ADT in Prostate Cancer Linked to Risk of Cardiac Death

A retrospective cohort study of 5,077 men with cT1c-T3, N0, M0 prostate cancer treated with brachytherapy (with or without neoadjuvant androgen-deprivation therapy [ADT]) at a single high-volume center found that patients with a history of congestive heart failure or myocardial infarction are at increased risk of cardiac-specific mortality following administration of ADT. Findings were reported in BJU International by Paul L. Nguyen, MD, of the Dana-Farber/Brigham and Women's Cancer Center, Boston, David Ziehr of Harvard Medical School, and colleagues.

“To date, no study has identified whether cardiac deaths contribute to the excess mortality of men with a history of congestive heart failure or myocardial infarction who have received ADT,” noted the investigators. “Further, it is unknown if an increased risk of cardiac-specific mortality associated with ADT is limited to men with congestive heart failure or past myocardial infarction, or extends to men with coronary artery disease risk factors or to those with no coronary artery disease comorbidity. Accordingly, the present study examined the association between receipt of ADT and cardiac-specific mortality in men stratified by coronary artery disease comorbidity.” The primary endpoint was cardiac-specific mortality.

All patients included in the analysis were treated at the Chicago Prostate Center, which specializes in prostate brachytherapy. Patients were observed for a minimum of 1 year, during which no deaths occurred. Follow-up began on the day of radioactive seed implantation and included measurement of serum PSA level and digital rectal exam every 3 months for 1 year, then every 6 months for 4 years, and annually thereafter. No patient was lost to follow-up. Median follow-up was 4.8 years.

On biochemical recurrence, patients underwent routine follow-up as well as a pelvic and bone scans. Subsequent scanning and salvage therapy with a gonadotropin-releasing hormone agonist were initiated at the discretion of the treating physician following disease recurrence and before symptomatic or radiographic progression.

Cardiac deaths included those attributed to congestive heart failure, myocardial infarction, coronary artery disease, valvular disease, and other cardiac vasculopathy, as determined by the treating physician. Survival time was defined as the interval between the date of radioactive seed implantation and the date of death or the last follow-up for living patients.

Of the 5,077 men who received brachytherapy, 1,521 (30%) received neoadjuvant ADT for a median duration of 4 months. The 5,077-patient cohort included 2,653 men (52.3%) with no history of coronary artery disease risk factors, 2,168 (42.7%) with one coronary artery disease risk factor (diabetes mellitus, 179; hypercholesterolemia, 326; and hypertension, 1663), and 256 men (5%) with coronary artery disease (136 congestive heart failure and 120 past myocardial infarction). Overall, 419 men died, 91 of cardiac causes.

Cardiac-specific mortality increased with coronary artery disease comorbidity, the investigators reported. Deaths determined to be of cardiac etiology occurred in 36 of 200 (18%) patients with no coronary artery disease risk factors, 43 of 176 (24.4%) patients with one risk factor and 12 of 43 (27.9%) patients with coronary artery disease–induced congestive heart failure or myocardial infarction. After median follow-up of 4.8 years, no association was detected between ADT and cardiac-specific mortality in men with no cardiac risk factors or in men with diabetes, hypertension, or high cholesterol. ADT was, however, associated with a 3.3-times increased risk of cardiac-specific mortality in men with prior congestive heart failure or prior myocardial infarction. In this subgroup, cardiac-related deaths occurred in 7% of men receiving ADT after 5 years vs 2% of men not receiving ADT.

“ADT was associated with a 5% absolute excess risk of cardiac-specific mortality at 5 years in men with congestive heart failure or prior myocardial infarction, suggesting that administering ADT to 20 men in this potentially vulnerable subgroup could result in one cardiac death,” the authors concluded.

"While androgen deprivation therapy can be a lifesaving drug for men with prostate cancer and significantly increase the cure rates when used with radiation for aggressive disease, this study also raises the possibility that a small subgroup of men who have significant heart disease could experience increased cardiac death on ADT,” said Nguyen. “Despite the demonstrated association with cardiac harm, providers must not lose sight of the strong evidence that supports the use of ADT to reduce prostate cancer mortality in men with aggressive disease. At this point, we do not advise withholding ADT from any patient with aggressive prostate cancer for whom the results of randomized trials have shown a survival benefit to ADT, even if the patient has a history of heart disease.”

Commenting on the findings, Robert Dreicer, MD, chairman of the department of solid tumor oncology at the Cleveland Clinic in Cleveland, Ohio, who was not involved in the study, said, “Unlike the clear association of metabolic syndrome and osteoporosis with ADT use, the relationship with cardiac morbidity/mortality has been less clear. This retrospective analysis with the ability to dig a bit deeper into risk factors has raised the issue of a potential increased risk of mortality in a subset of patients (ie, those post myocardial infarction and with congestive heart failure). It’s of interest and needs prospective validation.”