Basis for hormonal management of advanced prostate cancer

In the early 1940s, when it was established that most prostatic cancers were androgen dependent and could be controlled by androgen withdrawal, little was known about the mechanism of androgen action. Measurements of hormones, both in the circulation and in the tissue, were not available, nor were measurements of androgen receptors known at that time.

Since that time, a large body of information has been published regarding the mechanism of androgen-mediated action. With the understanding of androgen-mediated action has come the opportunity to develop drugs targeted to block specific steps in the sequence of androgen action, beginning in the hypothalamus-pituitary area and extending down to the intracellular processes of enzymatic reduction, receptor binding, and nuclear translocation of the hormone receptor complexes. The major focus in prostate cancer therapy currently is the role of the adrenal androgens.

It was established in the 1970s that, after castration, there was a 75% reduction in the dihydrotestosterone (DHT) present in prostate tissue. This observation contrasted with the finding that there was a greater than 90% reduction in circulating testosterone levels in the plasma after castration. Based on this important observation regarding tissue DHT concentrations after castration, attempts were made in the 1980s to block androgen totally using simultaneous gonadal and adrenal suppression. Dramatic results were reported after this type of therapy in the early uncontrolled studies. A luteinizing hormone-releasing hormone agonist plus flutamide was used for total androgen blockade. Other techniques for such blockade were available using megestrol acetate in combination with 17-beta-estradiol. One of the key issues has been whether the 25% residual DHT after castration provides a sufficient stimulus to growth of residual prostate tumor cells. The best evidence for the importance of the role of adrenal androgens came from clinical studies in which objective clinical responses were found in patients treated with various inhibitors of androgen action after relapse and castration. If "objectively stable" is included as a category after treatment, then approximately 33% of patients who have relapses after castration can be shown to have an additional response, albeit short, to adrenal androgen withdrawal.

Thus, the control of the relatively small amounts of DHT remaining after castration became a major focus for therapy in metastatic prostate cancer.