Cardiovascular Toxicity of Androgen Deprivation Therapy: A New Door Opens
Authors: Shabbir M.H. Alibhai
Journal: Journal of Clinical Oncology (2011)

Seventy years ago, androgen deprivation therapy (ADT) was ushered in as an important treatment approach for prostate cancer. With expanding indications and use in the past two decades, almost 50% of men diagnosed with prostate cancer in the current era are expected to receive ADT at some point after diagnosis. Early experience with one form of ADT, diethylstilbestrol, led to concerns about cardiovascular toxicity more than 30 years ago. Although diethylstilbestrol use has been virtually abandoned in favor of luteinizing hormone-releasing hormone agonists—the primary method of androgen deprivation at present—concerns remain about the cardiovascular toxicity of most forms of ADT. Several retrospective studies have shown a positive correlation between ADT and both cardiovascular morbidity and mortality. Keating et al used the Surveillance, Epidemiology, and End Results (SEER) database to study 73,196 patients with localized prostate cancer. They found that ADT use was associated with a greater risk of coronary heart disease, myocardial infarction (MI), and sudden cardiac death with adjusted hazard ratios (AHRs) of 1.11 (95% CI, 1.01 to 1.21; P .03), 1.16 (95% CI, 1.10 to 1.21; P .001), and 1.16 (95% CI, 1.05 to 1.27; P .004), respectively. A second, more recent study by the same authors using more current SEER data found similar results with an AHR of 1.28 (95% CI, 1.08 to 1.52) for MI and 1.19 (95% CI, 1.10 to 1.28) for sudden cardiac death. A third study, by Saigal et al, also using the SEER database, reported that 24% of men undergoing ADT experienced a cardiovascular event within 1 to 4 years of starting therapy compared with 18% of nonusers (AHR, 1.2; P .001). A fourth study using the prospective clinical CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) database reported an increased risk of death as a result of cardiovascular disease of 2.6 (P .002) among patients who underwent radical prostatectomy but only 1.2 among patients who were treated with radiation therapy (P .40). The total number of events among 4,892 patients was relatively small at 131. There is also supporting evidence from several randomized controlled trials (RCTs). In a secondary analysis of pooled data from three RCTs of short-term adjuvant ADT in men undergoing radiation, D’Amico et al found that 6 months of ADT was associated with a shorter time to fatal MI (P .017), but this risk seemed to be confined to men over the age of 65 years. One prospective RCT of radiation therapy with or without 6 months of ADT in 206 patients showed that ADT increased risk of cardiac death but only in patients with moderate to severe comorbidities. In contrast, multiple studies have demonstrated no relationship between ADT and cardiovascular events. Three large phase III RCTs (Radiation Therapy Oncology Group [RTOG] 85-31, RTOG 86-10, and RTOG 92-02) with sample sizes ranging from 456 to 1,554 men and follow-up of 8 to 10 years found no statistically significant increased risk of cardiovascular mortality with ADT use. However, nonfatal MIs were not captured, and relatively few fatal MIs were observed in each trial. Not only did two European-led RCTs (European Organisation for Research and Treatment of Cancer [EORTC] 22961 and 30891) fail to show any increased risk of cardiovascular toxicity from ADT, but both studies instead suggested a trend toward fewer fatal cardiovascular events in ADT users. Lastly, a retrospective cohort study by our group used administrative data from Ontario, Canada. Among 19,079 matched pairs of ADT users and nonusers age 66 years or older, the AHRs for MI and sudden cardiac death were 0.91 (95% CI, 0.84 to 1.00) and 0.96 (95% CI, 0.83 to 1.10), respectively. Thus, at least nine RCTs and four cohort studies have weighed in on the topic with quite different findings. In the article that accompanies this editorial, Punnen et al attempt to reconcile these disparate findings by examining the risk of cardiovascular mortality among four separate treatment groups: primary ADT, local therapy only (radical prostatectomy or radiotherapy), local treatment plus ADT, and no active treatment (watchful waiting or active surveillance). Perhaps not surprisingly, cardiovascular mortality was increased in the primary ADT group compared with the local therapy alone group (hazard ratio [HR], 1.94; 95% CI, 1.29 to 2.97). However, the risk of cardiovascular mortality was not increased in men treated with local treatment plus ADT (HR, 1.36; 95% CI, 0.65 to 1.98), which is surprising given that the local therapy component would not have been expected to impact cardiovascular mortality. Moreover, patients managed with no active treatment experienced increased cardiovascular mortality (HR, 2.46; 95% CI, 1.53 to 3.95), leading the authors to suggest that unmeasured covariates that lead to men not being treated with local therapy (and instead lead either to receipt of ADT or no active treatment) contribute to an excess cardiovascular mortality risk. Several aspects of the Punnen et al study deserve closer scrutiny. First, the study is not randomized and, although the data were collected prospectively in the CaPSURE clinical database (with patients recruited from 40 community-based urology practices in the United States), the data were analyzed retrospectively. Completeness of follow-up to death in CaPSURE is not clear. Importantly, cause of death was assigned by a consensus of the investigators (who were presumably not blinded to the study hypothesis), and death was considered a result of prostate cancer if prostate cancer was listed as a primary, secondary, or tertiary cause of death without mention of other cancer or cardiovascular disease as a higher-order cause. This is a fairly broad definition. Given that cardiovascular outcomes were not uniformly ascertained or measured, it is quite possible that attribution bias (a cognitive bias that affects the way we determine what was responsible for a given outcome) may explain some of the results. This is particularly important given the relatively small number of Editorials