Objectives:

With 184,500 new cases and 39,200 deaths anticipated in 1998, prostate cancer is second only to lung cancer in cancer mortality for men. This report is a systematic review of the evidence from randomized controlled trials on the relative effectiveness of alternative strategies for androgen suppression as treatment of advanced prostate cancer. Three key issues are addressed: (1) the relative effectiveness of the available methods for monotherapy (orchiectomy, luteinizing hormone-releasing hormone [LHRH] agonists, and antiandrogens), (2) the effectiveness of combined androgen blockade compared to monotherapy, and (3) the effectiveness of immediate androgen suppression compared to androgen suppression deferred until clinical progression. Outcomes of interest are overall, cancer-specific, and progression-free survival; time to treatment failure; adverse effects; and quality of life.

Two supplementary analyses were conducted for each key question: (1) meta-analysis of overall survival at 2 years (questions 1 and 2) and 5 years (questions 2 and 3), and (2) cost-effectiveness analysis.

Search Strategy:

The MEDLINE, CANCERLIT, and EMBASE databases were searched from 1966 to March 1998, and Current Contents to August 24, 1998, for the terms: leuprolide (Lupron^®); goserelin (Zoladex^®); buserelin (Suprefact®); flutamide (Eulexin^®); nilutamide (Anandron^®, Nilandron^®); bicalutamide (Casodex^®); cyproterone acetate (Androcur^®); diethylstilbestrol (DES); and orchiectomy (castration, orchidectomy). The search was then limited to human studies indexed under the MeSH term "prostatic neoplasms" and by the UK Cochrane Center search strategy for randomized controlled trials. Total yield was 1,477 references.

Selection Criteria:

The reports of efficacy outcomes were limited to randomized controlled trials. Phase II studies that reported on withdrawals from therapy and all studies reporting on quality of life were also included.

Data Collection and Analysis:

The systematic review used a prospectively designed protocol conducted by two independent reviewers, with disagreements resolved by consensus. The meta-analysis combined data on overall survival using a random effects model. The cost-effectiveness analysis used a decision analysis model of advanced prostate cancer with health states and transitions derived from the literature and estimates of effectiveness derived from the meta-analysis. The cost-effectiveness analysis is conducted from a societal perspective, consistent with the guidelines of the U.S. Public Health Service Panel on Cost-Effectiveness in Health and Medicine.

Main Results:

Survival after treatment with an LHRH agonist is equivalent to survival after orchiectomy. The available LHRH agonists are equally effective, and no LHRH agonist is superior to the others when adverse effects are considered. Survival may be somewhat lower with use of a nonsteroidal antiandrogen.

There is no statistically significant difference in survival at 2 years between patients treated with combined androgen blockade or monotherapy. Meta-analysis of the limited data available shows a statistically significant difference in survival at 5 years that favors combined androgen blockade. However, the magnitude of this difference is of questionable clinical significance. For the subgroup of patients with good prognosis, there is no statistically significant difference in survival. Adverse effects leading to withdrawal from therapy occurred more often with combined androgen blockade.

No evidence is yet available from randomized controlled trials of androgen suppression initiated at prostate-specific antigen (PSA) rise after definitive therapy for clinically localized disease. For patients who are newly diagnosed with locally advanced or asymptomatic metastatic disease, the evidence is insufficient to determine whether primary androgen suppression initiated at diagnosis improves outcomes. For patients with locally advanced or asymptomatic prostate cancer who undergo radiotherapy, the evidence shows longer survival after adjuvant androgen suppression initiated with radiotherapy, and continued for several years or more, than after radiotherapy alone followed by androgen suppression at progression.

Cost-Effectiveness Analysis:

Monotherapy with an LHRH agonist provided minimal or no extra benefits over orchiectomy at considerable increase in costs. However, the results are very sensitive to the quality of life associated with orchiectomy. At a cost-effectiveness threshold of $100,000/quality-adjusted life year (QALY), combined androgen blockade with an LHRH agonist must increase efficacy by 20 percent compared to orchiectomy before this drug combination is considered cost-effective. For patients diagnosed with locally advanced or asymptomatic metastatic disease, initiating primary antiandrogen therapy early, when patients enjoy a good quality of life, will result in higher costs and no added benefit.

Conclusions:

Although there is uncertainty over whether there is a survival advantage, earlier and more intensive androgen suppression is being adopted. Randomized controlled trials are needed to assess the effectiveness of various strategies for the timing of androgen suppression. Moreover, there are scant data on how quality of life is affected. Evidence on the effects of alternative androgen suppression strategies on the quality of life is urgently needed.