Combining endocrine agents with chemotherapy: which patients and what sequence?

In metastatic breast cancer, attempts to improve response to therapy by combining hormones and chemotherapy began in the 1970s. Since then, several randomized trials comparing single-agent hormone therapy or chemotherapy versus sequential combinations of these agents have been performed. In the majority of those studies, an increased response rate or an increased time to progression was observed when chemotherapy was added to hormone therapy or when hormone therapy was added to chemotherapy. However, in few of those trials was the increased response rate statistically significant or the response duration significantly prolonged, and no studies reported an improvement in overall survival. Furthermore, the studies did not make the correct comparisons of 1) hormone therapy alone followed by chemotherapy alone versus hormone therapy and chemotherapy given concurrently or 2) chemotherapy alone followed by hormone therapy versus concurrent chemotherapy and hormone therapy. To truly be advantageous, concurrent treatment should provide an increased response rate and response duration compared with the added or overall response rate and response duration of the same agents used sequentially. In the adjuvant setting, the timing and sequencing of hormone therapy and chemotherapy also has not been studied well. However, it has been accepted widely that adjuvant chemotherapy should be completed before beginning tamoxifen. No trials examining concurrent versus sequential treatment have been performed with hormone therapy and chemotherapy in the premenopausal setting or with aromatase inhibitors and chemotherapy in postmenopausal women. Considering the demonstrated importance of the timing of chemotherapy and tamoxifen in the postmenopausal setting, these questions should be explored further.