The Case
A 65-year-old man presented with locally advanced, high-risk prostate cancer. His medical history was remarkable for type 2 diabetes mellitus (T2DM) treated with metformin, 500 mg BID. He was also overweight and had dyslipidemia and hypertension, although he was not receiving medical therapy for any of these problems. He was an active smoker with a 27 pack-year history.
His prostate-specific antigen (PSA) level was 32 ng/mL; no other recent PSA measurements were available. Digital rectal examination revealed a fixed prostate (cT4) not amenable to surgical resection; his prostate biopsy showed an acinar adenocarcinoma in 8 of 12 cores, with a Gleason score of 4+4=8. He underwent a bone scan and CT scanning of the chest, abdomen, and pelvis, which showed no evidence of metastatic disease. He was offered treatment with external beam radiation therapy (EBRT) and androgen deprivation therapy (ADT) with degarelix.
Upon ADT initiation, his blood pressure (BP) was 140/90 mm Hg and his body mass index (BMI) was 27.2 kg/m2. Laboratory workup revealed a fasting glucose level of 123 mg/dL and a glycosylated hemoglobin (HbA1c) of 7.1%. His lipid profile showed: triglycerides, 180 mg/dL; total cholesterol, 170 mg/dL; high-density lipoprotein cholesterol (HDL-C), 30 mg/dL; and low-density lipoprotein cholesterol (LDL-C), 140 mg/dL. His serum creatinine level was 0.7 mg/dL and his calculated creatinine clearance, adjusted for overweight, was 103 mL/min. An electrocardiogram was normal.
According to the American College of Cardiology (ACC)/American Heart Association (AHA) Cardiovascular (CV) Risk Calculator,[1] the patient’s 10-year risk for atherosclerotic cardiovascular disease (CVD)-defined as coronary death, nonfatal myocardial infarction, or fatal or nonfatal stroke-was 49.6%. This CV risk calculation mandated strict metabolic control for the management of his CV risk factors.
Which of the following is the best way to manage cardiovascular comorbidities in this patient?
A. Lifestyle interventions only
B. Lifestyle interventions + moderate- intensity statin + BP target < 140/90 mm Hg
C. Lifestyle interventions + highintensity statin + BP target < 140/90 mm Hg
D. Lifestyle interventions + high-intensity statin + BP target < 130/80 mm Hg
E. Lifestyle interventions + highintensity statin + BP target < 130/80 mm Hg + aspirin
Correct Answer: E
Discussion
Prostate cancer is an exquisitely hormone-sensitive malignancy, and ADT is the mainstay of treatment in locally advanced and metastatic disease.[2,3] The therapeutic benefits of ADT are offset by a plethora of side effects, among which CVD is of greatest concern.[4] The association between ADT and fatal and nonfatal CVD is attested to by large retrospective and observational studies.[5,6] These data led to a joint statement issued by the AHA, the American Cancer Society, the American Urological Association, and the American Society for Radiation Oncology to raise awareness about CV consequences of ADT.[7] The aforementioned findings were not confirmed in a recent meta-analysis of randomized trials.[8] Potential reasons for this discrepancy may be the selection of a healthier population in clinical trials, underpowered post-hoc analysis, and short follow-up.[9]
The mechanism of action of the type of hormonal therapy prescribed may impact CVD risk. Hormonal treatment can be accomplished by reducing testosterone production (surgical orchiectomy or medical castration) or by blocking the interaction of androgen receptors with testosterone. The Swedish National Data Service reported an increased risk of incident CVD with gonadotropin-releasing hormone (GnRH) agonists and orchiectomy, and a decreased risk with anti-androgens.[10] In the meta-analysis by Zhao et al, GnRH agonists, and GnRH agonists plus anti-androgens, were associated with CVD, but not anti-androgens alone or orchiectomy.[5] A meta-analysis by Bosco et al showed an increased risk of nonfatal CVD with GnRH agonists, anti-androgens, and orchiectomy.[6] Recently, orchiectomy was reported to be associated with higher rates of CV events in older patients and those with a history of CV comorbidities within 1.5 years of initiating ADT.[11] With regard to GnRH antagonists vs agonists, reports are divergent. A nationwide French database reported no difference in CVD risk between GnRH agonists and antagonists.[12] However, post-hoc pooled data from six randomized trials showed that GnRH antagonists were associated with a significantly lower risk of cardiac events, compared with GnRH agonists. These same data led clinicians to the conclusion that it may be safer to prescribe antagonists in men at high risk for CVD.[13] These data supported our decision to start hormonal therapy with degarelix, a GnRH antagonist, in this case.
Several potential pathophysiologic mechanisms link ADT with CVD. Pro-atherogenic metabolic changes, similar to those of metabolic syndrome, have been described in patients receiving ADT. These include sarcopenic obesity (decrease in lean body mass and subcutaneous fat increase), dyslipidemia (increase in triglycerides, total cholesterol, LDL-C, and HDL-C), insulin resistance, and increased fasting plasma glucose levels.[14,15] However, in some respects, the metabolic changes seen with ADT are different from metabolic syndrome: an increase in subcutaneous rather than visceral fat, and an increase in HDL-C levels instead of the decrease typically seen in metabolic syndrome.[14]
The greatest risk of a first CV event after the initiation of ADT is within the first year of treatment. These early events may not be due solely to accelerated atherosclerosis, since this develops more chronically than acutely.[10] Testosterone at physiologic levels has many antithrombotic effects, including stimulation of nitric oxide production, reduction of thromboxane A2 release from platelets, and increased expression of tissue plasminogen activator.[16-18] Testosterone has also been noted to have a potential antiarrhythmic effect-shortening the QT interval.[19] Therefore, testosterone depletion may impact a man’s health through multiple physiologic channels. In addition, ADT has been associated with cytokine derangements in the tumor microenviroment, resulting in increased IFN-γ production by T lymphocytes (activated by stimulation of GnRH receptors in these cells), with subsequent plaque instability and rupture.[9]
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.[10] 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.[20]
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.[14] 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.[23] 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,[24] 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.
KEY POINTS
- 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,[25] 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.[27] 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 david.crawford@ucdenver.edu for consideration for a future installment of Clinical Quandaries.
References:
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