Does ADT for Prostate Cancer Increase Risk for Dementia?

Roxanne Nelson, BSN, RN

October 13, 2016

Androgen deprivation therapy (ADT) is an important component of prostate cancer treatment, but a new analysis suggests an association with dementia.

The observational study found more than twice the incidence of dementia among ADT users compared to nonusers. The absolute increased risk of developing dementia was 4.4% at 5 years, with a rate of 7.9% among ADT users vs 3.5% among nonusers.

The findings were published online October 13 in JAMA Oncology. However, in an accompanying editorial, experts emphasize the old adage that correlation does not mean causation.

Earlier this year, the same team reported a link between ADT and Alzheimer's disease, and last year, another group of researchers reported a link between ADT and neurocognitive dysfunction.

The new study, led by Kevin Nead, MD, DPhil, a radiation oncology resident at the University of Pennsylvania, Philadelphia, used a novel text-processing analytic approach for extracting biomedical data from ordinary patient medical records.

In addition to finding that the rate of dementia was doubled among ADT users compared to nonusers at 5 years, a further analysis that stratified data with respect to the duration of ADT treatment found that patients who had undergone at least 12 months of ADT had the greatest absolute increased risk for dementia (hazard ratio [HR], 2.36; P < .001).

"Multiple studies now suggest that androgen deprivation therapy may be associated with cognitive changes," said Dr Nead. "The current study supports the association between androgen deprivation therapy and cognitive changes by showing an association between androgen deprivation therapy and dementia.

 
ADT is a life-extending treatment in some men with prostate cancer. Dr Kevin Nead
 

"This reinforces the need for further evaluation of this association in prospective studies," he told Medscape Medical News. "We would, however, not recommend changes to clinical practice based on this study alone, given that ADT is a life-extending treatment in some men with prostate cancer."

That said, Dr Nead emphasized the importance of all prostate cancer patients having a detailed discussion with their physicians regarding the risks and benefits of ADT.

 
It would be reasonable to counsel patients regarding potential cognitive risks. Dr Kevin Nead
 

"Based on the body of literature that now exists, it would be reasonable to counsel patients regarding potential cognitive risks, as this has been shown in multiple retrospective and prospective studies," he explained. "The conversation regarding risks and benefits should continue between patients and their physicians during treatment, particularly if they develop bothersome side effects.

"But we don't, however, have any evidence to support specific screening for negative cognitive effects at this time for men on ADT," Dr Nead added.

Expanding the Focus

After reporting the association with Alzheimer's disease last year, for this study, Dr Nead and colleagues expanded the focus to include other forms of dementia.

Using an informatics approach, the team analyzed electronic medical record data from more than 1.2 million patients to examine the association of ADT with the subsequent development of dementia, including senile dementia, vascular dementia, frontotemporal dementia, and Alzheimer's dementia, among men with prostate cancer.

They reviewed records from the Stanford University Medical Center during a 20-year period (1994 to 2013); the final cohort included 9272 individuals with prostate cancer, of whom 1826 men (19.7%) had been treated with ADT.

Within this group, there were 314 new cases of dementia during a median follow-up of 3.4 years; the median time to dementia diagnosis was 4.0 years.

The authors found that there was a statistically significant positive association between use of ADT and dementia in propensity score–matched Cox proportional hazards regression analysis (HR, 2.17; P < .001) as well as in traditional multivariable adjusted analysis (HR, 2.21; P < .001).

When stratified by duration of use, patients who had been receiving ADT for at least 12 months had the greatest risk for dementia (HR, 2.36; P < .001). There was a statistically significant increased risk for dementia with increasing ADT duration (P < .001 for trend).

In stratification by age, patients younger than 70 years who had received ADT had lower cumulative probability of remaining dementia free in comparison with those in the same age range who did not receive ADT (log-rank P = .02).

The same pattern was true for those older than 70 years (log-rank P < .001). The authors did not observe any evidence of an interaction between use of ADT and age (Wald 0.29; P = .59).

New Style of Trial

In an accompanying editorial, Colin G. Walsh, MD, and Kevin B. Johnson, MD, both from Vanderbilt University, Nashville, Tennessee, note that although randomized clinical trials (RCTs) remain the criterion standard for rigorous clinical investigation, they are expensive to conduct and complex to administer.

"Observational cohort studies derived from mining extant clinical data, on the other hand, have many aspects not shared by traditional RCTs," they write.

One is that although the cost of maintaining a clinical data repository is large, the incremental cost of conducting cohort studies through data mining is a fraction of the cost of an RCT. Another aspect, they note, is that the "same processing that enables 1 data mining study may enable many others. The time required to analyze new cohorts is a fraction of that required for the initial effort.

"Although study recruitment, inclusion, and exclusion criteria are determined in a manner similar to that in an RCT, the algorithmic approach to identifying potential cohorts enables unprecedented scalability and speed of recruitment," write Dr Walsh and Dr Johnson.

The study authors "rightly frame" their conclusions as associations that are in need of further study, and "the adage holds true — correlation does not mean causation," say the editorialists. "However, results such as these have joined RCTs in high-profile journals and the lay press."

Therefore, the current study represents "another step to large-scale, low-cost, data-driven observational cohort studies that will require increased familiarity by readers with the statistical and technical aspects of data science applied to biomedical data," they add.

This study was supported by grants from the National Library of Medicine and the National Institute of General Medical Sciences. Coauthor Nigam Shah, PhD, holds patents related to the use of text-mining methods in clinical data. The other authors and the editorialists have disclosed no relevant financial relationships.

JAMA Oncology. Published online October 13, 2016.

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