Men with locoregional prostate cancer who were treated with a gonadotropin-releasing hormone (GnRH) agonist had a higher risk of incident diabetes and cardiovascular disease, according to an observational study published in the Journal of Clinical Oncology (2006;24:, 4448-4456).
“Physicians who are prescribing hormone therapy should talk about this potential risk with their patients,” lead author Nancy Keating, MD, MPH, Assistant Professor of Medicine and Health Care Policy at Harvard Medical School, said in an interview.
''Particularly for doctors prescribing this therapy in situations where there haven't been proven benefits, caution might be indicated until we know more about these potential risks, which could actually be more problematic for patients than the prostate cancer is, particularly if they have early disease and the prostate cancer isn't likely to cause them any problems in the next decade.
“For the people who need to be on hormone therapy because of advanced prostate cancer, it also might be worthwhile for doctors to occasionally screen for diabetes and maybe just that much more encourage lifestyle modifications like healthy diet and exercise to help prevent the risk of heart disease and diabetes.”
Dr. Keating cautioned, though, that the study is not definitive, as it wasn't a randomized trial.
Orchiectomy Associated with Diabetes, but Not CVD
The researchers initiated this study because work done by senior author Matthew R. Smith, MD, PhD, Assistant Professor of Medicine at Harvard, indicated that, within about 12 weeks of starting treatment with a GnRH agonist, men develop central obesity, lose muscle mass, and develop insulin resistance, Dr. Keating said.
These physiologic effects may contribute to the elevated rates of noncancer mortality observed in men with prostate cancer, and the researchers wanted to answer the question of whether these effects led to the development of clinically relevant endpoints.
“This question is particularly relevant because we know that a lot of men are getting this treatment, and the use of hormone therapy has increased markedly over the past decade, based on some other studies, and many men are getting this therapy for indications where there haven't been shown to be overall survival benefits,” Dr. Keating said.
The researchers used Surveillance, Epidemiology and End Results (SEER)-Medicare data for 73,196 men ages 66 and older who were diagnosed with locoregional prostate cancer between 1992 and 1999 and observed through 2001. Of these men, 36.3% received a GnRH agonist, and 6.9% had bilateral orchiectomy during follow-up.
Patients getting a GnRH agonist had a higher risk of incident diabetes (adjusted hazard ratio [HR] of 1.44), coronary heart disease (adjusted HR of 1.16), myocardial infarction (adjusted HR of 1.11), and sudden cardiac death (adjusted HR of 1.16). These risks were observed even after short-term therapy and remained during longer-term therapy.
Men who had orchiectomy had an increased risk of diabetes (adjusted HR of 1.34), but not coronary heart disease, myocardial infarction, or sudden cardiac death.
Dr. Keating said that she and her colleagues are not sure to what extent the small number of men who have orchiectomy in the United States contributed to the lack of an association with cardiovascular disease in the study, so they are collaborating with investigators in Europe, where orchiectomy is more common, to study the treatment further.
“It's also possible that there's something about the drug that raises the risk, but given our understanding of the way the drug works, we were quite surprised we didn't see the coronary heart disease risk with orchiectomy like we did with the GnRH agonist,” she said.
Need to be Selective in Prescribing HT
In terms of additional next steps, the researchers are currently working to obtain data that would enable them to replicate their findings in other populations. They encouraged other investigators to pool available data from randomized clinical trials to confirm the findings.
Dr. Keating and her colleagues would also like to investigate if there are characteristics (such as weight and overall health status) that predispose some men to developing diabetes or heart disease when they are receiving hormone therapy for prostate cancer, and Dr. Smith is planning to conduct intervention studies to determine if intensive diet and exercise and/or metformin can delay or reverse some of the physiologic effects of GnRH agonists.
William L. Dahut, MD, Chief of the NCI's Genitourinary/Gynecologic Clinical Research Section in the Medical Oncology Clinical Research Unit, said the study adds to the understanding that GnRH agonists are not without toxicities. “This is clearly a very important, well-done study,” he said.
“This study should give physicians some pause before starting patients on androgen deprivation unless there's a clear clinical indication for it.”
Dr. Dahut mentioned the study's reliance on Medicare coding for diagnosis and its retrospective nature as limitations, but said these concerns are not as great as they ordinarily would be given the large number of patients included.
“Obviously it's always better to have prospective data as opposed to retrospective, particularly when this is essentially data looking at SEER diagnosis, and so for trials that look at early hormonal therapy, if extensive measurement of cardiovascular status, insulin levels, and blood glucose levels can be incorporated early into those trials, that would obviously give more powerful data.”
Dr. Dahut also noted the issue of overtreatment of prostate cancer: ''One thing that's important to realize about this paper is that in the trials that do show benefit for androgen deprivation, benefits clearly are occurring despite these negative physiologic complications of the treatment, which in some ways more clearly defines the anticancer role of these therapies.
“The concern is that there's overtreatment,” he said, “and patients with other comorbid illnesses, patients who have fairly indolent disease manifested by, say, very slowly rising PSA, are probably being overtreated, and this hopefully will decrease some of the potential overtreatment.”