Whether androgen deprivation therapy (ADT) causes excess thromboembolic events (TEs) in men with prostate cancer (PCa) remains controversial and is the subject of the US Food and Drug Administration safety warning. This study aims to perform a systematic review and meta-analysis on previous studies to determine whether ADT is associated with TEs in men with PCa.
Medline, Embase, and Cochrane Library databases were searched for relevant studies. These studies comprised those that compared ADT versus control to treat PCa, reported TEs as outcome, and were published before January 2018. Multivariate adjusted hazard ratios (HRs) and associated 95% confidence intervals (CIs) were calculated using random- or fixed-effects models.
Five retrospective population-based cohort studies involving 170,851 ADT users and 256,704 non-ADT users were identified. Deep venous thrombosis (DVT) was found significantly associated with gonadotropin-releasing hormone (GnRH) agonists alone (HR = 1.47, 95% CI: 1.07–2.03; P = 0.017; I2 = 96.3%), GnRH agonists plus oral antiandrogen (AA) (HR = 2.55, 95% CI: 2.21–2.94; P < 0.001; I2 = 0.0%), and AA alone (HR = 1.49, 95% CI: 1.13–1.96; P = 0.004; I2 = 0.0%), but not with orchiectomy (HR = 1.80, 95% CI: 0.93–3.47; P = 0.079; I2 = 94.8%). In addition, pulmonary embolism (PE) was significantly associated with GnRH agonists alone (HR = 2.26, 95% CI: 1.78–2.86; P < 0.001; I2 was unavailable) and orchiectomy (HR = 2.12, 95% CI: 1.44–3.11; P < 0.001; I2 = 57.2%). This relationship was also supported with subgroup analyses based on different continents and races.
GnRH agonists alone, GnRH plus AA, and AA alone cause excess DVT in men with PCa after controlling the demographic and disease characteristics and other confounding factors, although statistically significant difference was not observed in orchiectomy group. Additionally, GnRH agonists alone and orchiectomy can increase the incidence of PE.
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Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.
Buja A, Lange JH, Perissinotto E, Rausa G, Grigoletto F, Canova C, Mastrangelo G. Cancer incidence among male military and civil pilots and flight attendants: an analysis on published data. Toxicol Ind Health. 2005;21:273–82.
FDA Drug Safety Communication. FDA requests label changes and single use packaging for some over-the-counter topical antiseptic products to decrease risk of infection. Clin Infect Dis. 2014;58:i–ii.
Falchook AD, Basak R, Mohiuddin JJ, et al. Use of androgen deprivation therapy with radiotherapy for intermediate-and high-risk prostate cancer across the United States. JAMA Oncol. 2016;2:1236–8.
Klotz L, Higano CS. Intermittent androgen deprivation therapy-an important treatment option for prostate Cancer. JAMA Oncol. 2016;2:1531–2.
Bekelman JE, Mitra N, Handorf EA, et al. Effectiveness of androgen-deprivation therapy and radiotherapy for older men with locally advanced prostate cancer. J Clin Oncol. 2015;33:716–22.
Bruce JY, Lang JM, McNeel DG, et al. Current controversies in the management of biochemical failure in prostate cancer. Clin Adv Hematol Oncol. 2012;10:716–22.
Sartor O, Silberstein J. Prostate cancer: primary ADT monotherapy not suitable for localized disease. Nat Rev Urol. 2014;11:309–10.
Gilbert SM, Kuo YF, Shahinian VB. Prevalent and incident use of androgen deprivation therapy among men with prostate cancer in the United States. Urol Oncol. 2011;29:647–53.
Sammon JD, Abdollah F, Reznor G, et al. Patterns of declining use and the adverse effect of primary androgen deprivation on all-cause mortality in elderly men with prostate cancer. Eur Urol. 2015;68:32–9.
Heidenreich A, Aus G, Bolla M, et al. EAU guidelines on prostate cancer. Eur Urol. 2008;53:68–80.
Keating NL, O’ Malley AJ, Freedland SJ, et al. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst. 2010;102:39–46.
Li S, Li X, Li J, et al. Experimental arterial thrombosis regulated by androgen and its receptor via modulation of platelet activation. Thromb Res. 2007;121:127–34.
Zhao J, Zhu S, Sun L, et al. 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:e107516.
Azoulay L, Yin H, Benayoun S, et al. Androgen-deprivation therapy and the risk of stroke in patients with prostate cancer. Eur Urol. 2011;60:1244–50.
Hu JC, Williams SB, O’Malley AJ, et al. Androgen-deprivation therapy for nonmetastatic prostate cancer is associated with an increased risk of peripheral arterial disease and venous thromboembolism. Eur Urol. 2012;61:1119–28.
Nguyen-Nielsen M, Borre M, Horváth-Puhó E, et al. Risk of venous thromboembolism among prostate cancer patients treated with androgen deprivation therapy in Denmark: a population-based cohort study, 1997-2011. Eur Urol Suppl. 2014;13:e976.
Klil-Drori AJ, Yin H, Tagalakis V, et al. Androgen deprivation therapy for prostate cancer and the risk of venous thromboembolism. Eur Urol. 2016;70:56–61.
Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. The Cochrane Collaboration. 2011. www.cochrane-handbook.org.
Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA. 2000;283:2008e12.
Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of non-randomized studies in meta-analyses. Eur J Epidemiol. 2010;25:603–5.
Egger M, Smith GD, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629.
Van Hemelrijck M, Adolfsson J, Garmo H, et al. Risk of thromboembolic diseases in men with prostate cancer: results from the population-based PCBaSe Sweden. Lancet Oncol. 2010;11:450–8.
Yii SC, Chung SD, Huang CY. The association between androgen deprivation therapy and pulmonary embolism: a population-based study. J Urol. 2017;24:36–7.
Higgins JPT, Thompson SG. Controlling the risk of spurious findings from meta-regression. Stat Med. 2004;23:1663–82.
Knapp G, Hartung J. Improved tests for a random effects meta-regression with a single covariate. Stat Med. 2003;22:2693–710.
Ehdaie B, Atoria CL, Gupta A, et al. Androgen deprivation and thromboembolic events in men with prostate cancer. Cancer. 2012;118:3397–406.
O’ Farrell S, Sandström K, Garmo H, et al. Risk of thromboembolic disease in men with prostate cancer undergoing androgen deprivation therapy. BJU Int. 2016;118:391–8.
Levitan N, Dowlati A, Remick SC, et al. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data. Medicine (Baltimore). 1999;78:285–91.
Brown BW, Brauner C, Minnotte MC. Noncancer deaths in white adult cancer patients. J Natl Cancer Inst. 1993;85:979–87.
Shahinian VB, Kuo YF, Freeman JL, et al. Increasing use of gonadotropin-releasing hormone agonists for the treatment of localized prostate carcinoma. Cancer. 2005;103:1615–24.
Shahinian VB, Kuo YF, Gilbert SM. Reimbursement policy and androgen-deprivation therapy for prostate cancer. N Engl J Med. 2010;363:1822–32.
Weight CJ, Klein EA, Jones JS. Androgen deprivation falls as orchiectomy rates rise after changes in reimbursement in the U.S. Medicare population. Cancer. 2008;112:2195–201.
Smith MR, Lee H, Nathan DM. Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab. 2006;91:1305–8.
Dockery F, Bulpitt CJ, Agarwal S, et al. Testosterone suppression in men with prostate cancer leads to an increase in arterial stiffness and hyperinsulinaemia. Clin Sci (Lond). 2003;104:195–201.
Bolla M, de Reijke TM, Van Tienhoven G, et al. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med. 2009;360:2516–27.
D’ Amico AV, Denham JW, Bolla M, et al. Short- vs long-term androgen suppression plus external beam radiation therapy and survival in men of advanced age with node-negative high-risk adenocarcinoma of the prostate. Cancer. 2007;109:2004–10.
Zumsteg ZS, Zelefsky MJ. Short-term androgen deprivation therapy for patients with intermediate-risk prostate cancer undergoing dose-escalated radiotherapy: the standard of care? Lancet Oncol. 2012;13:e259–e269.
This study was supported by grants from the National Natural Science Foundation of China (Grant No. 61301294). The supporting institution had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
SSW conceived the study idea. ZLG, YYH, LLG, FLC, SG, and STX performed literature search, study selection, and data extraction. ZLG, YYH, CMG, STX, and SSW performed statistical analyses and interpretation of corresponding results. ZLG drafted the initial manuscript. SSW modified the initial manuscript. SSW had primarily responsibility for final content. All authors made critical comment for the initial manuscript.
Conflict of interest
The authors declare that they have no conflict of interest.
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Guo, Z., Huang, Y., Gong, L. et al. Association of androgen deprivation therapy with thromboembolic events in patients with prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis 21, 451–460 (2018). https://doi.org/10.1038/s41391-018-0059-4
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