A study published in the December issue of JAMA shows that even though earlier investigations suggested that androgen deprivation therapy designed to inhibit the production of male sex hormones for the treatment of prostate cancer may increase mortality risk from cardiovascular causes, researchers of a meta-analysis of previous randomized trials did not find any links to men with unfavorable risk, nonmetastatic prostate cancer. They did however find a link of a lower risk of prostate cancer specific death and all-cause death with androgen deprivation therapy.

Androgen deprivation therapy (ADT) in the form of a gonadotropin-releasing hormone (GnRH) agonist is a mainstay of prostate cancer treatment. The U.S. Food and Drug Administration were prompted to issue a safety warning as well as a joint statement by several medical societies in order to raise awareness of a possible association between ADT and cardiovascular events after several studies indicated that ADT may increase the risk of cardiovascular death. However, these findings have not been confirmed in other studies.

Paul L. Nguyen, M.D., of the Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School, Boston, and his team conducted a meta-analysis of randomized controlled trials in order to find out if ADT is connected with cardiovascular mortality in men with unfavorable-risk, nonmetastatic prostate cancer, all-cause mortality, and prostate cancer-specific mortality (PCSM).

The researchers reviewed medical literature and found eight randomized trials (n = 4,141 patients) that met inclusion criteria for the meta-analysis. In these trials the median (midpoint) follow-up ranged between 7.6 and 13.2 years.

They reported that:

  • There were 255 cardiovascular deaths among the 2,200 individuals who were treated with ADT, equivalent to an overall incidence of cardiovascular death of 11%.
  • For the control group, they found there were 252 cardiovascular deaths among the 1,941 patients, for an overall incidence of 11.2%.
  • Among participants in short-course ADT trials (6 months or less), the percentage of cardiovascular death was 10.5% compared to 10.3% for the control group.
  • For patients who participated in long-course ADT trials (3+ years), the percentage of cardiovascular deaths was 11.5% vs. 11.5% for the control group.

Furthermore, the team discovered that patients’ age did not alter their findings, as there was no connection between cardiovascular mortality and ADT whether the median age of the patient was younger or older than 70 years.

443 PCSM deaths occurred among the 2,527 men in the ADT group and 552 PCSM deaths occurred among the 2,278 participants in the control group. The relative risk of PCSM was 31% lower for men who received ADT, with an incidence of 13.5 percent compared to 22.1% for the control group. In total there were 1,140 deaths among men in the ADT group and 1,213 total deaths among men in the control group, with examination suggesting that the relative risk of all-cause mortality was 14% lower for those who received ADT compared to men in the control group (incidence, 37.7% vs. 44.4% respectively).

The researchers explain:

“Overall, the results of our study should be generally reassuring to most men with unfavorable-risk prostate cancer considering ADT, because it was associated with improved survival without measure excess in cardiovascular mortality, but a few important points need to be raised. First, none of the trials were stratified by preexisting cardiovascular comorbidity; therefore, our study cannot exclude the possibility that a small subgroup of men with underlying cardiac disease (even if controlled) could experience excess cardiovascular mortality due to ADT.

A second issue is that although our study assessed total cardiovascular deaths, it could not exclude the possibility that cardiovascular deaths happen earlier in men receiving ADT. In conclusion, our meta-analysis of more than 4,000 patients could not find any evidence that ADT increases the risk of cardiovascular death among men with unfavorable-risk, nonmetastatic prostate cancer, but did find a significant association between ADT and improved prostate cancer-specific survival and overall survival.”

William K. Kelly, D.O., and Leonard G. Gomella, M.D., of Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, write that with over 600,000 individuals in the U.S., with prostate cancer receiving ADT treatment, the benefits and short- and long-term risk of ADT must be clearly outlined.

“…men with cardiac disease who have the highest risks from complications from ADT should follow the appropriate secondary preventive measures from the American Heart Association (lipid-lowering therapy, antihypertensive therapy, glucose-lowering therapy, and antiplatelet therapy). Although ADT has been part of the treatment regimen for several decades, clinicians treating patients with prostate cancer are still understanding the short-term and long-term biological effects of biochemical castration but now have better appreciation of these complications.”

Written by Grace Rattue