Approach to Androgen Deprivation in the Prostate Cancer Patient with Pre-existing Cardiovascular Disease
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Purpose of Review
Androgen deprivation therapy (ADT) is a mainstay of treatment for advanced prostate cancer. Several studies have reported an association between ADT and an increase in cardiovascular events, especially in those receiving gonadotropin-releasing hormone (GnRH) agonists compared to GnRH antagonists. We review the body of literature reporting the association of ADT and cardiovascular morbidity, and discuss the proposed mechanism of cardiovascular disease due to ADT including metabolic changes that may promote atherosclerosis and local hormonal effects that may increase plaque rupture and thrombosis.
GnRH agonists appear to increase the risk of cardiovascular morbidity by 20–25% in men on these agents compared those who do not receive ADT. GnRH antagonists may appear to have halve this risk while improving PSA progression-free survival.
GnRH antagonists may be superior to GnRH agonists for patients with significant cardiovascular disease, significant metastatic disease burden, or severe lower urinary tract symptoms.
KeywordsAndrogen deprivation Cardiovascular disease Gonadotropin-releasing hormone agonist Gonadotropin-releasing hormone antagonist Degarelix
Compliance with Ethical Standards
Conflict of Interest
Alyssa K. Greiman declares no potential conflicts of interest. Thomas E. Keane reports consultancies for Ferring, Bayer, and Jannsen.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.WHO. Globocan 2012. http://globocan.iarc.fr/Default.aspx
- 4.National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in OncologyTM. Prostate cancer. National Comprehensive Cancer Network: Fort Washington, PA, Version 1. 2017. Available from: https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed January 2017.
- 12.D’Amico A, Denham J, Crook J, Chen M, Goldhaber S, Lamb D, Joseph D, Tai K, Malone S, Ludgate C, Steigler A, Kantoff P. Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions. J Clin Oncol. 2007;25:2420–5.CrossRefPubMedGoogle Scholar
- 14.Levine G, D’Amico A, Berger P, Clark P, Eckel R, Keating N, Milani R, Sagalowsky A, Smith M, Zakai N. Androgen-deprivation therapy in prostate cancer and cardiovascular risk. A science advisory from the American Heart Association, American Cancer Society, and American Urologic Association: endorsed by the American Society for Radiation Oncology. Circulation. 2010;121:833–40.CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Studer U, Whelan P, Albrecht W, Casselman J, de Reijke T, Hauri D, Loidl W, Isorna S, Sundaram S, Debois M, Collette L. Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer (EORTC) Trial 30891. J Clin Oncol. 2006;24:1868–76.CrossRefPubMedGoogle Scholar
- 17.Roach III M, Bae K, Speight J, Wolkov H, Rubin P, Lee R, Lawton C, Valicenti R, Grignon D, Pilepich M. Short-term neoadjuvant androgen deprivation therapy and external beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610. J Clin Oncol. 2008;26:585–91.CrossRefPubMedGoogle Scholar
- 20.• Klotz L, Miller K, Crawford D, Shore N, Tombal B, Karup C, Malmberg A, Persson BE. Disease control outcomes from analysis of pooled individual patient data from five comparative randomized clinical trials of Degarelix versus lutenizing hormone-releasing hormone agonists. Eur Urol. 2014;66:1101–8. Post hoc analysis of five prospective phase 3 or 3b randomized trials comparing the efficacy of GnRH agonists against an antagonist which showed improved overall survival and adverse events with degarelix CrossRefPubMedGoogle Scholar
- 21.•• Albertsen P, Klotz L, Bertrand T, Grady J, Olesen T, Nilsson J. Cardiovascular morbidity associated with gonadotropin releasing hormone agonists and an antagonist. Eur Urol. 2014;65:565–73. Post hoc analysis of six prospective randomized trials comparing the efficacy of GnRH agonists against an antagonist which found that GnRH antagonists halved the number of cardiac events experienced by men with pre-existing cardiovascular disease compared to GnRH agonists CrossRefPubMedGoogle Scholar
- 28.FDA drug safety communication: update to ongoing safety review of GnRH agonists and notification to manufacturers of GnRH agonists to add new safety information to labeling regarding increased risk of diabetes and certain cardiovascular diseases. US Food and Drug Administration Web site. http://www.fda.gov/Drugs/DrugSafety/ucm229986.htm Accessed January 2017
- 34.• O’Farrell S, Garmo H, Holmberg L, Adolfsson J, Stattin P, Van Hemelrijck M. Risk and timing of cardiovascular disease after androgen-deprivation therapy in men with prostate cancer. J Clin Oncol. 2015;33(11):1243–51. Multivariate analysis of a cohort of 41,362 men with prostate cancer on ADT compared to age-matched prostate cancer-free men which found a 21% increased risk of cardiovascular disease in men on GnRH agonists compared with the comparison cohort. This risk was highest in the first 6 months of therapy CrossRefPubMedGoogle Scholar
- 37.•• Zhao J, Zhu S, Sun L, Meng F, Zhao L, Zhao Y, Tian H, Li P, Niu Y. Androgen deprivation therapy for prostate cancer is associated with cardiovascular morbidity and mortality: a meta-analysis of population-based observational studies. PLoS One. 2014;9(9):–e107516. Meta-analysis of six population-based observational studies comparing ADT versus control which found that GnRH therapy is associated with an increased risk of cardiovascular disease and cardiovascular mortality Google Scholar
- 38.•• Bosco C, Bosnyak Z, Malmberg A, Adolfsson J, Keating N, Van Hemelrijck M. Quantifying observational evidence for risk of fatal and nonfatal cardiovascular disease following androgen deprivation therapy for prostate cancer: a meta-analysis. Eur Urol. 2015;68:386–96. Meta-analysis of eight observational studies comparing ADT with control which found a relative risk of 1.38 for non-fatal cardiovascular disease in me non-GnRH agonist therapy compared to men not treated with ADT CrossRefPubMedGoogle Scholar
- 44.Chen H, Jueng E, Stephenson M, Leung P. Ribonucleic acids that are regulated by GnRH in vitro. Endocrinol Metab. 1999;84:743–50.Google Scholar
- 45.Tanriverdi F, Gonzalez-Martinez D, Hu Y, Kelestimur F, Bouloux P. GnRH-I and GnRH-II have differential modulatory effects on human peripheral blood mononuclear cell proliferation and interleukin-2 receptor gamma-chain mRNA expression in healthy males. Clin Exp Immunol. 2005;142:103–10.CrossRefPubMedPubMedCentralGoogle Scholar
- 49.Smith M, Klotz L, van der Meulen E, Colli E, Tanko L. Gonadotropin-releasing hormone blockers and cardiovascular disease risk: analysis of prospective clinical trials of degarelix. J Urol. 2011;186:1935–842.Google Scholar
- 50.Tombal B, Miller K, Boccon-GIbod L, et al. Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol. 2010;57:836–42.CrossRefPubMedGoogle Scholar
- 52.• Crawford E, Shore N, Moul J, Tombal B, et al. Long-term tolerability and efficacy of degarelix: 5-year results from a phase III extension trial with a 1-arm crossover from leuprolide to degarelix. Urology. 2014;83(5):1122–8. The 5-year results from the cross-over trial of CS21 where patients receiving leuprolide were crossed over to degarelix after one year which showed a durable PSA progression-free survival benefit for degarelix over leuprolide at 5 years CrossRefPubMedGoogle Scholar
- 53.Hopmans S, Duivenvoorden W, Werstuck G, Klotz L, Pinthus J. GnRH antagonist associates with less adiposity and reduced characteristics of metabolic syndrome and atherosclerosis compared with orchiectomy and GnRH agonist in a preclinical mouse model. Urol Oncol. 2014;32(8):1126–34.CrossRefPubMedGoogle Scholar
- 58.Mason M, Maldonado P, Steidle C, et al. Neoadjuvant androgen deprivation therapy for prostate volume reduction, lower urinary tract symptoms relief and quality of life improvement in men with intermediate–to high-risk prostate cancer: a randomized non-inferiority trial of degarelix versus goserelin plus bicalutamide. Clin Oncol. 2013;25:190–6.CrossRefGoogle Scholar
- 65.Kelly D, Jones T. Testosterone: a metabolic hormone in health and disease. J Endocrinol. 2013;217:24–45.Google Scholar
- 74.Bhatia N, Santos M, Jones L, Beckman J, Penson D, Morgans A, Moslehi J. Cardiovascular effects of androgen deprivation therapy for the treatment of prostate cancer: ABCDE steps to reduce cardiovascular disease in patients with prostate cancer. Circulation. 2016;133:537–41.CrossRefPubMedPubMedCentralGoogle Scholar
- 76.Conteduca V, Di Lorenzo G, Tartarone A, Aieta M. The cardiovascular risk of gonadotropin releasing hormone agonists in men with prostate cancer: an unresolved controversy. Crit Rev Ocol Hematol. 2013;8:2–51.Google Scholar