Guidelines suggest that every patient starting ADT for prostate cancer should be screened and assessed for CVD and CV risk factors. Preexisting CVD may further increase ADT’s deleterious side effects. In the Swedish population study, men with a history of two or more CVD events in the year prior to ADT initiation had the highest CVD risk. In a retrospective cohort of patients with high-risk prostate cancer, the addition of ADT to radiation therapy was associated with increased risk of all-cause mortality among men with previous congestive heart failure or myocardial infarction, but not in men without these prior events.
Clinicians must weigh the benefit of starting ADT against the potential CV toxicity on an individual patient basis. An internist, a primary care physician, a cardiologist, or a cardio-oncologist should be part of the tumor board or management team whenever possible. Evaluating the patient’s personal history of preexisting CVD is of utmost importance. There are no specific recommendations for the management of CVD in prostate cancer patients undergoing ADT. Similar to the “ABCDE” steps for controlling CV risk factors in cancer survivors, an “ABCDE” mnemonic was developed for prostate cancer patients: Awareness/Aspirin, Blood pressure, Cholesterol/Cigarettes, Diabetes/Diet, and Exercise.[21,22] This mnemonic emphasizes the importance of adhering to the established guidelines (ACC/AHA, American Diabetes Association, the Obesity Society) regarding the detection and management of CV comorbidities.
Lifestyle interventions include, but are not limited to: smoking cessation; 150 minutes per week of moderate-intensity physical activity; and a diet rich in fruits, vegetables, and whole grains, and low in saturated fat. While these interventions are recommended, they may be insufficient by themselves to achieve this patient’s metabolic goals. A recent meta-analysis showed that an exercise program can overcome many ADT adverse effects, but may not have a noticeable impact on many important cardiometabolic parameters, such as triglycerides, HDL-C, and fasting glucose level. Thus, Answer A is incorrect, since lifestyle interventions alone will likely be insufficient to modify this patient’s metabolic risk factors.
According to the 2013 ACC/AHA Guidelines on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, this patient fits in the statin benefit group of individuals aged 40–75 years with diabetes, LDL-C of 70–189 mg/dL, and an estimated 10-year atherosclerotic CVD risk of ≥ 7.5%. Dyslipidemia treatment for such persons consists of therapy with a high-intensity statin. Therefore, Answer B is incorrect, because moderate-intensity statin therapy will be insufficient for achieving the desired cholesterol reductions.
- Androgen deprivation therapy (ADT) for prostate cancer is associated with increased risk of fatal and nonfatal cardiovascular (CV) events.
- The type of ADT used, preexisting CV events, and CV comorbidities modify the magnitude of this risk.
- Currently for those patients with CV risk factors, strict comorbidity management as delineated by national guidelines is indicated.
- An “ABCDE” mnemonic may help with remembering the various useful interventions in comorbidity management: Awareness/Aspirin, Blood pressure, Cholesterol/Cigarettes, Diabetes/Diet, and Exercise.
According to the 2017 ACC/AHA Guideline for the Prevention, Detection, Evaluation, and Management of High BP in Adults, this patient has stage 2 hypertension (≥ 140 mm Hg systolic or ≥ 90 mm Hg diastolic). Therefore, at least one BP-lowering medication should be initiated. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are attractive options in patients with T2DM since they decrease CVD mortality in this population.[22,26] Because this man’s 10-year atherosclerotic CVD risk is ≥ 10%, a BP target of less than 130/80 mm Hg is recommended. Thus, Answer C is incorrect.
In 2016, the US Preventive Services Task Force published its latest statement on aspirin use in CVD prevention. The patient in this case fits in the group of adults aged 60 to 69 years with a ≥ 10% atherosclerotic CVD risk; in this group, the decision to initiate low-dose aspirin should be individualized. This man has a low bleeding risk and a high CVD risk because of his comorbidities and impending initiation of ADT. There is also interesting evidence about aspirin use and its benefit in cancer-specific mortality in prostate cancer patients, especially high-risk patients.[28,29] Thus, aspirin use is recommended, and Answer D is incorrect.
According to current national guideline recommendations, summarized in the Table, Answer E is the correct answer in this case. The patient has a 10-year atherosclerotic CVD risk > 10% and must start lifestyle interventions, high-intensity statin therapy, BP lowering with a goal of < 130/80 mm Hg, and low-dose aspirin. Several other interventions are worthwhile in the management of CV comorbidities, since they are tightly interconnected with CVD outcomes. These include weight management (lowering BMI and abdominal perimeter) and T2DM treatment goals. Adherence to published clinical guidelines is highly recommended in patients with prostate cancer and metabolic comorbidities who will be starting hormonal therapy.[30,31]
Outcome of This Case
The importance of lifestyle interventions was explained to the patient and he was sent to a tobacco cessation clinic. Antihypertensive treatment was started with enalapril 10 mg/d; strict BP monitoring was advised to achieve the goal of < 130/80 mm Hg. His metformin dose was increased to 850 mg TID, and he achieved a fasting glucose level of 80–130 mg/dL and HbA1c of < 7.0%. He was also started on high-intensity statin therapy (rosuvastatin 20 mg/d) and aspirin. His last lipid profile showed triglycerides of 156 mg/dL, total cholesterol of 126 mg/dL, HDL-C of 32 mg/dL, and LDL-C of 62 mg/dL. The patient completed EBRT and 24 months of hormonal therapy with degarelix. His last scans showed him to be disease-free, and his last PSA level was 0.01 ng/dL.
Financial Disclosure: Dr. Flaig receives an honorarium from BN ImmunoTherapeutics, and receives research funding from Bavarian Nordic, Dendreon, GTX, and Novartis; he serves as a consultant to GTX. Dr. Bourlon serves on advisory boards for Asofama (Astellas) and Janssen Pharmaceuticals. The other authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
Acknowledgments: The authors acknowledge the Aramont Foundation and Canales de Ayuda Foundation for their support of Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán Urologic Oncology Clinic research projects.
E. David Crawford, MD, serves as Series Editor for Clinical Quandaries. Dr. Crawford is Professor of Surgery, Urology, and Radiation Oncology, and Head of the Section of Urologic Oncology at the University of Colorado School of Medicine; Chairman of the Prostate Conditions Education Council; and a member of ONCOLOGY's Editorial Board.
If you have a case that you feel has particular educational value, illustrating important points in diagnosis or treatment, you may send the concept to Dr. Crawford at firstname.lastname@example.org for consideration for a future installment of Clinical Quandaries.
1. ACC/AHA Pooled Cohort Equations and Calculator. http://my.americanheart.org/cvriskcalculator. Accessed April 19, 2018.
2. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25:1596-605.
3. Bolla M, Van Tienhoven G, Warde P, et al. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol. 2010;11:1066-73.
4. Rhee H, Gunter JH, Heathcote P, et al. Adverse effects of androgen-deprivation therapy in prostate cancer and their management. BJU Int. 2015;115(suppl 5):3-13.
5. 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.
6. Bosco C, Bosnyak Z, Malmberg A, et al. 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.
7. Levine GN, D’Amico AV, Berger P, et al. Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. Circulation. 2010;121:833-40.
8. Nguyen PL, Je Y, Schutz FA, et al. Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. JAMA. 2011;306:2359-66.
9. Tivesten A, Pinthus JH, Clarke N, et al. Cardiovascular risk with androgen deprivation therapy for prostate cancer: potential mechanisms. Urol Oncol. 2015;33:464-75.
10. O’Farrell S, Garmo H, Holmberg L, et al. Risk and timing of cardiovascular disease after androgen-deprivation therapy in men with prostate cancer. J Clin Oncol. 2015;33:1243-51.
11. Chen DY, See LC, Liu JR, et al. Risk of cardiovascular ischemic events after surgical castration and gonadotropin-releasing hormone agonist therapy for prostate cancer: a nationwide cohort study. J Clin Oncol. 2017;35:3697-705.
12. Scailteux LM, Vincendeau S, Balusson F, et al. Androgen deprivation therapy and cardiovascular risk: no meaningful difference between GnRH antagonist and agonists—a nationwide population-based cohort study based on 2010-2013 French Health Insurance data. Eur J Cancer. 2017;77:99-108.
13. Albertsen PC, Klotz L, Tombal B, et al. Cardiovascular morbidity associated with gonadotropin releasing hormone agonists and an antagonist. Eur Urol. 2014;65:565-73.
14. Gupta D, Salmane C, Slovin S, Steingart RM. Cardiovascular complications of androgen deprivation therapy for prostate cancer. Curr Treat Options Cardiovasc Med. 2017;19:61.
15. Zareba P, Duivenvoorden W, Leong DP, Pinthus JH. Androgen deprivation therapy and cardiovascular disease: what is the linking mechanism? Ther Adv Urol. 2016;8:118-29.
16. Campelo AE, Cutini PH, Massheimer VL. Testosterone modulates platelet aggregation and endothelial cell growth through nitric oxide pathway. J Endocrinol. 2012;213:77-87.
17. Li S, Li X, Li J, et al. Inhibition of oxidative-stress-induced platelet aggregation by androgen at physiological levels via its receptor is associated with the reduction of thromboxane A2 release from platelets. Steroids. 2007;72:875-80.
18. Jin H, Lin J, Fu L, et al. Physiological testosterone stimulates tissue plasminogen activator and tissue factor pathway inhibitor and inhibits plasminogen activator inhibitor type 1 release in endothelial cells. Biochem Cell Biol. 2007;85:246-51.
19. Zhang Y, Ouyang P, Post WS, et al. Sex-steroid hormones and electrocardiographic QT-interval duration: findings from the third National Health and Nutrition Examination Survey and the Multi-Ethnic Study of Atherosclerosis. Am J Epidemiol. 2011;174:403-11.
20. Nanda A, Chen MH, Braccioforte MH, et al. Hormonal therapy use for prostate cancer and mortality in men with coronary artery disease-induced congestive heart failure or myocardial infarction. JAMA. 2009;302:866-73.
21. Montazeri K, Unitt C, Foody JM, et al. ABCDE steps to prevent heart disease in breast cancer survivors. Circulation. 2014;130:e157-e159.
22. Bhatia N, Santos M, Jones LW, et al. 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.
23. Yunfeng G, Weiyang H, Xueyang H, et al. Exercise overcome adverse effects among prostate cancer patients receiving androgen deprivation therapy: an update meta-analysis. Medicine (Baltimore). 2017;96:e7368.
24. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:2889-934.
25. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2017 Nov 13. [Epub ahead of print]
26. McMenamin UC, Murray LJ, Cantwell MM, Hughes CM. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in cancer progression and survival: a systematic review. Cancer Causes Control. 2012;23:221-30.
27. Bibbins-Domingo K. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: US Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2016;164:836-45.
28. Liu Y, Chen JQ, Xie L, et al. Effect of aspirin and other non-steroidal anti-inflammatory drugs on prostate cancer incidence and mortality: a systematic review and meta-analysis. BMC Med. 2014;12:55.
29. Jacobs EJ, Newton CC, Stevens VL, et al. 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.
30. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014;129:S102-S138.
31. Kalyani R, American Diabetes Association. Standards of medical care in diabetes—2018. Diabetes Care. 2018;41(suppl 1):S1-S2.