Antiandrogen withdrawal syndrome associated with prostate cancer therapies: incidence and clinical significance.

The antiandrogen withdrawal syndrome is a well established phenomenon in prostate cancer. It is widely accepted that a subset of patients will benefit from the withdrawal of antiandrogen or steroidal hormone from hormonal therapy, exhibiting decreasing prostate-specific antigen (PSA) values and clinical improvement. The pathophysiology of antiandrogen withdrawal syndrome is not completely understood, although androgen receptor gene mutations seem to be the likely explanation. Currently, it is not possible to identify the subset of patients whose tumours will respond to antiandrogen or steroid withdrawal. Tumours that will respond may be classified as androgen-independent and hormone-sensitive tumours as opposed to androgen-independent and hormone-insensitive tumours that do not respond. Patients who respond to antiandrogen withdrawal experience approximately 6 months with improved quality of life; however, it is unknown if this translates into prolonged survival. At the very least, antiandrogen withdrawal offers a therapeutic modality that is not associated with adverse effects and improves quality of life even if only for a very limited time. Recent reports suggest that adding a secondary hormonal therapy such as amino- glutethimide, ketoconazole or steroidal hormones may enhance the response rate and prolong response time to the antiandrogen withdrawal syndrome. However, unless there is proof that this secondary hormonal manipulation prolongs survival, maintenance of quality of life is mandatory because of the possible adverse effects from these potent drugs. The fact that about 30% of patients will respond to antiandrogen or steroid withdrawal in hormone refractory prostate cancer must be taken into account in clinical trials of new cytotoxic agents which have been and will be conducted. Cessation of flutamide for at least 4 weeks and, in the case of bicalutamide, even 8 weeks, is mandatory before antiandrogen withdrawal syndrome can be excluded as the cause of decreasing PSA values. The antiandrogen withdrawal syndrome offers another piece of the puzzle of prostatic carcinoma, but at the same time it demonstrates how different advanced prostate cancer cells may react to therapeutic strategies and, therefore, hormone refractory prostate cancer remains a difficult challenge which must be solved in the future.