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Androgen deprivation therapy for prostate cancer and dementia risk: a systematic review and meta-analysis

BACKGROUND: Androgen deprivation therapy (ADT) to treat prostate cancer may be associated with an increased risk of dementia, but existing studies have shown conflicting results. Here we synthesize the literature on the association of ADT for the treatment of prostate cancer with dementia risk.

METHODS: We conducted a systematic review of articles reporting the outcome of dementia among individuals with prostate cancer in those exposed to ADT versus a lesser-exposed comparison group (for example, ADT versus no-ADT; continuous versus intermittent ADT) using PubMed (1966–present), Web of Science (1945–present), Embase (1966–present) and PsycINFO (1806–present).

The search was undertaken on 4 December 2016 by two authors. We meta-analyzed studies reporting an effect estimate and controlling for confounding. Random- or fixed-effects meta-analytic models were used in the presence or absence of heterogeneity per the I2 statistic, respectively. Small study effects were evaluated using Egger and Begg’s tests.

RESULTS: Nine studies were included in the systematic review. Seven studies reported an adjusted effect estimate for dementia risk. A random-effects meta-analysis of studies reporting any dementia outcome, which included 50 541 individuals, 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 meta-analyzed studies reporting all-cause dementia (HR, 1.46; 95% CI, 1.05–2.02; Po0.001) and Alzheimer’s disease (HR, 1.25; 95% CI, 0.99–1.57; P = 0.06). There was no evidence of bias from small study effects (Egger, P = 0.19; Begg, P = 1.00).

CONCLUSION: The currently available combined evidence suggests that ADT in the treatment of prostate cancer may be associated with an increased dementia risk. The potential for neurocognitive deficits secondary to ADT should be discussed with patients and evaluated prospectively.

INTRODUCTION
Androgen deprivation therapy (ADT) is a mainstay of treatment for metastatic and locoregional prostate cancer.1 Globally, there are over a million new diagnoses of prostate cancer each year2 and an estimated 50% of men with prostate cancer will ultimately utilize ADT.3 Therefore, the potential individual and health system implications of adverse effects of ADT are significant.

Androgens have a demonstrated role in neuron growth, function, and maintenance.4 Correspondingly, men diagnosed with dementia have lower testosterone levels, preceding disease onset,5,6 and testosterone supplementation has been shown to improve spatial and verbal memory in men with dementia.7 Androgens may also specifically impact Alzheimer’s disease risk through modulation of β-amyloid protein accumulation with ADT users demonstrating increased circulating β-amyloid protein levels.8 ADT has also been convincingly linked to impairments in cognitive function9 with impaired cognitive performance as early as 6 months following the initiation of ADT in prospective studies.10 

Recent analyses have suggested a link between the use of ADT in the treatment of prostate cancer and an increased risk of dementia.11,12 However, other studies have failed to support this association,13,14 including the largest study examining this association to date.15 Currently, a comprehensive analysis of this rapidly evolving and controversial topic has not been undertaken and the clinical implications of these findings taken collectively are unclear. In this study, our aim is to undertake a systematic review and meta-analysis of the available data on ADT in the treatment of prostate cancer and dementia risk.

MATERIALS AND METHODS
The MOOSE statement guidelines were utilized for this systematic review and meta-analysis.16

Eligibility criteria
Eligible studies included all published articles that reported the outcome of a dementia diagnosis among individuals with prostate cancer, examining individuals exposed to ADT versus a lesserexposed comparison group (for example, ADT versus no-ADT; continuous versus intermittent ADT). Inclusion criteria for the quantitative meta-analysis were studies that reported an effect estimate (for example, hazard ratio) and controlled for confounding, or reported measurement of or adjustment for dementia that could be used to calculate an adjusted effect estimate.

Information sources
We carried out electronic searches in PubMed (1966–present), Web of Science (1945–present), Embase (1966–present) and PsycINFO (1806–present). The search was undertaken on 4 December 2016. The search strategy used for each database query can be found in Table 1. We additionally queried the reference lists of included articles. Two investigators (KTN and SS) independently assessed the eligibility of each study by using the title and abstract for initial screening followed by review of the full text and the data extraction with consensus reached by discussion. We used a data extraction sheet developed on the basis of the Cochrane Consumers and the Communication Review Group’s data extraction template (http://cccrg.cochrane.org/author-resources). Searchers extracted the following items from each study: first-author, type of article (for example, peer reviewed or abstract), location, year of publication, dates of the data collection or enrollment, cohort type (for example, prospective or retrospective), sample size, number of individuals on ADT, outcome (for example, all-cause dementia, Alzheimer’s disease and so on), how the outcome was delineated (for example, ICD-9 codes), type of effect statistic (for example, hazard ratio), effect statistic error measures (for example, confidence interval) and effect statistic P-value. Authors were contacted for additional details as needed. We assessed the internal validity of each study included in the qualitative review based on modified Newcastle-Ottawa Scale criteria.17

Statistical analysis
We conducted a meta-analysis to calculate summary statistic hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of dementia in prostate cancer patients exposed to a course of ADT versus a lesser-exposed comparison group (for example, no ADT, shorter ADT duration, intermittent ADT). We included comparison groups exposed to a lesser amount of ADT given evidence for a dose effect of ADT on dementia risk11,18 and that this would be expected to bias the result towards the null. Only effect estimates that accounted for confounding factors (for example, multivariable adjusted or propensity score matched) were utilized in the quantitative meta-analysis. In our primary meta-analysis, we included all eligible studies reporting a dementia outcome. Where eligible studies were clearly overlapping, we included the study with the largest number of events. We additionally conducted meta-analyses separately among those studies examining the outcomes of all-cause dementia and Alzheimer’s disease. The proportion of heterogeneity due to study variation was quantified using the I2 statistic.19 Random- or fixedeffects meta-analytic models were used in the presence and absence of statistically significant heterogeneity, respectively. Heterogeneity was explored as per the Cochrane Handbook for Systematic Reviews of Interventions.20 The presence of small study effects was evaluated by visualization of a funnel plot and calculating Begg and Egger statistics. Tests were considered significant if the two-sided P-value was less than 0.05. All analyses were carried out using Stata version 12 (StataCorp, College Station, TX, USA).

RESULTS
Our study selection process is summarized in Figure 1. In total, we reviewed 176 studies by title and abstract with 26 studies undergoing full text review. We excluded 17 studies after full text review because they did not examine individuals with prostate cancer exposed to ADT versus a lesser-exposed comparison group (n = 10), did not examine the diagnosis of dementia as an outcome (n = 6), or were a subgroup analysis of an included study (n = 1). Nine studies meeting our inclusion criteria are summarized in Table 2, which included five studies examining all-cause dementia, two studies examining Alzheimer’s disease and one study reporting on senile dementia. Eight studies compared patients treated with or without any ADT. One study23 compared intermittent versus continuous ADT. In this study, all patients underwent 7 months of induction gonadotropin-releasing hormone agonist and an anti-androgen followed by randomization to continued continuous ADT or intermittent treatment per PSA values.

Figure 1. Flow diagram of literature search and study selection for the systematic review and meta-analysis. ADT, androgen deprivation therapy.



We assessed study quality using modified Newcastle-Ottawa Scale criteria as shown in Table 3. Two studies21,22 did not implement methodology to account for confounding, or report an effect estimate for dementia risk, and were therefore excluded from the quantitative meta-analysis. Wiechno et al.,22 found similar Mini-Mental Status Examination scores between ADT (27.59) and non-ADT (27.41) users (P = 0.66). Shahinian et al.21 reported a statistically significantly increased risk of senile dementia among ADT users (5.99 versus 4.31%, Po0.001). However, rates of prevalent senile dementia were higher at baseline and this was not accounted for in the analysis. 

In our primary meta-analysis (Figure 2), we included six of the remaining eligible studies,11,13–15,23,24 as a study by Nead et al.11 overlapped with a cohort reporting a greater number of dementia events.18 A random-effects meta-analysis of these studies, which included 50 541 individuals, yielded a summary hazard ratio of 1.47 (95% CI, 1.08–2.00; P = 0.02) for the risk of dementia following ADT in the treatment of prostate cancer. A meta-analysis of studies examining all-cause dementia (n = 5) resulted in a summary hazard ratio of 1.46 (95% CI, 1.05–2.02; Po0.001). A meta-analysis of studies examining Alzheimer’s disease (n = 3) showed a summary hazard ratio of 1.25 (95% CI, 0.99–1.57; P = 0.06). A funnel plot to evaluate small study effects can be found in Supplementary Figure 1. There was no evidence of small study effects as evaluated by the Egger (P = 0.12) or Begg (P=1.00) tests.

Figure 2. Forest plots with summary hazard ratios for the risk of dementia among individuals on androgen deprivation therapy for the treatment of prostate cancer for any dementia outcome (a) and by subgroups of dementia outcomes (b). CI, confidence interval; HR, hazard ratio

I2 statistics to evaluate the proportion of heterogeneity due to study variation were 76% (95% CI, 47–89; Po0.001) for the primary analysis, 81% (95% CI, 55–92; Po0.001) for all-cause dementia, and 40% (95% CI, 0–82; P = 0.19) for Alzheimer’s disease. We further explored sources of heterogeneity in our primary analysis by excluding outlying studies, as described.20 We did not observe statistically significant heterogeneity when individually excluding outlying studies by Nead et al.18 (I2, 49%; 95% CI, 0–81; P = 0.10) or Khosrow-Khavar et al.15 (I2, 33%; 95% CI, 0–74; P = 0.20). Additionally, our results remained consistent with exclusion of the outlying studies by Nead et al.18 (HR, 1.15; 95% CI, 1.01–1.30; P = 0.04) or Khosrow-Khavar et al.15 (HR, 1.65; 95% CI, 1.37–1.98; Po0.001). Heterogeneity was not resolved with the individual removal of any other study.

In sensitivity analyses, we found consistent results when excluding Hershman et al.23 as the control group was exposed to intermittent ADT (HR, 1.42; 95% CI, 1.02–1.98; P = 0.04), Chung et al.13 given the possibility of remote overlap with Kao et al.14 (HR, 1.46; 95% CI, 1.05–2.02; P = 0.02), and Capitanio et al.24 as this study is published in abstract form only (HR, 1.48; 95% CI, 1.00–2.20; P = 0.05).

DISCUSSION
In this systematic review and meta-analysis of up to 50 541 individuals with prostate cancer, we found a positive, statistically significant, increased risk of dementia among those treated with ADT. We also found a consistent, statistically significant association when examining all-cause dementia. We did not find a statistically significant association of ADT with Alzheimer’s disease risk. There was no evidence that small study effects introduced a bias and our findings were consistent despite multiple conservative sensitivity analyses. This comprehensive analysis of studies examining the association of ADT with dementia further demonstrates that ADT may increase future dementia risk.


A causal association between ADT in the treatment of prostate cancer and an increased risk of dementia is one potential explanation for our findings and is supported by a number of factors. First, this association is biologically plausible. Neuron death, including secondary to the pathognomonic neurofibrillary tangle formation from abnormal tau production in Alzheimer’s disease, is the overarching cause of dementia in general. Androgens have been demonstrated to play a key role in neuron growth and axonal regeneration.4 Second, this association is coherent with the laboratory data showing that low testosterone levels predict future dementia5,6 and, in addition to ADT, result in elevated β-amyloid protein levels.8 Third, our findings are consistent with the data, supporting an increased risk of dementia among prostate cancer patients undergoing orchiectomy (HR, 1.67; Po0.001).25 Finally, in studies that evaluated dose response, there is evidence of a dose-response effect with those undergoing ADT for the longest duration having the greatest risk of dementia.11,18 

Androgen deprivation therapy may increase dementia risk through adverse effects on vascular health. Both decreased testosterone levels and ADT have been associated with cardiometabolic diseases, including diabetes, coronary artery disease, stroke and peripheral arterial disease,26–29 which have in turn been associated with dementia risk.30–32 Autopsy series demonstrate that the sensitivity and specificity for a clinical diagnosis of Alzheimer’s disease are in the 70–90% and 40–70% range, respectively, with primary alternative pathologies, including cerebrovascular disease.33 Therefore, it is likely that studies examining Alzheimer’s disease include individuals with alternative pathologies such as vascular dementia. If the impact of ADT on vascular disease is a primary driver of the association between ADT and dementia, this misclassification could artificially strengthen the association of ADT and Alzheimer’s disease. Alternatively, the magnitude of effect of ADT on Alzheimer’s disease-specific risk factors4,8 may be smaller and thus larger samples sizes would be needed to demonstrate a statistically significant association. This may explain the finding in our study of a non-significant (P = 0.06) association between ADT and Alzheimer’s disease compared to a statistically significant association of greater magnitude with all-cause dementia.

An alternative explanation for these findings is that the largely observational and retrospective analyses included in this review are confounded. In general, individuals in the general population undergoing ADT are older and have a greater burden of medical comorbidities.15 All of the studies included in our quantitative metaanalysis, except one,23 were retrospective population-based analyses. Therefore, given concern for confounding by factors like age, we only included effect estimates that accounted for confounding factors. Specifically, four studies undertook multivariable regression,13–15,24 two studies undertook propensity score matching,11,18 and one study was a multivariable adjusted secondary analysis of the randomized data.23 While confounding alone is unlikely to completely explain the association seen between ADT and dementia, it cannot be excluded as a source of bias in our analysis.

Our primary analysis showed significant between study heterogeneity with details of individual studies summarized in Tables 2 and 3. Exclusion of the outlying studies15,18 individually resulted in resolution of heterogeneity with consistent results compared to our primary analysis. The study by Nead et al.12 differed from other included studies, in that, it used informatics-based text analysis of the electronic medical record to the capture data from clinical notes, in addition to the coded date used in the other studies. This clinical text analysis has been shown to have a high degree of accuracy in detecting health outcomes34 and may capture events that would be missed using more traditional methods. While it could represent an opportunity for outcome misclassification, it is unclear that this would be differential and therefore introduce a bias, but this cannot be excluded. The outlying study by Khosrow-Khavar et al.15 conducted an analysis utilizing a United Kingdom based primary care database. While the authors acknowledge the limitations of this data source such as incomplete data regarding secondary care and the lack of standardization of outcome definitions,35 this represents the largest study to date and utilizes robust methodology to control for bias.

This study has limitations that warrant consideration. First, as detailed above, this meta-analysis largely included retrospective studies and we therefore only included studies that conducted multivariable adjusted regression analyses. Second, studies largely relied on diagnostic codes for dementia diagnosis, which may be subject to misclassification.36 Even in controlled settings not reliant on diagnostic codes, the diagnosis of dementia remains clinical and susceptible to misclassification. While there is evidence to support relatively high accuracy in the clinical diagnosis of dementia,33,37 we cannot exclude the introduction of a misclassification bias given the reliance of included studies on claims-based analysis. Third, we were not able to evaluate the risk of dementia by prostate cancer risk groups, which would provide clinically important information for risk-benefit evaluation, particularly among intermediate risk patients.38 Finally, we were unable to conduct subgroup analyses by type of ADT, which will be important in future studies as various forms of ADT have differing effects on the hypothalamic–pituitary–gonadal axis and could differentially impact dementia risk.39

The chronic health implications of cancer therapies are of increasing importance as survival rates following cancer diagnoses continue to improve.40 Additionally, as screening recommendations and treatment practices for prostate cancer evolve,41,42 informed and thoughtful utilization of systemic therapies will be critical. In this study, we further support the association of ADT in the treatment of prostate cancer with an increased risk of dementia and add to the growing body of evidence linking ADT with neurocognitive dysfunction.9,10,43 Further prospective studies are needed to validate this finding and to explore ways of reducing this possible cognitive harm. Additionally, we should continue to evaluate the impact of ADT on short-and long-term cognitive function in general. In the meantime, the potential for neurocognitive deficits secondary to ADT, specifically dementia, should be discussed with patients.

CONFLICT OF INTEREST
P Nguyen has consulted for Ferring and Dendreon and receives research funding from Astellas. The remaining authors declare no conflicts of interest.

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Prostate Cancer and Prostatic Diseases (2017) 00, 1–6

© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1365-7852/17

Written By: KT Nead1, S Sinha2 and PL Nguyen2
1Department of Radiation Oncology, Perelman Center for Advanced Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
2Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. 

A letter from the desk of the associate editor: J. Kellogg Parsons