Intermittent Complete Androgen Blockade in Metastatic Prostate Cancer

Introduction: Intermittent hormonal treatment of prostate cancer was first developed based upon experimental study results. Using the Shionogi mouse breast cancer model, it was shown that the tumor grows rapidly in the presence of androgens, then undergoes apoptotic regression when androgens are removed. This apoptotic potential can be reinduced several times by cyclic replacement and withdrawal of androgens. These results led to the concept being evaluated in clinical trials. Method: In most of the clinical studies a protocol is used in which the patient receives 36 weeks of androgen deprivation. For those patients whose prostate-specific antigen (PSA) drops to less than 4 ng/ml within 32 weeks of therapy, the androgen withdrawal is stopped at 36 weeks, and not reintroduced until PSA increases to 20 ng/ml. This cycle is then repeated until the patient's tumor becomes hormone-sensitive. Results: Akakura et al. in 1993, reported on 7 patients who had a total of 12 episodes off-hormone therapy after achieving PSA complex remission, with further response after each re-exposure. Bruchovsky et al. in 1997, reported on 47 patients who entered a study of intermittent hormone therapy to evaluate the effect of cyclic withdrawal and replacement therapy in 14 D2, 10 D, 19 C, 2 B2, 2 A2 patients. Treatment was initiated with combined androgen blockade and continued for at least 6 months until a serum PSA nadir was observed. The first two treatment cycles lasted 73 and 75 weeks, with a mean time-off therapy of 30 and 33 weeks and an overall mean percentage time-off therapy of 41 and 45%. Serum testosterone returned to the normal range within 8 weeks (range: 1-26 weeks) of stopping treatment. The off-treatment period in both cycles was associated with an improvement in sense of well-being, and the recovery of libido and potency in the men who reported normal or near-normal sexual function before the start of therapy. In 7 patients with stage D2 disease, the cancer progressed to an androgen-independent state. The mean and median times to progression were 128 and 108 weeks. Seven patients died, one from a non-cancer-related illness, with mean and median overall survival times of 210 and 166 weeks. Conclusion: These studies demonstrated that the androgen-dependent state of prostate cancer can be maintained during a course of intermittent androgen suppression, supporting the possibility of multiple apoptotic regressions under well-regulated conditions. Oliver et al. in 1997, conducted a retrospective study of 20 patients and concluded that intermittent androgen deprivation reduced induction of hormone-resistant prostate cancer, with no acute or major risk associated with the use of intermittent androgen suppression. More clinical studies are required to clarify the indication for intermittent hormone therapy and evaluate improvement in quality of life and survival. In the future, approaches to the improvement of therapeutic apoptosis could include intermittent hormone therapy, associated with additive cytotoxic therapeutic strategies.