Dementia Risk Not Higher in ADT-Treated Prostate CA Patients

Kristin Jenkins

September 06, 2017

There was no increased risk for Alzheimer's disease following treatment with androgen deprivation therapy (ADT) in a group of men age 67 years and older with advanced prostate cancer, a new study concludes. The patients were enrolled in Medicare. The finding contrasts with recent reports suggesting that there is an increased risk for cognitive impairment in patients who receive ADT.

If anything, the new study suggests that Alzheimer's disease occurred at a decreased rate among men treated with ADT compared to those who were not, say the authors, led by Clement Joseph McDonald, MD, of the US National Institutes of Health, in Bethesda, Maryland.

The new study, published online August 25 in the Journal of Clinical Oncology, analyzed 14 years of claims data from more than 1.2 million men with prostate cancer.

The claims data were collected from the Virtual Research Data Center of the Centers for Medicare & Medicaid Services.

During the period 2001 to 2014, 35% of participants were treated with either chemical or surgical ADT. Of these patients, 8.9% developed Alzheimer's disease, and 18.8% developed dementia; 26% to 33% died without developing either condition.

Unadjusted rates of Alzheimer's disease and all-cause mortality per 1000 patient-years were higher among ADT recipients than for nonrecipents: 17.0 and 15.5 per 1000 person-years in recipients and nonrecipients, respectively. The unadjusted rates of all-cause mortality were 73.0 and 51.6 per 1000 person-years, respectively, the study authors report.

The unadjusted rates for dementia in those treated with ADT were 38.5% compared to 32.9% for those who did not receive ADT, with unadjusted mortality rates of 60.2% compared to 40.4%. The average observation time was 5.5 years.

However, after adjusting for other cancer therapies, as well as covariates that included underlying patient characteristics, each of 22 chronic diseases, and age and year of prostate cancer diagnosis, the team found that patients treated with ADT were not at increased risk for Alzheimer's disease. In a competing risk model analyses, there was even a 2% decrease in the rate of Alzheimer's disease that "possibly was attitributable to the high death rate."

In a set of parallel analyses, a 1% risk for dementia was seen in men treated with ADT, but that risk was "not clinically important," the investigators conclude. No dose effect of ADT on Alzheimer's disease or dementia was observed, and men treated with ADT were more likely to die before progression to either Alzheimer's or dementia. "These analyses found no risk of Alzheimer's disease [with ADT treatment] and only minuscule increases in the risk of dementia, not the nearly two-fold increase reported in the previous studies."

The new finding contrasts with recently reported studies that found an increased risk for both Alzheimer's disease and cognitive impairment, as reported by Medscape Medical News. Nevertheless, the controversy as to whether ADT is detrimental to cognitive health in men with advanced prostate cancer continues. Dr McDonald and colleagues point out that a meta-analysis of six studies showed that the risk for dementia was 47% higher following ADT than it was following another type of management. It also demonstrated that all-cause dementia was 46% more likely and that the risk for Alzheimer's disease was 25% higher among men treated with ADT.

The differences in the conclusions reached by the current study and the earlier meta-analysis could be the result of different methods and source data, the authors suggest. They note that the current study was much larger and had "more complete ascertainment" than the previously reported study.

However, another expert is not convinced. In an accompanying editorial, the lead author of the earlier meta-analysis, Kevin T. Nead, MD, MPhil, of the Department of Radiation Oncology at the University of Pennsylvania Perelman School of Medicine, Philadelphia, says that in spite of the current study's findings, "evidence of an association is building."

Although the current study "represents an important addition to the continued investigation of ADT and dementia risk," conflicting results indicate that prospective evaluation is needed to definitively determine whether there is a causal relationship between treatment with ADT and increased dementia risk, he says.

"This potential link is particularly relevant as the population of older long-term cancer survivors continues to grow, and the connection magnifies the chronic health implications of adverse treatment effects," he points out. However, definitive answers are unlikely in the near future, he comments.

Until more is known, clinicians must be prepared to counsel patients about the potential risks of ADT treatment relative to the absolute benefits, he says. "A complete understanding of the adverse effects of this therapy is paramount to permit informed decision making and patient selection."

In future, studies will need to specifically examine dementia and should include men with intermediate-risk disease as well as those already at increased risk for cognitive decline, Dr Nead suggests. "Given the widespread use and effectiveness of ADT, investigations that replicate and assess causality of an association between ADT and dementia are critical before changes in patient care are considered."

Approached for comment, Alexander Kutikov, MD, professor and chief of urologic oncology at Fox Chase Cancer Center, in Philadelphia, Pennsylvania, acknowledged that the current study ― and others like it that use administration or institutional cohorts ― provide mixed data. "Immense selection biases plague such studies, thus making interpretation challenging," he told Medscape Medical News. "Fidelity of dementia and Alzheimer's [disease] diagnosis indexing is also likely imperfect in such datasets."

Still, these latest data dovetail with those of a recent prospective randomized trial, he pointed out. They show that in older men with low testosterone and age-associated memory impairment, treatment with testosterone for 1 year was not associated with improved memory or other cognitive functions in comparison with treatment with placebo.

Dr Kutikov recommended that in discussing treatment options with patients, clinicians should "communicate that some data raise concerns, while other data dispute the findings." Unlike Dr Nead, however, Dr Kutikov said that "the overall level of evidence for causality is very low, as this latest analysis underscores, and thus, in my opinion, should not have a great impact on decision making."

The question of whether ADT affects cognitive function should be "stitched into" the next large randomized therapeutic trial, he added. "Only studies of prospectively randomized cohorts who have systematic, objective, longitudinal assessments of cognitive function will definitively answer this question."

This study was funded by the National Institutes of Health. The authors, Dr Nead, and Dr Kutikov have disclosed no relevant financial relationships.

J Clin Oncol. Published on August 28, 2017. Abstract, Editorial

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