ASCO 2017: Androgen deprivation therapy in the treatment of prostate cancer and dementia risk: A systematic review and meta-analysis

Chicago, IL (UroToday.com) Since the introduction of the concept of castration as a treatment for advanced or metastatic prostate cancer (PCa) by Huggins & Hodges in 1941, castration and subsequently androgen deprivation therapy (ADT) have remained the standard first-line therapy for metastatic PCa. Built on the premise that PCa is driven by the androgen axis, ADT essentially shuts down androgen synthesis by manipulating the androgen axis. While known to be associated with specific short and long-term side effects, including hot flashes, gynecomastia, increased risk of heart disease, etc, the risk of developing dementia has been controversial.

While there have been conflicting associations in retrospective database studies or small prospective studies,1-4 the decision to continue treating patients with ADT has not been significantly affected. Without many other options, ADT remains the mainstay of therapy.

In this review and meta-analysis, now published in Prostate Cancer and Prostate Disease,1 the authors reviewed the literature in this field. Using the PRISMA statement guidelines, two authors independently searched for all papers that reported dementia as an outcome among prostate cancer patients exposed to ADT vs. some lesser comparison (no ADT or intermittent ADT). After confirming validity of each study per the Newcastle-Ottawa Scale criteria, they completed a meta-analysis of the data.

Ultimately, nine studies were included after having met the inclusion criteria. Seven of those studies reported an adjusted effect estimate for dementia risk. Once all the data was combined to include 50,541 individuals, a random-effects meta-analysis of studies reporting any dementia outcome showed an increased risk of dementia among ADT users (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.08–2.00; p = 0.02). We separately assessed the risk of all-cause dementia (HR, 1.46; 95% CI, 1.05–2.02; p < 0.001) and Alzheimer’s disease (HR, 1.25; 95% CI, 0.99–1.57; p = 0.06), but only all-cause dementia was significant. The statistic to evaluate the proportion of heterogeneity due to study variation was 76% (95% CI, 47–89; p < 0.001) for the primary analysis. There was no evidence of bias from small study effects (Egger’s test p = 0.19; Begg’s test p = 1.00).

While the studies are primarily retrospective, the currently available evidence suggests that ADT may be associated with an increased risk of dementia. The potential for neurocognitive deficits secondary to ADT should be discussed with patients and evaluated prospectively.

However, the inherent issue with these studies is selection bias. Negative studies or negative analyses were likely not published. Additionally, in this elderly patient population, competing risks may have outweigh dementia diagnosis.

Until a prospective study with close, specific follow-up for dementia is completed, this answer will remain unanswered.

Presented By: Kevin Thomas Nead, MD, MPhil, Radiation Oncology, Perelman School of Medicine, Philadelphia, PA

Co-Authors: Sumi Sinha, Paul L. Nguyen
Institution(s): Department of Medicine, Hospital of the University of Pennsylvania, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; Harvard Medical School, Boston, MA; Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA

Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
Twitter: @tchandra_uromd

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA

References:
1. Nead KT, Sinha S, Nguyen PL. Androgen deprivation therapy for prostate cancer and dementia risk: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2017 Mar 28. doi: 10.1038/pcan.2017.10. [Epub ahead of print] Review.

2. Khosrow-Khavar F, Rej S, Yin H, Aprikian A, Azoulay L. Androgen Deprivation Therapy and the Risk of Dementia in Patients With Prostate Cancer. J Clin Oncol. 2017 Jan 10;35(2):201-207. Epub 2016 Nov 21.

3. Nead KT, Gaskin G, Chester C, Swisher-McClure S, Leeper NJ, Shah NH. Association Between Androgen Deprivation Therapy and Risk of Dementia. JAMA Oncol. 2017 Jan 1;3(1):49-55. doi: 10.1001/jamaoncol.2016.3662.

4. Gonzalez BD et al. Course and Predictors of Cognitive Function in Patients With Prostate Cancer Receiving Androgen-Deprivation Therapy: A Controlled Comparison. J Clin Oncol. 2015 Jun 20;33(18):2021-7. doi: 10.1200/JCO.2014.60.1963. Epub 2015 May 11.
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