Meta-analysis of the Impact of Androgen Deprivation Therapy on Cardiovascular Death in Patients with Prostate Cancer
Reporter: J Taylor Whaley
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 3, 2011
Presenter: Paul Nguyen, MD Presenter's Affiliation: Dana Farber/ Brigham and Women's Cancer Center
Although ADT has been shown in prospective, randomized trials to improve prostate cancer mortality in high risk localized, prostate cancer, various retrospective data have suggested that androgen deprivation therapy (ADT) has increased risk of diabetes mellitus, coronary artery disease, myocardial infarction, and sudden cardiac death.
Keating et al (JCO, 2006) reported an observational study of a population-based cohort of over 73,000 Medicare enrollees age 66 years or older who were diagnosed with locoregional prostate cancer during 1992 to 1999. All patients were treated with androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist. They noted an association with an increased risk of incident diabetes, coronary heart disease, myocardial infarction, and sudden cardiac death with ADT.
Similarly, D'Amico et al (JCO, 2007) performed a retrospective analysis of 1,372 men who were enrolled onto three randomized trials between February 1995 and June 2001. They found that men age 65 years or older who received 6 months of androgen suppression experienced shorter times to fatal MIs compared with men in this age group who did not receive androgen suppression.
These results, along with other retrospective data led to published warnings regarding the use of androgen deprivation and increased risk of cardiovascular death. The warning was released by the American Heart Association, American Cancer Society, and American Urological Association. Specifically, they concluded "It is plausible that ADT could increase cardiovascular risk on the basis of its adverse impact on risk factors for cardiovascular disease."
Based on this warning, the authors decided to perform a meta-analysis of randomized data for men with high-risk localized prostate cancer treated with or without androgen deprivation to evaluate the impact of ADT on cardiovascular deaths.
Materials and Methods
The authors searched Medline databases for scientific publications evaluating the effectiveness of ADT in prostate cancer.
Searched dates included January 1966 through April 2011
Inclusion criteria included the following:
Randomized trial comparing ADT vs. no ADT
Localized prostate cancer
Follow up greater than 1 year
Trial reported cardiovascular death
830 papers were identified; 8 very robust randomized trials (4141 patients) met the inclusion criteria
Including RTOG, Harvard, EORTC, and ECOG trials
Median follow up in those trials was 7.6 - 13.2 years
Local therapy included radiation (5), surgery (1), or no local treatment (2)
ADT Duration was short term (less than 6 months) in 3 trials and long term (3 years or greater) in 5 trials.
No excess cardiovascular deaths associated with ADT within the group of patients identified in the 8 randomized trials comparing the efficacy of ADT in high risk prostate cancer.
Patients treated with ADT were noted to have 11% risk of cardiovascular death. Patients without ADT treatment were noted to have 11.2% risk of cardiovascular death. The difference was not statistically significant.
ADT did decrease the risk of prostate cancer specific mortality with a relative risk of 0.68. This means that ADT decreased the risk of prostate cancer specific mortality by 32%. ADT also decreased the risk of all cause mortality with a relative risk of 0.88. This means that there is a 12% decrease in the risk of all cause mortality with the use of ADT in high risk prostate cancer.
There was no subset of patients identified that had increased risk of mortality. This included analysis for short course ADT, long term ADT, ADT in patients younger or older than 70 years old, and ADT with radiation.
This is a meta-analysis and therefore included trial level data. This means that no individual patient data was available for evaluation.
The authors could not exclude that there may be increased risk within a small subset of patients at increased risk for cardiovascular death.
Androgen deprivation therapy decreased the risk of prostate cancer specific mortality and all cause mortality in high-risk prostate cancer. It was not associated with increased risk of cardiovascular death.
This data is reassuring that ADT can be used safely in patients with high-risk prostate cancer.
Future randomized trials comparing ADT vs. no ADT should stratify by cardiovascular co-morbidities to further evaluate subsets of patients that may suffer increased risk of toxicity.
This large meta-analysis of high-risk prostate cancer failed to identify an increased risk of ADT with cardiovascular death in any subset of patients from 8 large randomized trials
There could be a subset of patients with history of CHF or prior MI that may be negatively impacted by ADT; however, this subset has yet to be identified and no prospective data exists in this particular scenario
Randomized data suggests that the benefit of ADT in high risk prostate cancer outweighs any small increased risk of increased cardiovascular death.