Stage IV Prostate Cancer
In some series, pretreatment levels of PSA are inversely correlated with progression-free duration in patients with metastatic prostate cancer who receive hormonal therapy. After hormonal therapy is instituted, reduction of PSA to undetectable levels provides information regarding the duration of progression-free status; however, decreases in PSA of less than 80% may not be very predictive. Orchiectomy and estrogens yield similar results, and selection of one or the other depends on patient preference and the morbidity of expected side effects. Estrogens are associated with the development or exacerbation of cardiovascular disease, especially in high doses. Diethylstilbestrol (DES) in a dose of 1 mg per day is not associated with cardiovascular complications as frequent as those found at higher doses; however, the use of DES has decreased because of cardiovascular toxic effects, and DES is no longer commercially available in the United States. The psychological implications of orchiectomy are objectionable to many patients, and many will choose alternative therapy if effective. Combined orchiectomy and estrogens are not indicated to be superior to either treatment administered alone.
Approaches using LHRH agonists and/or antiandrogens in patients with stage IV prostate cancer have produced response rates similar to standard hormonal treatments.[17,18] In a randomized trial, the LHRH analog leuprolide (1 mg subcutaneously every day) was found to be as effective as DES (3 mg orally every day) in any T, any N, M1 patients but caused less gynecomastia, nausea and vomiting, and thromboembolisms. In other randomized studies, the depot LHRH analog goserelin was found to be as effective as orchiectomy [20,21,22] or DES at a dose of 3 mg per day. A depot preparation of leuprolide, which is therapeutically equivalent to daily leuprolide, is available as a monthly or 3-monthly depot. Castration has been shown to be superior to monotherapy with bicalutamide. A small randomized study comparing 1 mg of DES orally 3 times per day to 250 mg of flutamide 3 times per day in patients with metastatic prostate cancer showed similar response rates with both regimens but superior survival with DES. More cardiovascular and/or thromboembolic toxic effects of borderline statistical significance were associated with the DES treatment.[Level of evidence: 1iA] A variety of combinations of hormonal therapy have been tested.
On the basis that the adrenal glands continue to produce androgens after surgical or medical castration, case series studies were performed in which antiandrogen therapy was added to castration. Promising results from such case series led to widespread use of the strategy, known as maximal androgen blockage (MAB) or complete androgen blockade. Subsequent randomized controlled trials, however, cast doubt on the efficacy of adding an antiandrogen to castration. In a large, randomized controlled trial comparing treatment with bilateral orchiectomy plus either the antiandrogen flutamide or placebo, no difference in OS was reported.[Level of evidence: 1iA] Although it has been suggested that MAB may improve the more subjective end point of response rate, prospectively assessed quality of life was worse in the flutamide arm than in the placebo arm, primarily because of more diarrhea and worse emotional function in the flutamide-treated group.[Level of evidence: 1iC] A meta-analysis of 27 randomized trials of 8,275 patients comparing conventional surgical or medical castration to MAB-castration plus prolonged use of an antiandrogen such as flutamide, cyproterone acetate, or nilutamide-did not show a statistically significant improvement in survival associated with MAB.[Level of evidence: 1iA]