Maximal androgen blockade for the treatment of metastatic prostate cancer—a systematic review

INTRODUCTION: Maximal androgen blockade (mab) versus castration alone in patients with metastatic prostate cancer has been extensively evaluated in randomized trials. The inconsistent results have led to the publication of multiple meta-analyses. The present review examines the evidence from meta-analytic reports to determine whether mab using agents such as flutamide, nilutamide, and cyproterone acetate (cpa) is associated with a survival advantage. METHODS: We conducted a systematic review of the literature (medline, embase, and the Cochrane Library through July 2004; cancerlit through October 2002) for meta-analyses that compared mab with castration alone in previously untreated men with metastatic prostate cancer (D1 or D2, N+/M0 or M1). Two reviewers selected papers for eligibility; disagreement was resolved by all the authors through consensus. RESULTS: The literature search identified six meta-analyses that met the eligibility criteria of the review. Two of those reports were based on individual patient data (ipd), and four were based on data from the published literature. All six meta-analyses pooled data on overall survival. The best evidence came from the largest meta-analysis, conducted by the Prostate Cancer Trialists Collaborative Group and based on ipd (8725 patients) from 27 trials. That analysis detected no difference in overall survival between mab and castration alone at 2 or 5 years. However, a subgroup analysis showed that mab with nonsteroidal anti-androgens (nsaas) was associated with a statistically significant improvement in 5-year survival over castration alone (27.6% vs. 24.7%; p = 0.005). The combination of mab with cpa, a steroidal anti-androgen, was associated with a statistically significant increased risk of death (15.4% vs. 18.1%; p = 0.04). Compared with castration alone, mab was associated with more side effects (that is, gastrointestinal, endocrine function) and reduced quality of life in domains related to treatment symptoms and emotional functioning. CONCLUSIONS: The small survival benefit conferred by mab with nsaa is of questionable clinical significance given the added toxicity and concomitant decline in quality of life observed in patients treated with mab. Therefore, combined treatment with flutamide or nilutamide should not be routinely offered to patients with meta-static prostate cancer beyond the purpose of blocking testosterone flare. Monotherapy, consisting of orchiectomy or the administration of a luteinizing hormone–releasing hormone agonist is recommended as standard treatment.