Androgen deprivation is one of the most effective therapies against any solid tumor; unfortunately, with time almost all prostate cancers will become androgen refractory. All current forms of androgen-deprivation therapy (ADT) function by either lower levels of circulating androgens or blocking the binding of androgen to the androgen receptor. All most all androgen-refractory prostate cancer remains sensitive to androgen; therefore ADT should be continued in castration-resistant disease. Relative to testosterone and dihydrotestosterone, the adrenal androgens are weak. There are four general forms of ADT: (1) ablation of androgen sources; (2) inhibition of androgen synthesis; (3) antiandrogens; and (4) inhibition of LH-RH and/or LH. Bilateral orchiectomy reduces testosterone by 90% within 24 hours of surgery. Nonsteroidal antiandrogens cause LH and testosterone levels to increase. Serious liver toxicity is a possible side effect of all antiandrogens. Antiandrogens can act agonistic on some tumors; antiandrogen withdrawal results in PSA declines in 15% to 30% of patients. Bicalutamide 150 mg monotherapy appears to have equivalent efficacy to medical or surgical castration for locally advanced or metastatic prostate cancer. All LH-RH agonists induce a testosterone increase on initial exposure. Coadministration of an antiandrogen functionally blocks the effects of testosterone. The magnitude and rapidity of the initial response to ADT are strong predictors of the durability of that response. The side effects of ADT include osteoporosis, hot flashes, sexual dysfunction, cognitive function alterations, changes in body habitus, gynecomastia, and anemia. These side effects can be progressive but are responsive to other treatments. There is no evidence 3 months of neoadjuvant ADT before radical prostatectomy improves biochemical outcomes. There is considerable evidence that ADT combined with external-beam radiation therapy improves overall survival, cancer-specific survival, and freedom from disease progression. The optimal timing and duration of ADT in this combination remains undefined. Based on a large meta-analysis of many clinical trials, combined androgen blockade with nonsteroidal antiandrogens provides about a 3% survival benefit at 5 years compared with standard ADT. The natural history of prostate cancer progression is protracted. Many men with evidence of disease will never require ADT. The use of ADT in low-risk, localized prostate cancer significantly increases overall (non–prostate cancer) mortality. In lymph node metastatic prostate cancer ADT improves overall survival if the primary tumor is removed but has no significant effect if the primary tumor is not removed.
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