Probability of Dementia Higher in Men Receiving Androgen Deprivation Therapy

The longer the duration of androgen deprivation therapy, the greater the risk of dementia.
The longer the duration of androgen deprivation therapy, the greater the risk of dementia.

Androgen deprivation therapy (ADT) has been linked to an increased risk of dementia. The results, which were published in JAMA Oncology,1 showed an absolute increase in risk of 4.4% over 5 years in men with prostate cancer who were treated with ADT compared to those who did not receive ADT (7.9% vs 3.5%, respectively).

ADT is typically used as an adjunct to radiotherapy in individuals with stage T1b, T1c, T2a, or T2b prostate cancer and is associated with a reduction in 10-year mortality from 8% to 4%.3  It is estimated that 500,000 men in the US receive ADT annually,4 and approximately 50% of men treated worldwide for prostate cancer will receive ADT.5

Using data from the Stanford University Health System, the investigators followed the cases of 9272 men over age 18 that were diagnosed with prostate cancer from 1994 to 2013, with the period of follow-up started with the initiation of ADT treatment. Treatment history was identified through medical records and pharmacy orders. Among the cohort, 1826 patients were identified as having received ADT, while 7446 were designated as ‘non-users'. Overall, 314 new cases of dementia were identified.

Kevin T. Nead, MD, MPhil, of Stanford University School of Medicine, and colleagues identified a trend associated with duration of therapy. Those who had received ADT for at least 12 months had the highest risk of dementia diagnosis (HR: 2.17; 95% CI, 1.58-2.99; P< .001) The risk increased in a statistically significant manner with each incremental increase in ADT duration.

The influence of ADT treatment continued to show significance with increasing age, as the cumulative probability of developing dementia at 5 years was higher in men receiving ADT who were older and younger than 70 years (13.7% and 2.3%, respectively), compared to men both older and younger than 70 years who were not receiving ADT (6.6% and 1.0%, respectively).

The authors proposed several possible mechanisms to explain the potential adverse effect of ADT on cognition, including reduction of an important role androgen plays in modulating the accumulation of beta-amyloid proteins in the brain associated with dementia. They argued that decreases in circulating androgen also impacts normal interactions with testosterone that may increase the propensity for dementia, such as reducing neuroprotective properties both directly and through conversion of testosterone to estrogen, and by increasing the risk of damaging cardiometabolic processes.

The effects of ADT on cognition have been previously reported,5,6 although the current study is the first to show a direct link to Alzheimer disease.

Given the significant benefits of ADT in treating prostate cancer, and its broad use worldwide, this study contributes an important understanding of the long-term risks associated with such treatment and points to the need for further studies of the full impact and potential strategies to stratify patients according to risk.

Disclosures: Dr Shah reports holding several patents for text-mining methods in clinical data. No other disclosures were reported.

References

  1. Nead KT, Gaskin G, Chester C, Swisher-mcclure S, Leeper NJ, Shah NH. Association Between Androgen Deprivation Therapy and Risk of Dementia. JAMA Oncol. 2016 Oct 13; doi:10.1001/jamaoncol.2016.3662.
  2. Jones  CU, Hunt  D, McGowan  DG,  et al.  Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med. 2011;365:107-118.
  3. Shahani  S, Braga-Basaria  M, Basaria  S.  Androgen deprivation therapy in prostate cancer and metabolic risk for atherosclerosis. J Clin Endocrinol Metab. 2008;93:2042-2049.
  4. Meng  MV, Grossfeld  GD, Sadetsky N,  et al.  Contemporary patterns of androgen deprivation therapy use for newly diagnosed prostate cancer. Urology. 2002;60:7-11.
  5. Gonzalez  BD, Jim  HS, Booth-Jones  M,  et al.  Course and predictors of cognitive function in patients with prostate cancer receiving androgen-deprivation therapy: a controlled comparison. J Clin Oncol. 2015;33:2021-2027.
  6. McGinty  HL, Phillips  KM, Jim  HS,  et al.  Cognitive functioning in men receiving androgen deprivation therapy for prostate cancer: a systematic review and meta-analysis. Support Care Cancer. 2014;22:2271-2280.
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