We applaud the authors for pursuing the interesting hypothesis that estrogens may enhance the activity of chemotherapy in prostate cancer.
Unlike these authors, we did not find evidence of activation of coagulation with transdermal estradiol therapy.1 It is possible that this difference was due to differences in pharmacokinetics of the intramuscular and transdermal formulation. Other explanations should also be considered. As the authors do not report the results of their assays in control groups of patients treated with intramuscular estradiol valerate alone or chemotherapy alone, it is difficult to ascertain whether the observed changes in measures of coagulation were indeed related to estradiol or to the combination with chemotherapy. Clearly, further study is necessary to more robustly characterize the effects of parenteral estrogens on coagulation.
We would caution against making the assumption that biochemical evidence of coagulation activation can be used as a surrogate for thromboembolic complications. Evidence for this assumption is lacking. For example, in a prospective observational study that involved 21,690 participants, elevated D-Dimers were associated with an increased risk of subsequent venous thrombosis in the general population, but in patients with cancer, D-Dimer levels did not predict future venous thrombosis.2 Furthermore, we caution against the use of anticoagulation therapy based on biochemical evidence of coagulation activation alone. Before such clinical approaches can be recommended, a surrogacy relation between specific changes in biochemical markers of coagulation and specific adverse clinical outcomes needs to be established in prospective clinical trials. Then, the safety and efficacy of anticoagulation therapy administered on the basis of biochemical evidence of coagulation activation must be prospectively tested.
We share the authors' enthusiasm for further studies of estrogen-based prostate cancer therapy. Based on preclinical evidence that diethylstilbestrol specifically inhibits the expression of beta-tubulin Type IVa, an isotype that is thought to mediate taxane resistance3–5 and improves efficacy of docetaxel in a xenograft model6 we joined Dr. Bruce Montgomery of the University of Washington to investigate the safety and efficacy of diethylstilbestrol with docetaxel in androgen-independent prostate cancer.
We also believe that the greatest promise of parenteral estrogens may lie in front-line hormonal therapy for prostate cancer. To this end, we are developing a double-blind randomized trial that will compare transdermal estradiol to conventional androgen deprivation in the initial hormonal management of prostate cancer.