Hormone-refractory prostate cancer? Anti-androgen withdrawal and intermittent hormone therapy

Objective: To separate hormone-dependent from hormonally relapsed prostate cancers, a D3 category has been proposed. The term has become synonymous with a hormone-refractory state with the implication that any further hormonal treatment would not be beneficial. In this review we examine some data on androgen receptor expression, anti-androgen withdrawal syndrome and intermittent androgen deprivation (IAD) in patients with advanced prostate cancer. Materials: The literature on the mechanism of the withdrawal phenomenon in patients with prostate cancer submitted to hormone therapy was reviewed. Experimental and clinical data are reported. Results. The progression of prostate cancer in patients treated with combined androgen blockade (CAB) is associated with the activation of previously androgen-repressed genes, some of which may code for autocrine and paracrine growth factors that substitute for androgens in maintaining the viability of the tumorigenic stem cells. If androgens are replaced before progression begins, the surviving stem cells should give rise to an androgen-dependent tumor, which would be amenable to retreatment by CAB. This theory provides the rationale for intermittent androgen deprivation. We suggest that IAD could be more effective in patients with initial prostate-specific antigen (PSA) progression after radical prostatectomy. Conclusions: Response to withdrawal therapies or second-line treatments is an example of a "hormonal" therapy that may benefit a proportion of patients with hormone-refractory disease, suggesting that the tumor is still androgen-dependent, Whether IAD enhances progression-free survival or overall survival must be verified in randomized clinical trials. Until further studies have been completed, the therapeutic concept of IAD should be treated as experimental.