Health and Prostate

Megestrol acetate has several mechanisms of action that suggest a potential beneficial role in treating progressive metastatic prostate cancer. It inhibits the release of luteinizing hormone, 5 a-reductase conversion of testosterone to dihydrotestosterone, binding of androgen to its receptor, and at high doses may be cytotoxic. Based on clinical reports that suggest a dose-response effect, Dawson et al. studied two doses for the CALGB (160 mg versus 640 mg). The prostate-specific antigen response was only 12%, however, with no dose effect and no association with prior response to antiandrogen withdrawal. An unexpected tumor flare was observed in some patients, suggesting that megestrol acetate had agonistic activity. There was a similar low response rate reported in a smaller retrospective study.

The palliative benefit of both estrogens and orchiec-tomy in the treatment of advanced prostate cancer was first reported in 1941, by Huggins and Hodges. In the setting of hormone-sensitive disease, the inhibitory effect of estrogen is due to suppression of pituitary gonadotropins and in turn testosterone. Additionally, estrogens have been shown experimentally to be cytotoxic in a hormone-resistant prostate model and against the PC-3 and DU 145 prostate cancer cell lines. Estrogens, primarily in the form of diethylstilbestrol (diethylstilbestrol) were used as the primary form of medical castration until the 1980s, when their thromboembolic and cardiac toxicities caused them to be generally abandoned in favor of the newer and equally efficacious luteinizing hormone-releasing hormone-analogues. However, high-dose estrogen therapy retains a potential role in the therapy of androgen-insensitive disease.

In 1952, Hertz first reported the beneficial effects of intravenously conjugated estrogens and diethylstilbestrol sulfate in patients with hormone-refractory prostate cancer. Subsequently, Flocks et al. reported on 34 men with refractory disease treated with diethylstilbestrol diphosphate (diethylstilbestrol-DP, diethylstilbestrol-P, Stilphostrol, Honvan, Fosfestrol) , The diethylstilbestrol-DP is an inactive estrogen that is dephosphorylated in vivo to diethylstilbestrol. It is water soluble and can therefore be administered intravenously in large doses. Using doses of 250 to 1250 mg given daily as a short IV infusion for 5 to 20 days, subjective benefit was noted in 21 of 27 men with prior estrogen therapy and in 5 of 7 men with both previous estrogen therapy and orchiectomy. There were three objective responses. In 1993, Droz et al. reviewed the results of six subsequent phase II trials of diethylstilbestrol-DP involving 139 patients (130 hormone-refractory) and found no measurable tumor responses. There was a > 50% reduction in prostatic acid phosphatase in 37 of 99 assessed patients, and subjective benefit occurred in 74 men. The doses in these studies ranged from 0.5 to 4.0 grams per day administered intravenously for 7 to 10 days. The cardiovascular toxicity was 5%. The median survival was only 5 months.

TABLE. Secondary Hormonal Manipulation: Addition of Megestrol Acetate

TABLE. Oncologists First Choice of Second-Line Hormone Therapy

The apprehension in using estrogen therapy is primarily related to concerns about cardiovascular toxicity in an elderly population. In two trials by the European Organization for Research on Treatment of Cancer (EORTC) that used oral diethylstilbestrol at a standard dose of 3 mg per day, there was lethal cardiovascular toxicity in 11% of 185 men. Risk factors were identified and included older age, weight > 75 kg, and prior cardiovascular disease. Although concomitant use of aspirin seems warranted as prophylaxis, in two randomized trials comparing goserelin to diethylstilbestrol, aspirin apparently did not protect against the excess cardiovascular toxicity of diethylstilbestrol. However, in these studies, aspirin was not evaluated in a randomized fashion. Other common side effects of estrogen therapy include nausea, vomiting, weight gain, edema, and gynecomastia. Abnormal liver function tests are less common.