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ADT for prostate cancer may increase risk for dementia
Treatment with androgen deprivation therapy may increase the risk for dementia in men with prostate cancer, according to observational study results.
ADT is commonly used when treating prostate cancer, but carries the risk for serious adverse health events. Recent research has linked receipt of ADT with an increased risk for neurocognitive dysfunction, including Alzheimer disease.
“We noticed a link between low testosterone and cognitive impairment, but no one had really looked at whether receiving ADT was associated with dementia,” Kevin T. Nead, MD, MPhil, radiation oncology resident at University of Pennsylvania Perelman School of Medicine, told HemOnc Today. “ADT results in lower testosterone, so we wanted to see if this treatment resulted in a risk increase.”
Nead and colleagues accessed data from the Stanford University health system and used a novel text-processing method to identify men diagnosed with prostate cancer between 1994 and 2013. The metric identified treatment strategies after prostate cancer diagnosis, including receipt of ADT.
Further text-processing of electronic health records identified cases of new-onset dementia. Among men who received ADT, incident dementia diagnoses were ascertained after ADT receipt and at least 180 days after initial diagnosis.
“Most observational research relies on discrete variables that are entered into medical records, like billing or diagnostic codes,” Nead said. “These are easily extractable data, but most of the electronic health record is comprised of nondiscrete variables that are recorded in clinical notes. Our group developed our method to pull that information out of the clinical notes and capture the data that is hiding inside medical records that normally wouldn’t be used.”
The researchers identified 9,455 men with prostate cancer. A total of 183 men had a prior diagnosis of dementia and were excluded. The final cohort included data from 9,272 men (mean age, 66.9 ± 10 years), of whom 19.7% (n = 1,826) received ADT.
Patients who received ADT tended to be older (mean, 69.9 ± 11 vs. 66.2 ± 10.8; P < .001), of nonwhite race (P < .001), and to have a history of smoking (P < .001). These patients further had a greater history of prior cardiovascular disease, diabetes or malignant neoplasms (P < .001 for all).
Median follow-up was 3.4 years (interquartile range [IQR], 1-7.2).
The researchers observed 314 new dementia diagnoses in the cohort. Median time to diagnosis was 4 years (IQR, 1.8-7.9).
Men who received ADT had a significantly higher risk for developing dementia (HR = 2.17; 95% CI, 1.58-2.99).
This persisted after the exclusion of patients with Alzheimer disease (HR = 2.32; 95% CI, 1.72-3.12) and patients diagnosed with dementia within the first 2-years of follow-up (HR = 2.39; 95% CI, 1.78-3.21).
The increased risk for dementia remained significant after the researchers excluded patients who received chemotherapy (HR = 2.35; 95% CI, 1.82-3.03).
ADT produced a 4.4% absolute increased risk for dementia at 5 years (7.9% for men who received ADT vs. 3.5% for men who did not).
The greatest risk increase occurred among men who received ADT for at least 12 months (HR = 2.36; 95% CI, 1.64-3.38).
An age-stratified analysis found that men aged 70 years or younger who received ADT had a lower cumulative probability of remaining dementia free than similarly aged men who did not receive ADT (log-rank P = .02). Similar results were seen among men aged 70 years or older (log-rank P < .001).
The researchers acknowledged study limitations, including the potential bias introduced by the reliance on electronic health records and text-processing models. They further noted that patients with cardiometabolic conditions — which are also risk factors for dementia — may be more likely to receive definitive radiotherapy with ADT.
The researchers further noted that because of their study’s observational design, they could not produce a definitive causal link between ADT receipt and risk for dementia.
“This is still a retrospective study, and I think it still falls into the category of a hypothesis-generating study,” Nead said. “Our study has identified important research questions, but we are not at the point where our data reflect something that would change standards of care. There is certainly a role for similar retrospective studies, but if we want a definitive answer about the impact of our findings, a prospective study needs to be done — preferably a randomized trial.”
The methods by which Nead and colleagues extracted data for their study may represent a new approach to conducting observational researching, according to Colin G. Walsh, MD, MA, and Kevin B. Johnson, MD, MS, of the department of biomedical informatics at Vanderbilt University Medical Center.
“Nead and colleagues implement falsification analyses to demonstrate that spurious associations are not identified in their approach,” Walsh and Johnson wrote in a related editorial. “To prove a method’s rigor, potentially false leads must be suggested and null hypotheses proven. Randomized clinical trials are powered to detect changes in relevant outcomes, noninferiority and superiority. However, the fact that falsification analyses are important here underscores the potential for computational methods to identify spurious results.”
Collaboration is needed for the widespread understanding and adoption of informatics research.
“The informatics and clinical communities will need to collaborate on core educational competencies to enable readers to assess the validity of study designs and results,” Walsh and Johnson wrote. “Such studies do not supplant the critical need for randomized controlled trials, but they represent another step in the potential of information technology to catalyze scientific inquiry.” – by Cameron Kelsall
For more information:
Kevin T. Nead, MD, MPhil, can be reached at kevin.nead@uphs.upenn.edu.
Disclosure: One study researcher reports pending patents related to text-mining data for clinical research. Nead and the other researchers report no relevant financial disclosures. Walsh and Johnson report no relevant financial disclosures.