Risk of Alzheimer Dementia After Androgen Deprivation Therapy

EBM Focus - Volume 10, Issue 49

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Reference - J Clin Oncol 2015 Dec 7 early online (level 2 [mid-level] evidence)

  • Androgen deprivation therapy (ADT) for prostate cancer is associated with an increased risk of cognitive impairment, but the clinical significance is unknown.
  • In this study, ADT duration ≥ 12 months was associated with an increased risk of Alzheimer dementia compared to no ADT in men with prostate cancer.
  • The low incidence of Alzheimer dementia and short median follow-up limit the ability to evaluate the significance of the small increase in risk.

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 (NCCN, Cancer 2008 Sep 1;113(5):1097). 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.

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 for each patient based on age at prostate cancer diagnosis; race; smoking status; antiplatelet, anticoagulant, antihypertensive, and statin medication use; and a history of cardiovascular disease, diabetes, or malignancy and 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% 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. The overall result was consistent in a multivariate regression analysis including all patients and in analyses of men receiving chemotherapy and men with follow-up duration ≥ 5 years.

While the results of this study are important when counseling patients on therapeutic options for treating prostate cancer, 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.

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