A combination of androgen-deprivation therapy (ADT) and radiation therapy can significantly lengthen survival for men with high-risk prostate cancer, at least those men without a history of heart disease, according to the results of a new meta-analysis.
The meta-analysis of eight randomized trials (JAMA 2011;306:2359-2366), which included a total of 4,141 prostate cancer patients, found no difference in the rate of cardiovascular deaths in men receiving ADT compared with those who did not. It also found that the use of ADT was associated with a lower risk of prostate cancer-specific mortality and all-cause mortality.
“This message should be reassuring for the vast majority of patients considering ADT,” said lead author Paul Nguyen, MD, Director of Prostate Brachytherapy at Dana-Farber/Brigham and Women's Cancer Center. “If a patient needs ADT for prostate cancer, he should go ahead and have it. Hormones can save lives.”
In the past few years, however, the Food and Drug Administration and some professional organizations have raised a caution flag about this treatment regimen, citing several studies that linked ADT to a higher risk of heart problems. Earlier this year, he reported on the results of a large, retrospective cohort study that found that men with high-risk prostate cancer and preexisting heart conditions, such as congestive heart failure (CHF) and myocardial infarction (MI) who were treated with ADT along with radiation therapy had an increased risk of dying (OT, 9/25/11).
AHA/ACS/AUA Science Advisory
In February 2010, the American Heart Association, the American Cancer Society, and the American Urological Association issued a joint Science Advisory alerting physicians to the potential risk, making suggestions regarding the evaluation and management of patients, both with and without known cardiac disease.
The statement concluded that ADT could increase cardiovascular risk on the basis of its adverse impact on risk factors for cardiovascular disease and that there may be a relationship between ADT and cardiovascular risk. In May 2010, the FDA said that a preliminary and ongoing analysis found that patients receiving gonadotropin-releasing hormone (GnRH) agonists were at a small increased risk for diabetes, heart attack, stroke, and sudden death. In October 2010, the FDA asked manufacturers to add new warnings to labeling for the use of ADT, in particular GnRH agonists.
“Over the last few years there has been a lot of concerning studies that have come out suggesting that ADT might be associated with cardiovascular events and cardiovascular deaths,” Nguyen said. “This led to a lot of concern by patients and doctors in the clinic about whether patients should be getting ADT. In the past year, these types of warnings were turning public opinion against the therapy.” Other recent studies did not find an elevated heart disease risk with the use of ADT.
“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, non-metastatic prostate cancer, but did find a significant association between ADT and improved prostate-cancer specific survival and overall survival. It remains unknown whether these results are also applicable to the subgroup of men with a prior history of CHF or MI, and therefore stratification of future randomized trials by cardiovascular comorbidity is needed.”
Asked to comment on the study, A. Oliver Sartor, MD, Medical Director of the Tulane Cancer and Professor of Cancer Research in the Departments of Medicine and Urology at Tulane Medical School, said: “We have been preaching the concept of ADT and radiation therapy for high-risk prostate cancer patients, and it has become the standard of care. It is reassuring that despite many concerns raised about the combination of ADT with radiation therapy, it is safe, effective, and appropriate for the vast majority of men.
“Most patients with significant heart failure or a history of recent MI are excluded from randomized trials. This retrospective study focused on a healthier group of patients. Those with prior history of MI or CHF may be a distinct subset of patients.”
Because the risk estimates had emerged from studies that were not randomized controlled trials, the Dana-Farber researchers undertook a meta-analysis of trials that met these standards and included data on adverse side effects, as well as the efficacy of ADT.
The 4,141 patients enrolled in the eight randomized trials with a median follow-up of 7.6 to 13.2 years mostly had locally advanced prostate cancer that had spread beyond the prostate gland, but had not metastasized to other organs. Inclusion criteria required the intervention group to have received GnRH agonist-based ADT, the control group with no immediate ADT, complete information available on cardiovascular deaths, and a median follow-up of more than one year.
The pooled analysis found that cardiovascular deaths were not significantly different in the patients who underwent ADT (11%) compared with the control patients (11.2%). Among 4,805 patients from 11 trials with overall death data, ADT was associated with lower prostate-cancer specific mortality (13.5%) compared with control patients (22.1%), and also prolonged survival. The all-cause mortality rate in the treated patients was 37.7% compared with 44.4% in the control group.
The researchers broke down the results into subgroups and found that ADT was not associated with excess cardiovascular death in trials of at least three years (long duration) of ADT or in trials of six months or less (short duration) of ADT, in men receiving radiation, or in which the median age of enrollment was 70 years or older. In five trials, the median age was over 70; and in three trials, the median age was younger than 70.
“Our primary endpoint was cardiovascular deaths. We found a decrease in prostate cancer specific mortality and overall mortality with ADT in the form of luteinizing-hormone releasing hormone agonists. For the average patient, ADT is safe from a cardiovascular perspective,” Nguyen said. “There are some subgroup analyses in multiple studies that show that perhaps the population that is most vulnerable are those with prior cardiovascular morbidity, such as CHF or MI. In our analysis, we could not stratify by these comorbidities. We expect that overall, 10% or less could have such prior history.”
The remaining question is whether androgen deprivation might increase risk in men with an established history of previous heart disease, but those data weren't available, he noted.
“It's still prudent to be cautious with these patients, and have them be evaluated by a cardiologist before starting treatment. The findings do not exonerate ADT from the increased risks of diabetes, insulin resistance, and weight gain. We do not discount that, but there is benefit in ADT for patients with high-risk prostate cancers.”
Sartor agreed that doctors still have to be cautious about monitoring for high blood pressure and cholesterol levels. Attention to cardiovascular risk factors is still a significant issue in men in this age group, he said.
“The number one cause of death among these men is cardiovascular disease. I do not think doctors should be neglectful of cardiovascular risk factors. But they do not have to suffer undo concern that this is a cardiotoxic therapy among men who do not have a history of MI or CHF.”
Summing up, Nguyen said, “For the majority of men who have unfavorable risk prostate cancer, ADT is going to reduce their risk of dying of prostate cancer and reduce the risk of dying overall. We did not see any evidence of increased risk of dying of cardiac causes.”