Physicians have known since 1941 that testosterone suppression benefits patients with symptomatic metastatic prostate cancer.[1] The pioneering study in this regard showed that estrogen therapy achieved comparable efficacy to castration by improving acid and alkaline phosphatase levels associated with relief of cancer-related symptoms. More than 6 decades later, however, many of the therapies subsequently developed for achieving androgen deprivation still suffer from serious limitations.
Although effective, estrogen therapy carried significant cardiovascular toxicity that severely limited its utility. Specifically, a series of Veterans Administration Cooperative Urological Research Group studies raised serious concerns regarding cardiac morbidity and mortality in patients receiving diethylstilbestrol(Drug information on diethylstilbestrol) (DES).[2,3] The most commonly used estrogenic agent for achieving medical castration, DES inhibits luteinizing hormone-releasing hormone (LHRH) through negative feedback on the hypothalamus-pituitary axis.
In the 1960s and 1970s, research into antiandrogenic compounds culminated in the development of several agents that block the testosterone receptor while producing minimal side effects.[4,5] Although monotherapy with steroidal antiandrogens, including cyproterone acetate, megestrol acetate, and medroxyprogesterone(Drug information on medroxyprogesterone) acetate, produce side effects including impotence and libido loss, nonsteroidal antiandrogens such as flutamide(Drug information on flutamide), nilutamide (Nilandron), and bicalutamide(Drug information on bicalutamide) (Casodex) avoid these problems because they act only at the androgenic receptors. Nevertheless, oncologists generally do not consider antiandrogens to be an optimal choice for metastatic prostate cancer because these agents are perhaps less effective than both orchiectomy and the therapeutic class that superseded antiandrogens, LHRH agonists.[6]
Advantages and Disadvantages of LHRH Agonists
Introduced in the United States in 1984,[7] LHRH agonists essentially deplete the pituitary hormone and downregulate pituitary LHRH receptors, rendering the pituitary nonresponsive to further stimulation by LHRH. Currently available LHRH agonists include leuprolide, goserelin (Zoladex), buserelin(Drug information on buserelin), and triptorelin(Drug information on triptorelin) (Trelstar). Available in various formulations, these drugs are administered via depot injections that last as long as 12 months.
However, disadvantages of LHRH agonists include high repeating costs, libido loss, impotence, and hot flashes. Importantly, the testosterone surge that occurs after initial injection of LHRH agonists can cause tumor flare in up to 63% of patients with advanced disease.[8] In certain men with advanced prostate cancer, these flares are accompanied by pain and serious side effects that can include urethral obstruction and spinal cord compression, which can lead to paralysis and, rarely, death.[9] Accordingly, oncologists frequently administer short-term or long-term antiandrogens to prevent testosterone surge in patients taking LHRH agonists.
The goal of this activity is to clarify challenging treatment issues of HER2+ breast cancer including incorporation of predictive and prognostic biomarker tests and evidence-based data into practice when determining individualized strategies that improve patient survival and quality of life.
