Level 2 [mid-level] evidence
Androgen deprivation therapy (ADT) is frequently used for men with metastatic prostate cancer, although it has been associated with an increased risk of adverse events including cognitive decline.1 The studies to date, however, have been no more than a year in duration and the deficits reported have typically been subtle changes assessed on memory tests, not clinical diagnoses such as Alzheimer disease or mild cognitive impairment (MCI). A recent retrospective cohort study using data from electronic medical records evaluated the risk of developing Alzheimer dementia after ADT in 16,888 men with prostate cancer, 14.2% of whom were treated with ADT. Men receiving chemotherapy as well as men with a history of dementia and those diagnosed with Alzheimer dementia before initiating ADT were excluded. However, a diagnosis of MCI was not part of the exclusion criteria and baseline rates of MCI were not assessed.2
During the median follow-up of 2.7 years, 0.74% of men were diagnosed with Alzheimer dementia. A propensity score-matched analysis was performed to adjust for factors associated with dementia. The propensity score was determined based on the following for each patient: age at prostate cancer diagnosis; race; smoking status; antiplatelet, anticoagulant, antihypertensive, and statin medication use; and a history of cardiovascular disease, diabetes, or malignancy. All 2,397 men with prostate cancer receiving ADT were matched to 11,985 men with prostate cancer not receiving ADT. Compared to no ADT, ADT was associated with an increased risk of Alzheimer dementia (hazard ratio, 1.88; 95% confidence interval [CI], 1.1-3.2). In analyses assessing ADT duration, ADT for ≥ 12 months was associated with an increased risk of Alzheimer dementia (hazard ratio, 2.12; 95% CI, 1.11-4.03) compared to no ADT, but ADT for < 12 months was not.
While the results of this study are important, there are some significant limitations to consider. Although 16,888 patients from two large hospitals were included in the analysis, only 125 patients developed Alzheimer dementia during follow-up. This low incidence rate is reflected in the wide confidence intervals associated with the hazard ratios for Alzheimer dementia and this decreases the ability to clearly assess risk. Also, the median follow-up time was 2.7 years while the median time to a diagnosis of Alzheimer dementia was 4 years. A longer follow-up would likely have increased the rate of incident Alzheimer dementia diagnoses but was not possible given the datasets used. Additionally, the failure to assess MCI at baseline may hide a significant source of bias, since MCI is a significant risk factor for developing Alzheimer dementia. This risk factor should have been controlled for in the propensity score, especially given the short median follow-up time. Overall, the results of this study suggest that ADT may increase the risk of Alzheimer dementia in men with prostate cancer, but the magnitude of the absolute risk appears small.
Alan Ehrlich, MD, is a deputy editor for DynaMed, Ipswich, Mass., and assistant clinical professor in Family Medicine, University of Massachusetts Medical School in Worcester.
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NCCN Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network web site. https://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed September 7, 2016; Nelson CJ, Lee JS, Gamboa MC, Roth AJ. Cognitive effects of hormone therapy in men with prostate cancer: a review. Cancer. 2008;113:1097-1106
Nead KT, Gaskin G, Chester C, et al. Androgen deprivation therapy and future Alzheimer’s disease risk. J Clin Oncol. 2016;34:566-571