Androgen Deprivation Monotherapy for Localized Prostate Cancer: Can It Be Justified?

The importanceof local control hasbeen firmlyestablished in treating prostate cancer (PCa). TheMedical Research Council PR07 randomized trial demonstrated that the addition of radiotherapy (RT) to androgen deprivation therapy (ADT) improved survival versus ADT alone in locally advanced PCa [1]. Similarly, Cooperbergetal extracteddata fromtheCancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry and, after adjusting for age and risk (Kattan or Cancer of the Prostate Risk Assessment [CAPRA] score), observed that PCa mortality for ADT as monotherapy (ie, primary ADT [PADT]) relative to radical prostatectomy was three times higher [2]. In this month’s issue of European Urology, Sammon et al remind us that ADT is not therapy for the primary tumor in men with organ-confined PCa [3]. ADT has clear benefits for palliation of metastatic disease and for improving survival in patients with high-risk disease in conjunctionwith locoregional therapy.However, theuse of PADT is controversial, and guidelines in North America and Europe do not endorse its use for localized disease [4]. Sammonet al showa trend towarddeclininguseof PADT in theUS Medicare population, which the authors attribute in part to a decrease in reimbursement and an increase in awareness of the adverse effects [3]. Although the trends are reassuring, PADT is still commonly used and most often in the subset of patientswithhigherriskdiseasewhowouldbenefit fromlocal control. The adoption of clinical guidelines depends on the distribution and awareness of the evidence supporting them [5]. The current paper helps this effort. A registry-based analysis such as that by Sammon et al [3] has some important limitations. The mechanism of the survival disadvantage in patients receiving PADT, for example, cannot be determined definitively because cause of death is not reported. It can be hypothesized that the detrimental effect of PADT is due to an increase in cardiovascular mortality; however, studies on this topic have shown conflicting results. A recent meta-analysis of observational studies demonstrated a detrimental effect of ADT on cardiovascular mortality; however, the association was limited to gonadotropin-releasing hormone agonists [6]. In a comparison ofUS and Japanese cohorts,men in Japan managed with PADT enjoyed significantly improved overall survival despite similar PCa survival compared with USmen [4]. In contrast, Nguyen et al performed a pooled analysis of randomized trials in unfavorable-risk PCa (nonmetastatic) and found that ADT usewas not associatedwith an increased risk of cardiovascular death and, in fact, decreased PCaspecific mortality and all-cause mortality. Yet, in this metaanalysis, close to 50% of the patients received short-duration ADT ( 3 yr), and the effects of ADT on patients with preexisting cardiovascular disease were not reported [7]. Ziehr et al determined that in men treated with RT, adjuvantADTwasassociatedwitha5%absoluteexcess riskof cardiac-specific mortality at 5 yr in men with congestive heart failureor priormyocardial infarction [8]. Consequently, it is likely that the detrimental effect of PADT on cardiovascular mortality is sensitive to the presence of cardiovascular risk factors and disease in the population studied [4]. An interesting finding in the paper by Sammon et al [3] is the increase in PCa-specific mortality reported for the PADT group. Supplemental Tables 3 and 4 illustrate thatmenwith life expectancies >5 yr treated with ADT had higher PCa mortality relative to patients managed with observation [3]. This finding conflicts with several large studies. In 2008, Lu-Yao et al published a population-based cohort study of E U RO P E AN URO LOG Y 6 8 ( 2 0 1 5 ) 4 0 – 4 1