Innovative approaches to the hormonal treatment of advanced prostate cancer

Androgen ablation therapy is the treatment of choice for the palliation of patients with advanced prostate cancer. In addition to palliation, maximal androgen ablation (MAA), with a combination of medical or surgical castration and an antiandrogen, has been shown to increase the survival of patients with metastatic prostate cancer in at least three large well-conducted trials. A subgroup analysis of these trials has suggested that patients, particularly those with low volumes of metastatic disease, fared much better when treated with MAA than with castration alone. This observation has prompted many clinicians to begin androgen ablation earlier in men with advanced but not necessarily metastatic prostate cancer, thus exposing them to prolonged periods of androgen ablation and its side effects. These include impotence, loss of libido, loss of muscle mass, malaise, and psychological disturbances. In order to offer the putative advantages of early hormone therapy but to mitigate its side effects a number of innovative methods of androgen ablation are under investigation. These include 'sequential androgen blockade' and 'intermittent androgen suppression'. Sequential androgen blockade uses a 5 alpha-reductase inhibitor to reduce the conversion of testosterone to dihydrotestosterone in conjunction with an antiandrogen or androgen-receptor blocker to prevent residual androgen from reaching the androgen receptor. Circulating testosterone levels are not reduced thus minimizing side effects. Intermittent androgen suppression uses combined therapy to rapidly reduce serum testosterone and induce tumor regression. From time to time treatment is stopped and androgen concentrations rise. This method reduces the total time of exposure to castrate levels of androgen and, although prostate-specific antigen levels rise during the second phase of therapy suggesting tumor growth, proponents of this cycling method suggest that this should prolong the time to androgen independence of the tumor. Early results with both methods suggest that the time to progression is long and side effects are minimized as compared to MAA. Large scale trials will be needed to determine the exact risks and benefits of these novel methods of androgen ablation.