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Current Urology Reports
Published in: Current Urology Reports 6/2017

01-06-2017 | Prostate Cancer (S Prasad, Section Editor)

Approach to Androgen Deprivation in the Prostate Cancer Patient with Pre-existing Cardiovascular Disease

Authors: Alyssa K. Greiman, Thomas E. Keane

Published in: Current Urology Reports | Issue 6/2017

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Abstract

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.

Recent Findings

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.

Summary

GnRH antagonists may be superior to GnRH agonists for patients with significant cardiovascular disease, significant metastatic disease burden, or severe lower urinary tract symptoms.
Literature
1.
2.
3.
4.
5.
Mariani A, Glover M, Arita S. Medical versus surgical androgen suppression therapy for prostate cancer: a 10-year longitudinal cost study. J Urol. 2001;165(1):104–7.CrossRefPubMed
6.
Drudge-Coates L. GnRH blockers: a changing paradigm in the management of prostate cancer. Int J Urol Nurs. 2009;3:85–92.CrossRef
7.
Klotz L, Boccon–Gibod L, Shore N, Andreou C, Persson B, Cantor P, et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008;102:1531–8.CrossRefPubMed
8.
9.
Keating N, O’Malley A, Smith M. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;23:4448–56.CrossRef
10.
Tsai H, D’Amico A, Sadetsky N, Chen M, Carrol P. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst. 2007;99:1516–24.CrossRefPubMed
11.
Saigal C, Gore J, Krupski T, Hanley J, Schonlau M, Litwin M. Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer. Cancer. 2007;110:1493–500.CrossRefPubMed
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.CrossRefPubMed
13.
D’Amico A, Chen M, Renshaw A, Loffredo M, Kantoff P. Causes of death in men undergoing androgen suppression therapy for newly diagnosed localized or recurrent prostate cancer. Cancer. 2008;113:3290–7.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
16.
Efstathiou J, Bae K, Shipley W, Hanks G, Pilepich M, Sandler H, Smith M. Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: analysis of RTOG 92-02. Eur Urol. 2008;54:816–23.CrossRefPubMed
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.CrossRefPubMed
18.
Efstathiou J, Bae K, Shipley W, Hanks G, Pilepich M, Sandler H, Smith M. Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: RTOG 85-31. J Clin Oncol. 2009;27:92–9.CrossRefPubMed
19.
Bolla M, de Reijke T, Van Tienhoven G, Van den Bergh A, Oddens J, Poortmans P, Gez E, Kil P, et al. EORTC Radiation Oncology Group and Genito-Urinary Tract Cancer Group. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med. 2009;360:2516–27.CrossRefPubMed
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 CrossRefPubMed
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 CrossRefPubMed
22.
Huhtaniemi I, White R, McArdle C, Persson B. Will GnRH antagonists improve prostate cancer treatment? Trends Endocrinol Metab. 2009;20:43–50.CrossRefPubMed
23.
Varenhorst E, Wallentin L, Carlstrom K. The effects of orchidectomy, estrogens, and cyproterone acetate on plasma testosterone, LH, and FSH concentrations in patients with carcinoma of the prostate. Scand J Urol Nephrol. 1982;16:31–6.CrossRefPubMed
24.
Millar R, Lu Z, Pawson A, Flanagan C, Morgan K, Maudsley S. Gonadotropin-releasing hormone receptors. Endocr Rev. 2004 Apr;25(2):235–75.CrossRefPubMed
25.
Harris W, Mostaghel E, Nelson P, Mongomery B. Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion. Nat Clin Pract Urol. 2009;6(2):76–85.CrossRefPubMedPubMedCentral
26.
Calais da Silva F, Bono A, Whelan P, Brausi M, et al. Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: results from a randomized phase 3 study of the South European Uroncological Group. Eur Urol. 2009;55(6):1269–77.CrossRefPubMed
27.
Keating N, O’Malley A, Freeland S, Smith M. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst. 2010;102(1):39–46.CrossRefPubMedPubMedCentral
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
29.
Van Hemelrijck M, Garmo H, Holmberg L, et al. Absolute and relative risk of cardiovascular disease in men with prostate cancer: results from the population-based PCBaSe Sweden. J Clin Oncol. 2010;28:3448–56.CrossRefPubMed
30.
Martin-Merino E, Johansson S, Morris T, Garcia RL. Androgen deprivation therapy and the risk of coronary heart disease and heart failure in patients with prostate cancer: a nested-case-control study in UK primary care. Drug Saf. 2011;34(11):1061–77.CrossRefPubMed
31.
Azoulay L, Yin H, Bernayoun S, Renoux C, Boivin J, Suissa S. Androgen-deprivation therapy and the risk of stroke in patients with prostate cancer. Eur Urol. 2011;60(6):1244–50.CrossRefPubMed
32.
Hu J, Williams S, O’Malley A, Smith M, Nguyen P, Keating N. Androgen-deprivation therapy for nonmetastatic prostate cancer is associated with an increased risk of peripheral arterial disease and venous thromboembolism. Eur Urol. 2012;61(6):1119–28.CrossRefPubMedPubMedCentral
33.
Jespersen C, Norgaard M, Borre M. Androgen-deprivation therapy in treatment of prostate cancer and risk of myocardial infarction and stroke: a nationwide Danish population-based cohort study. Eur Urol. 2014;65(4):704–9.CrossRefPubMed
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 CrossRefPubMed
35.
Alibhai S, Duong-Hua M, Sutradhar R, Fleshner N, Warde P, et al. Impact of androgen deprivation therapy on cardiovascular disease and diabetes. J Clin Oncol. 2009;27:3452–8.CrossRefPubMedPubMedCentral
36.
Gandaglia G, Sun M, Popa I, Schiffmann J, Abdollah F, et al. The impact of the androgen deprivation therapy on the risk of coronary heart disease in patients with non-metastatic prostate cancer: a population-based study. BJU Int. 2014;114(6b):E82–9.CrossRefPubMed
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
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 CrossRefPubMed
39.
40.
Wilcox C, Jautto A, Steigler A, Denham J. Androgen deprivation therapy for prostate cancer does not increase cardiovascular mortality in the long term. Oncology. 2012;82(1):56–8.CrossRefPubMed
41.
Nguyen P, Je Y, Schutz F, Hoffman K, Hu J, Parekh A, Beckman J, Choueiri T. Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. JAMA. 2011;306(21):2359–66.CrossRefPubMed
42.
43.
Jacobson J, Nisula B, Steinberg A. Modulation of the expression of murine lupus by gonadotropin-releasing hormone analogs. Endocrinology. 1994;134:2516–23.CrossRefPubMed
44.
Chen H, Jueng E, Stephenson M, Leung P. Ribonucleic acids that are regulated by GnRH in vitro. Endocrinol Metab. 1999;84:743–50.
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.CrossRefPubMedPubMedCentral
46.
Grasso G, Massai L, De Leo V, Muscettola M. The effect of LHRH and TRH on human interferon-gamma production in vivo and in vitro. Life Sci. 1998;62(22):2005–14.CrossRefPubMed
47.
Andersson J, Libby P, Hansson G. Adaptive immunity and atherosclerosis. Clin Immunol. 2010;134(1):33–46.CrossRefPubMed
48.
Dixit V, Yang H, Udhayakumar V, Sridaran R. Gonadotropin-releasing hormone alters the t helper cytokine balance in the pregnant rat. Biol Reprod. 2003;68:2215–21.CrossRefPubMed
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.
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.CrossRefPubMed
51.
Crawford E, Tombal B, Miller K, et al. A phase III extension trial with a 1-arm crossover from leuprolide to degarelix: comparison of gonadotropin-releasing hormone agonist and antagonist effect on prostate cancer. J Urol. 2011;186:889–97.CrossRefPubMed
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 CrossRefPubMed
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.CrossRefPubMed
54.
Radu A, Pichon C, Camparo P, Antoine M, et al. Expression of follicle-stimulating hormone receptor in tumor blood vessels. N Engl J Med. 2010;363(17):1621–30.CrossRefPubMed
55.
Robinson D, Sandblom G, Johansson R, Garmo H, Stattin P, Mommsen S, et al. Prediction of survival of metastatic prostate cancer based on early serial measurements of prostate specific antigen and alkaline phosphatase. J Urol. 2008;179:117–22.CrossRefPubMed
56.
Schrӧder F, Tombal B, Miller K, Boccon-Gibod L, Shore N, Crawford E, et al. Changes in alkaline phosphatase levels in patients with prostate cancer receiving degarelix or leuprolide: results from a 12-month, comparative, phase III study. BJU Int. 2009;106:182–7.CrossRef
57.
Axcrona K, Aaltomaa S, Da Silva C, et al. Androgen deprivation therapy for volume reduction, lower urinary tract symptom relief and quality of life improvement in patients with prostate cancer: degarelix vs goserelin plus bicalutamide. BJU Int. 2012;110:1721–8.CrossRefPubMed
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.CrossRef
59.
Anderson J, Al-Ali G, Wirth M, et al. Degarelix versus goserelin (+antiandrogen flare protection) in the relief of lower urinary tract symptoms secondary to prostate cancer: results from a phase IIIb study (NCT 00831233). Urol Int. 2013;90:321–8.CrossRefPubMed
60.
Bono A, Salvadore M, Celato N. Gonadotropin-releasing hormone receptors in prostate tissue. Anal Quant Cytol Histol. 2002;24:221–7.PubMed
61.
Rick F, Schally A, Block N, et al. LHRH antagonist cetorelix reduces prostate size and gene expression of proinflammtory cytokines and growth factors in a rat model of benign prostatic hyperplasia. Prostate. 2001;71:736–47.CrossRef
62.
Giuliano F, Behr-Roussel D, Oger S, et al. Ozarelix, an LHRH antagonist, exerts a direct relaxing effect on human prostate in vitro. J Urol. 2009;181:693.CrossRef
63.
Hatoum H, Crawford E, Nielsen S, et al. Cost-effectiveness analysis comparing degarelix with leuprolide in hormonal therapy for patients with locally advanced prostate cancer. Expert Rev Pharmacoecon Outcomes Res. 2013;13:261–70.CrossRefPubMed
64.
Lee D, Porter J, Gladwell D, Brereton N, Nielsen S. A cost-utility analysis of degarelix in the treatment of advanced hormone-dependent prostate cancer in the United Kingdom. J Med Econ. 2014;17(4):233–47.CrossRefPubMed
65.
Kelly D, Jones T. Testosterone: a metabolic hormone in health and disease. J Endocrinol. 2013;217:24–45.
66.
Corona G, Rastrelli G, Monami M, et al. Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study. Eur J Endocrinol. 2011;165:687–701.CrossRefPubMed
67.
Zareba P, Duivenvoorden W, Leong D, Pinthus J. Androgen deprivation therapy and cardiovascular disease: what is the linking mechanism? Ther Adv Urol. 2016;8(2):118–29.CrossRefPubMed
68.
Smith M. Androgen deprivation therapy and risk for diabetes and cardiovascular disease in prostate cancer survivors. Curr Urol Rep. 2008;9(3):197–202.CrossRefPubMedPubMedCentral
69.
Smith M, Finkelstein J, McGovern F, et al. Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab. 2002;87:599–603.CrossRefPubMed
70.
Bourghardt J, Wilhelmson A, Alexandeson C, De Gendt K, Verhoeven G, Krettek A, et al. Androgen receptor-dependent and independent atheroprotection by testosterone in male mice. Endocrinology. 2010;151:5428–37.CrossRefPubMed
71.
Falk E. Mophologic feature of unstable atherothrombotic plaques underlying acute coronary syndromes. Am J Cardiol. 1989;3:114–20.CrossRef
72.
Libby P. Molecular and cellular mechanisms of the thrombotic complications of atherosclerosis. J Lipid Res. 2009;50(suppl):S352–237.PubMedPubMedCentral
73.
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.CrossRefPubMedPubMedCentral
75.
Jacobs E, Newton CC, Stevens V, Campbell P, Freedland S, Gapstur S. Daily aspirin use and prostate cancer-specific mortality in a large cohort of men with nonmetastatic prostate cancer. J Clin Oncol. 2014;32:3716–22.CrossRefPubMed
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.
Metadata
Title
Approach to Androgen Deprivation in the Prostate Cancer Patient with Pre-existing Cardiovascular Disease
Authors
Alyssa K. Greiman
Thomas E. Keane
Publication date
01-06-2017
Publisher
Springer US
Published in
Current Urology Reports / Issue 6/2017
Print ISSN: 1527-2737
Electronic ISSN: 1534-6285
DOI
https://doi.org/10.1007/s11934-017-0688-5

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