Androgen ablation in addition to radiation therapy for prostate cancer: is there true benefit?

Prostate cancer patients may now be identified as having a high risk of failing single-modality treatment based on pretreatment prostate specific antigen (PSA), Gleason score, and palpable stage. In particular, a PSA greater than 20 ng/mL portends a biochemical failure rate of 50% to 80% when radiation therapy, surgery, or androgen ablation is administered individually. A number of randomized trials as well as retrospective data show that failure rates are significantly reduced by combining androgen ablation and radiation. The improved results, however, are complicated by the ability to salvage radiation alone-treated patients with androgen ablation and the possibility of less effective salvage (or no effective salvage in the case of permanent androgen ablation) for patients treated with androgen ablation plus radiation. Thus, survival, which is obscured by high rates of intercurrent deaths in this elderly population, is the most important end point in such studies. Two randomized trials, one from the Radiation Therapy Oncology Group (RTOG) and one from the European Organization for Research on Treatment for Cancer (EORTC), of radiation therapy plus adjuvant (as opposed to neoadjuvant) androgen ablation have reported survival gains over radiation therapy alone. In contrast, one neoadjuvant trial from the RTOG failed to show a survival benefit when androgen ablation was added to radiation therapy. In this study, however, androgen ablation was administered for only 4 to 5 months, which may be insufficient. The weight of the evidence to date indicates a true benefit with androgen ablation plus radiation therapy over radiation therapy alone. There are clearly many unanswered questions concerning the optimal timing of androgen ablation and radiation therapy (neoadjuvant versus adjuvant), length of time that androgen ablation should be administered (6 months versus 3 years versus permanent), type of androgen ablation (total androgen ablation or not), and appropriate patient population (definition of high risk). The planned future clinical trials will address many of these issues; however, the full potential of this approach requires an understanding of the fundamental mechanisms involved.