ADT for Prostate Cancer Not Linked to Cardiovascular Death

Roxanne Nelson

December 06, 2011

December 6, 2011 — In contrast to several studies that have linked androgen-deprivation therapy (ADT) for prostate cancer to a higher risk for fatal cardiovascular (CV) events — which triggered warnings from the US Food and Drug Administration (FDA) for these drugs — a new meta-analysis has failed to find any such association.

The meta-analysis, published in the December 7 issue of JAMA, analyzed data from 8 randomized studies with more than 4000 men, and found no significantly different rate of CV events between patients treated with ADT and control subjects.

Among the 2200 patients who received treatment with ADT, 255 deaths were related to CV deaths. The overall incidence of CV death was 11.0% in ADT-treated patients (heterogeneity test: Q = 33.58; P < .001; I² = 79.2%).

In the control group, there were 252 CV deaths among 1941 participants, for an overall incidence of 11.2% (heterogeneity test: Q = 33.81; P < .001; I² = 79.3%).

The corresponding relative risk (RR) for CV death in the ADT group, compared with the control group, was not significant (RR, 0.93; P = .41).

Proceed With Caution

However, an accompanying editorial cautions that even though these results appear to directly contradict those of some previous studies, this meta-analysis evaluated the use of ADT only in a very controlled setting and with a very specific population of patients and disease states.

The editorialists, William K. Kelly, DO, and Leonard G. Gomella, MD, both from Thomas Jefferson University in Philadelphia, Pennsylvania, note that although randomized controlled trials provide essential data for understanding the risks and benefits of therapy in a specific population of patients, these trials frequently exclude important patient groups. These include individuals with multiple comorbidities, older patients, and those with poor performance status.

"Differences in patient populations, study design, selection bias, limited number of cardiovascular events, and other uncontrollable confounding factors also may have contributed to the divergent conclusions on the risk of cardiovascular morbidity and mortality with ADT," they write.

Therefore, trials might not address the "risks of treatment in the populations that may represent a large proportion of patients who may need the therapy," say the editorialists. "This may be one reason population-based studies with ADT showed a higher incidence of cardiovascular morbidity and mortality, compared with the controlled prospective trials with ADT."

The study's first author, Paul L. Nguyen, MD, director of prostate brachytherapy and clinical trials for genitourinary radiation oncology, at the Dana-Farber Cancer Institute in Boston, Massachusetts, concurs. "Patients in randomized trials tend to be healthier than the average patient and tend to have less underlying cardiac disease," he told Medscape Medical News. "It is absolutely possible that men with severe cardiac disease, such as a history of myocardial infarction or congestive heart failure, may still have a higher risk of cardiovascular death from ADT. We could not rule this out from our study. Further investigation is needed in that 5% to 10% of men with significant underlying cardiac disease, and we are actively pursuing this."

It is very important that future studies of ADT stratify patients based on their CV comorbidities, added the study's senior author, Toni K. Choueiri, MD, assistant professor of medicine at Harvard Medical School in Boston.

Risks Noted and Advisories Issued

The association between ADT and an increased incidence of CV disease and related mortality was first raised in 2006, when a population-based study reported an increased risk for coronary heart disease, myocardial infarction, and sudden cardiac death in men using ADT (J Clin Oncol. 2006;24:4448-4456). Data from 2 other studies confirmed this increased risk (Cancer. 2007;110:1493-1500 and J Natl Cancer Inst. 2007;99:1516-1524).

As previously reported by Medscape Medical News, the results of these studies led to the FDA issuing a warning in 2010 about the potential risk for heart disease and diabetes in men treated with gonadotropin-releasing hormone agonists. Earlier that year, the American Heart Association, the American Cancer Society, the American Urological Association, and the American Society for Radiation Oncology issued a joint scientific report, advising that "there may be a relationship" between ADT therapy for prostate cancer and CV risk.

Allay the Fears?

Does this latest meta-analysis allay some of the fears about prescribing this therapy?

"Our study should be reassuring to the majority of men with unfavorable-risk prostate cancer who are considering ADT. It does not appear to cause an excess risk of CV-related death," said study author Dr. Nguyen.

Dr. Nguyen noted that even though it is important to raise awareness about the possible adverse cardiac effects of ADT, it might be that the pendulum has swung too far away from ADT, even for men with unfavorable-risk disease in whom ADT has been shown to save lives.

"For men with significant underlying cardiac disease, we recommend that they have a careful examination by a cardiologist, and that the benefits of ADT be weighed against the potential harms, as we could not specifically analyze this subgroup and, thus, cannot rule out harm," he added.

Coauthor Dr. Choueiri told Medscape Medical News that he agrees with this recommendation. "This adds to the complexity of therapies and the risk/benefit ratio," he said. "In men with significant CV disease, a close follow-up with a cardiologist is needed, with an honest discussion about the pros and cons."

Study Details

In the 4141 patients in the meta-analysis, CV death was not significantly different between ADT-treated patients and control subjects. Long-term ADT treatment (at least 3 years) was not associated with excess CV death (11.5% vs 11.5%; RR, 0.91; P = .34), nor was short-term ADT treatment (6 months or less) (10.5% vs 10.3%; RR, 1.00; P = .99).

In addition, in the 4805 men from 11 trials that included overall morality data, prostate-cancer-specific mortality was lower in ADT-treated patients than in control subjects (443 of 2527 vs 552 of 2278 events; 13.5% vs 22.1%; P < .001). They also had a lower rate of all-cause mortality (1140 of 2527 vs 1213 of 2278 events; 37.7% vs 44.4%; P < .001).

ADT Associated With Thromboembolic Events

However, a separate study, published online November 9 in Cancer, reports that ADT appears to be associated with a higher risk for a thromboembolic event.

The authors, led by Behfar Ehdaie, MD, from the Memorial Sloan-Kettering Cancer Center in New York City, used data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)-Medicare database to identify 154,611 patients with prostate cancer. Of this group, 58,466 (38%) received ADT.

At a median follow up of 52 months, 15,950 men reported at least 1 thromboembolic event. Of these, 8829 (55%) men had been treated with ADT and 7121 (45%) had not. The authors found that ADT was associated with an increased risk for a thromboembolic event (adjusted hazard ratio, 1.56; P < .0001). In addition, the duration of therapy was associated with the total number of events (P < .0001).

These results add to an expanding body of literature "that suggests concerns regarding ADT are warranted," they write, adding that it also emphasizes the importance of identifying men who are at the highest risk for complications and implementing strategies to prevent them.

Men considering ADT should be assessed for risk factors, including obesity, smoking, prolonged immobility, and personal history of stroke or thromboembolic event, before ADT is started, the authors note.

In addition, patients and their physicians need to be aware of and vigilant about watching for thromboembolic complications, they suggest. "Most importantly, the treatment decision-making process should include a careful discussion, tailored to the individual patient based on his health and the characteristics of his disease, of the expected benefits and potential harms of ADT and other treatment options," they conclude.

Dr. Nguyen pointed out that although database studies are very important for making clinical observations that require a large number of patients, the downside is the potential for confounding. "It is hard to be sure that patients selected for ADT don't already have a higher risk of developing certain events, including vascular events," he said. "It will be interesting to see if these results will also be seen in randomized data."

He added that these findings are not necessarily inconsistent with the results of his team's study — no excess of CV death. "We have good evidence from prospective studies that ADT causes some negative consequences on the CV system," Dr. Nguyen said. "It just may be that it is not severe enough or of a big enough magnitude to lead to cardiovascular death."

The study by Dr. Nguyen's team was supported by a JCRT Foundation grant; a Doris Duke Clinical Research Fellowship; David and Cynthia Chapin; Richard, Nancy, and Karis Cho; and a grant from an anonymous Family Foundation. Dr. Nguyen and colleagues have disclosed no relevant financial relationships. Dr. Gomella reports financial relationships with Janssen, Centocor Ortho Biotech, Ferring, sanofi-aventis, GlaxoSmithKline, and Dendreon, Endo. Dr. Kelly has disclosed no relevant financial relationships. The study by Dr. Ehdaie's team was supported by the Sidney Kimmel Center for Prostate and Urologic Cancers, in part by funds from David H. Koch through the Prostate Cancer Foundation, and by a grant from the National Cancer Institute. Dr. Ehdaie and colleagues have disclosed no relevant financial relationships.

JAMA. 2011;306:2359-2366, 2382-2383. Abstract, Editorial

Cancer. Published online November 9, 2011. Abstract

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