Chemoendocrine therapy with prolonged estrogen priming in advanced breast cancer: endocrine pharmacokinetics and toxicity

Abstract

Recent efforts to improve response rates in advanced breast cancer have used short, alternating courses of antiestrogen therapy followed by estrogen priming to cytokinetically enhance tumor cell sensitivity to antimetabolites. Based on recent in vitro and in vivo studies, we have introduced a chemoendocrine regimen that uses prolonged courses of estrogen priming. The present protocol consists of alternating monthly cycles of tamoxifen (TAM) and estradiol during which sequential (24-hr) methotrexate, 5-fluorouracil, and leucovorin are administered at 2-week intervals. Twenty-five patients with metastatic breast cancer received greater than 80 endocrine cycles and greater than 300 courses of chemotherapy by this protocol; two-thirds of these patients had previously failed other endocrine or chemotherapy regimens. Most patients experienced grade 1 or 2 myelosuppression or gastrointestinal symptoms during at least one treatment cycle; however, overall toxicity was considered to be mild and therapy was very well tolerated. Serum levels of estradiol, estrone, TAM, and TAM metabolites were measured during all phases of the endocrine cycle in five patients on chronic therapy. Concentrations of TAM and its more abundant metabolite, N-desmethyltamoxifen (N-desTAM), rose twofold during antiestrogen therapy and fell during estrogen priming, with mean levels persisting greater than 100 ng/ml throughout the priming interval. Mean estradiol (E2) and estrone (E1) levels rose during priming and were sustained fivefold and tenfold above the basal postmenopausal levels measured during antiestrogen treatment. Calculating the serum molar ratios of [TAM + N-desTAM]/[E2 + E1] during each phase of the treatment cycle confirmed that estrogen priming was achieved pharmacologically by this endocrine schedule. Clinical remissions were observed in this small patient sample with seven of 18 patients achieving either complete (28%) or partial (11%) responses, and an additional 39% obtaining disease stabilization. Further clinical study is necessary to evaluate the optimal response rate of this regimen and to determine whether cyclic estrogen priming by this schedule results in enhanced tumor cell proliferation in vivo.