Oncologists, geriatricians, neurologists, and urologists who follow the medical literature (and Medscape Medical News) may recall a study published last year that raised a red flag about use of a common prostate cancer treatment and an increased future risk for Alzheimer's disease (AD).
Gary Nead, MD, a radiation oncologist from Stanford University in California and colleagues reported in December 2015 that men who were taking androgen deprivation therapy (ADT), which includes a wide variety of treatments, had an increased risk of developing AD compared to men who did not have the therapy. In fact, the data suggested that the risk for AD was nearly doubled in men who were receiving ADT.
Furthermore, the researchers used state-of-the-art data-mining technology to retrospectively scan more than 5 million medical records from two major American health systems in search of the associations between prostate cancer, an ADT prescription, and a later diagnosis of AD.
But now there is a big reaction to the big data.
Writing in letters appearing August 10 in the Journal of Clinical Oncology, where the study was first published, experts from around the world strongly caution against the study's conclusion and warn that the subject is more complex than the study allowed.
In their letter, Richard Bowen, MD, of the Medical University of South Carolina in Charleston, and two associates say that the study authors lumped 29 different ADTs together in their analysis.
That's a problem, because ADTs have different mechanisms of action and different effects on the hormones of the hypothalamic-pituitary-gonadal axis of the brain, which, in addition to testosterone, "likely" influence normal brain health, they write.
For example, they point out that gonadotropin-releasing hormone (GnRH) agonists suppress circulating levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex steroids. Furthermore, flutamide causes an increase in all of these hormones, and bicalutamide increases LH and FSH but leaves testosterone levels unchanged.
Details such as these are key, they suggest, because of a "large body of preclinical research that indicates that LH promotes AD pathology and that treatments that lower LH, including GnRH agonists such as leuprolide acetate, decrease AD pathology.
"Reanalysis of these results might be expected to demonstrate a decreased risk of AD with ADTs that decrease LH and an even greater [increased] risk of AD with ADTs that decrease testosterone but increase LH," they write.
This heterogeneity of ADTs "seems not to have been taken into account by Nead et al; this likely explains why the conclusion is inconsistent with previous studies," Dr Bowen and colleagues conclude.
In another letter, Claire Brady, MD, from Cork University Hospital in Ireland, and colleagues point out that the men who were taking ADT were older (mean age, 70.9 years) than those in the non-ADT group (mean age, 66.7 years; P < .001). "This age difference is fundamentally important as AD is a disease of aging, with incidence doubling every 5 years after age 65 years," they write
They then state the obvious: "Those who received ADT were an older population and could be considered to be at higher risk of AD as a result of age alone.
The Irish team also points out that brain health is "closely linked" to cardiovascular health, with shared risk factors that influence both. ADT has been linked with cardiovascular disease, hyperlipidemia, and diabetes, they say.
"Determination of the causality of AD is therefore increasingly more complex, and the possible impact of cardiovascular disease cannot be underestimated," they summarize.
A third letter, from Jeffery Leow, MD, of Brigham and Women's Hospital in Boston, and colleagues points out that ADT often means that patients need injections "every several months." In the ongoing office visits and physician encounters, such patients may be "more likely to be diagnosed with adverse events," including AD.
The Boston letter writers also mention two recent studies that found that patients with prostate cancer who receive ADT have higher rates of impaired cognitive performance at baseline, which may contribute to the eventual development of AD (J Clin Oncol. 2015;33:2021-27, 4314-15). There was also a suggestion in both of these studies that disease stage is "likely an important confounder of ADT and AD" (with higher-stage disease being a greater risk). But the study by Dr Nead and colleagues could not account for disease stage, which is another weak point, they add.
In a fourth letter, Michael Froehner, MD, and Manfred P. Wirth, MD, of the University Hospital Carl Gustav Carus in Dresden, Germany, say that ADT was "clearly used more often" in patients with confounding factors that were subsequently found to be associated with a higher incidence of AD.
They suspect that further "unmeasured or hidden" confounders were also present in the ADT treatment group, such as less judicious use of ADT among patients from lower socioeconomic groups. "The association observed between androgen deprivation therapy and risk of Alzheimer's disease should be communicated with caution," they say.
In a response to these letters, Dr Nead, who is now at the University of Pennsylvania in Philadelphia, and coauthors were gracious. They agree that stratification based on the form of ADT is a "critical future step to understand the association between ADT and Alzheimer's disease."
Perhaps most importantly, they "fully agree that the results of this study should be communicated to patients with caution."
Dr Nead and coauthors acknowledge that ADT has been shown in randomized clinical trials to improve survival in men with prostate cancer. On the other hand, they say their study provides data to support further research of the impact of ADT on the risk for AD.
Dr Bowen has financial ties to Patiently and Health First and a patent pending related to Alzheimer's disease. Dr Froehner has financial ties to Astellas Pharma, Amgen, and Novartis. One of Dr Nead's coauthors has ties to AstraZeneca, GlaxoSmithKline, Janssen Pharmaceuticals, and LEO Pharma; another has stock/ownership with Kyron. None of the other authors have disclosed any relevant financial relationships.
J Clin Oncol. 2016;34:2804-2805. Full text
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