For many men there comes a time in the treatment process when ADT stops working and the PSA will again begins to rise! Unfortunately, the prostate cancer cells “learn” how to grow without testosterone being present. At this point, we call the cancer androgen independent (AID).

When the cancer does become AID, there are still a number of treatments available. As usual with prostate cancer, there are no clear-cut “best ways” to proceed. However, there is a consensus that prior to moving ahead with formal chemo-therapy using Taxotere you should try a second line hormonal manipulation using antiandrogen withdrawal (AAWD) either alone or in combination with high dose Ketoconazole (Nizoral) plus hydrocortisone or aminoglutethimide (Cytadren).

“In approximately 50% of patients whose cancer has started to grow again despite treatment that includes an antiandrogen, the cancer has been noted to regress by simply stopping the anti-androgen. This unusual response is referred to as the Anti-Androgen Withdrawal Response (AAWR). Scientists theorize that prostate cancer cells exposed to antiandrogens for a prolonged time may mutate (undergo genetic change) that paradoxically causes the anti-androgen to stimulate cancer growth.” –( Prostate Cancer Research Institute)

The question does remain whether or not to just stop the androgen blockade or to stop the blockade and start Ketoconazole. An interesting phase III Trial (CALGB 9583) reported in the Journal of Clinical Oncology, Vol 22, No 6 (March 2004) pp 1025-1033 tried to answer this question. Eric Small, Susan Halabi, Nancy Dawson, et al, authored the trial.
The findings of this trial were that 11% of patients undergoing AAWD alone and 27% of patients who underwent AAWD along with Ketoconazole (K) had a PSA response (p=.0002). Objective responses were observed in only 2% of patients treated solely with AAWD as opposed to 20% of the combined group (p=.02). Despite these statistical differences, there was no difference in survival!

The anti-androgen withdrawal response (AAWR) may be seen, in up to 50% of patients who have PSA relapse while receiving androgen blockade. An AAWR response usually lasts 6 to 8 months, but for some patients, may last as long as 2 years. –( Prostate Cancer Research Institute)

What does this tell us? It tells us that there is a significant PSA response resulting from both simple AAWD as well as AAWD combined with K. When you become androgen independent, before starting Ketoconazole you should stop all anti-androgen drugs. Since there was no ultimate survival difference between the AAWD group and the combined group it is unclear if there is actually any tangible benefit, other than reducing PSA, to adding Ketoconazole.

Joel T. Nowak MA, MSW