to endocrine therapy is attractive in theory(5), but there is no consensus regarding such treatment in postmenopausal women with tamoxifen-responsive disease.(3,4) Individual phase III trials that compared chemotherapy plus tamoxifen versus tamoxifen alone did not show a significant survival benefit in older women.(6–9) A recent meta-analysis of all existing trials based on individual patient data found that the addition of chemotherapy to tamoxifen is only marginally beneficial in older women, in contrast to major survival improvements in premenopausal populations (see Figure 4, reference 10 for the EBCTCG metaanalysis) Figure 4 Southwest Oncology Group trial SWOG-8814 (North American Breast Intergroup 0100) forest plots of hazard ratios and 95% confidence intervals for major subsets for disease-free survival. Panel A describes the disease-free survival advantage for chemotherapy ... Most individual trials in postmenopausal women tested the addition of regimens based on cyclophosphamide, methotrexate and 5-fluorouracil (CMF) to tamoxifen(3,4, 6–8, 10), but in certain breast cancer study populations, CMF may be inferior to anthracycline-based regimens(11–16). No clinical trials have shown, however, that anthracycline-based therapy adds to the benefit of tamoxifen specifically in postmenopausal patients with ER+ disease. Moreover, interference with drug-induced cytotoxicity has been found in vitro when tamoxifen is added to cancer cell lines concurrently with chemotherapy(17–20), yet concurrent tamoxifen and CMF has been a common practice in clinical trials. Our two objectives were to determine if chemotherapy, consisting of 6 months of cyclophosphamide, doxorubicin (AdriamycinR), and 5-fluorouracil (CAF) plus 5 years of tamoxifen, was superior to tamoxifen alone; and to assess if CAF followed by tamoxifen was better than CAF plus concurrent tamoxifen. The CAF program we used was the most dose-intense combination among the commonly used regimens when this trial was designed.(11) This report presents 10-year outcomes for both objectives.