Adverse effects of androgen deprivation and the limits of national tumor registries

EUROPEAN UROLOGY 61 (2012) 701–704 available at www.sciencedirect.com journal homepage: www.europeanurology.com Platinum Priority – Editorial and Reply from Authors Referring to the article published on pp. 690–700 of this issue Adverse Effects of Androgen Deprivation and the Limits of National Tumor Registries Matthew R. Cooperberg Department of Urology, University of California, San Francisco, 1600 Divisadero St., Box 1695, San Francisco, CA 94143–1695, USA For nearly a half-century, androgen-deprivation therapy (ADT) has been a mainstay of the treatment of prostate cancer (PCa). ADT is virtually always the first-line approach for patients with metastatic disease, and multiple randomized trials have shown that combining external-beam radiation therapy with ADT improves mortality rates for men with intermediate- to high-risk disease [1–4]. Primary ADT as monotherapy for men with clinically localized disease is not known to improve survival compared with conservative management except for men with high-risk disease [5], and among this high-risk subset, ADT monotherapy is inferior to treatment regimens which include local therapy [6,7]. Although ADT monotherapy for localized disease is therefore not endorsed by practice guidelines on either side of the Atlantic [8,9], it is commonly used, particularly among older men [10]. Overall, up to 46% of men with PCa receive ADT at some point during treatment [11]. Use of ADT is also widely variable across clinical practice sites and providers [12,13]. It should be noted that this discussion to a large extent reflects a Western perspective; in Asia, primary ADT has a greater role, and apparently better efficacy and less toxicity [14,15]. Recent studies have raised concerns regarding the long- term effects of ADT on musculoskeletal, endocrine, cardio- vascular, hematologic, and cognitive functions, though the strength of evidence for each of these areas varies substantially. There is little argument that ADT can reduce muscle and bone mass and increase skeletal fracture risk— risk that can be partially reduced with zoledronic acid or denosumab [16,17]. ADT likewise increases fat mass, low- density lipoprotein and triglyceride levels, and insulin resistance [18,19]. Whether these changes translate to actual increased cardiovascular mortality is a more controversial question. Analyses of large registries have suggested that a link between ADT use and major cardiovascular morbidity does in fact exist [18,20,21]. Secondary analysis of trials randomizing men to radiation therapy with and without hormonal therapy, however, has consistently found no increase in cardiovascular mortality, even with long-term treatment [4,22,23]. The article by Van Hemelrijck et al. in this issue of European Urology explores the impact of ADT in a population-based Swedish cancer registry, focusing in particular on the incidence of multiple adverse events over time among men receiving ADT [24]. On its face, this concept may be intuitive; it is known, for example, that men who experience one skeletal event are at higher risk for subsequent events [25], and of course men with established cardiovascular disease are at greater risk for additional cardiovascular events. An effort to quantify this cumulative risk in the setting of ADT is certainly laudable. The authors identified adverse events in 26% of the cohort with a median 4-yr follow-up, and in fact, patients experiencing at least one event—particularly a cardiovascular complication— were more likely to experience additional events. The study has substantial strengths, most notably its thorough capture of nearly all PCa in the country, as well as reasonably robust follow-up [24]. However, the study also has major limitations. First, the analysis considered all forms of hormonal therapy together. In particular, 11% of the cohort received antiandrogens only; these medications do not have the same metabolic consequences as castrating therapies, and they should not have been included. Likewise, orchiec- tomy has been shown in at least some studies to have different effects from medical castration [18]. Considering all these treatments together markedly limits the clinical interpretation of the results. Furthermore, no information was available on duration of therapy. The translation of World Health Organization grade to Gleason score in the analysis was performed incorrectly and may have introduced significant error into the multivariable analysis. DOI of original article: 10.1016/j.eururo.2011.09.010 E-mail address: mcooperberg@urology.ucsf.edu. 0302-2838/$ – see back matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.