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ADT raised risk for cardiac death in men with prostate cancer
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In men receiving treatment for prostate cancer, androgen deprivation therapy was associated with excess risk for cardiac-related death in those with congestive HF or prior MI.
Researchers found that androgen deprivation therapy (ADT) was associated with a 5% absolute excess risk for cardiac mortality in men with congestive HF or prior MI, which could lead to one cardiac death for every 20 men in that subgroup administered ADT.
Paul L. Nguyen, MD, from the department of radiation oncology at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital, and colleagues conducted a retrospective cohort study of 5,077 men (median age, 69.5 years) with cT1c-T3N0M0 prostate cancer. All received treatment with brachytherapy with or without neoadjuvant ADT from 1997 to 2006 at Chicago Prostate Center.
Using a competing risks analysis, the researchers evaluated the association of ADT with cardiac mortality, adjusting for age, year of brachytherapy and ADT treatment propensity score. Participants were stratified into three groups: no CAD risk factors; CAD risk factors; heart disease including congestive HF and MI. Median follow-up was 4.8 years.
Nguyen and colleagues detected no association between ADT and CV mortality in the 2,653 men with no cardiac risk factors (ADT, 1.08%; no ADT, 1.27%; adjusted HR=0.83; 95% CI, 0.39-1.78) or in the 2,168 men with diabetes, hypertension or hypercholesterolemia (ADT, 2.09%; no ADT, 1.97%; adjusted HR=1.33; 95% CI, 0.7-2.53).
However, ADT was associated with significantly increased CV mortality in the 256 men with congestive HF or prior MI (ADT, 7.01%; 95% CI, 2.28-13.82; no ADT, 2.01%; 95% CI, 0.38-6.45; adjusted HR=3.28; 95% CI, 1.01-10.64).
“This study … raises the possibility that a small subgroup of men who have significant heart disease could experience increased cardiac death on ADT,” Nguyen said in a press release. “I would still say that for men with significant heart problems, we should try to avoid ADT when it is not necessary — such as for men with low-risk disease or men receiving ADT only to shrink the prostate prior to radiation. However, for men with high-risk disease, in whom the prostate-cancer benefits of ADT likely outweigh any potential cardiac harms, ADT should be given even if they have heart problems, but the patient should be followed closely by a cardiologist.”
Disclosure: The study was supported by Fitz’s Cancer Warriors, David and Cynthia Chapin, the Prostate Cancer Foundation, Hugh Simons in honor of Frank and Anne Simons and an anonymous family foundation. Several researchers report financial ties with Astellas Pharmaceuticals, Ferring Pharmaceuticals, Intuitive Surgical and Medivation Inc.
Perspective
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E. David Crawford, MD
Androgen deprivation therapy (ADT) is the backbone of treatment for locally advanced and metastatic prostate cancer. Administration of ADT unrolls a cascade of side effects, including hot flashes, decreased libido, erectile dysfunction, decreased bone mineral density, weight gain and mental changes. Diethylstilbestrol (DES), one of the earliest forms of ADT, was associated with significant cardiovascular events and is rarely used anymore to treat prostate cancer. It was felt that the current methods of ADT were devoid of such side effects. However, in the past several years, side effects such as hyperglycemia and insulin resistance, dyslipidemia and an increased risk of cardiovascular disease (CVD) have been reported.
The authors identify a subset of men receiving relatively short-term ADT who experienced a cardiovascular event, identifying those with existing CVD as the risk factor. So, what can we learn from this retrospective review? ADT should be used with caution in men with preexisting CVD, particularly a prior myocardial infarction or congestive heart failure. Second, a short duration of therapy is capable of causing death. Finally, this is something that occurs with luteinizing hormone-releasing hormone (LHRH) agonists, but because these men did not receive either bilateral orchiectomy or an LHRH antagonist, we cannot comment on their risk profile.
In their references, they mention that a study that showed a decreased rate of cardiovascular disease events in men who receive an LHRH antagonist. This review evaluated data from randomized phase 3 trials that compared a gonadotrophin-releasing hormone (GnRH) antagonist with a LHRH agonist. Multivariate analysis demonstrated a lower incidence of cardiovascular events in men with a history of cardiovascular disease at baseline (HR = 0.44; 95% CI, 0.26-0.74). A possible mechanism is the presence of GNRH receptors on T cells stimulated by an LHRH agonist, leading to cytokine release, inflammation in atherosclerotic plaques and progression of the lesion in coronary vessels. The antagonist may not stimulate the cytokine release. These data are from a retrospective review and must be interpreted with caution.
References:
Albertsen PC. Eur Urol. 2014;65:565-573.
Smith MR. J Urol. 2010;184:2313-2319.
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