Radiation Therapy and Tamoxifen: Concurrent or Sequential? That Is the Question

Randomized controlled trials have had an important impact on the treatment of women with early breast cancer. Many women routinely receive breast-conserving surgery plus radiation therapy, adjuvant chemotherapy, or hormonal therapy based on the results of randomized trials. However, despite the extensive use of combinations of chemotherapy, hormonal therapy, and radiation therapy, the optimal sequencing of these different adjuvant treatments for patients with early breast cancer remains unclear. Unfortunately, there have been few randomized trials addressing this important issue. In a randomized trial by Recht et al, 1 the optimal sequencing of radiation and chemotherapy in patients treated with breast-conserving surgery was evaluated. Of 244 patients, 122 were allocated to receive radiation therapy before anthracycline-based chemotherapy and 122 were allocated to receive radiation therapy after the same chemotherapy. The median length of follow-up was 58 months. Although the study was relatively small by today’s standards, there was a trend for an increased risk of distant recurrence for patients treated with radiation therapy first (36% v 25%; hazard ratio HR, 1.62; 95% CI, 1.01 to 2.62;P .05). As a result, breast irradiation is now usually given after anthracycline-based chemotherapy. In early 1990s, investigators from the North American Breast Intergroup conducted a randomized trial in postmenopausal women with node-positive, hormone receptor–positive breast cancer, which compared tamoxifen, administered concurrently with cyclophosphamide, doxorubicin, and fluorouracil (n 550) with tamoxifen given after the completion of the same chemotherapy (n 566). 2 This was an important clinical question because there was some concern that the cytostatic effect of concurrent tamoxifen might interfere with the cytotoxic effects of chemotherapy on cancer cells. Preclinical data had demonstrated that human breast tumor cells in culture pretreated with tamoxifen were protected from the cytotoxicity of chemotherapy. 3 This concern was not shared by all investigators; several cooperative groups recommended the concurrent use of chemotherapy and tamoxifen in trials evaluating these agents. Furthermore, it had already been observed that combined chemotherapy and tamoxifen increased the risk of thromboembolic complications in patients. 4 With a median follow-up of 8.5 years, the results of the Intergroup study were presented at the 2000 American Society of Clinical Oncology Annual Meeting. The 8-year disease-free survival estimates were 67% for patients treated with sequential chemotherapy and tamoxifen compared with 62% for patients treated with concurrent chemotherapy and tamoxifen (P .05). 2 This study led to important