Summary: Older males who were treated with androgen deprivation therapy for prostate cancer had an increased risk of developing Alzheimer’s disease over a ten-year follow-up.
Source: University of Pennsylvania School of Medicine
For patients with prostate cancer, treating the disease with androgen deprivation therapy (ADT) is linked to a higher likelihood of being diagnosed with Alzheimer’s disease or dementia, compared to patients who do not receive the therapy, according to a study from researchers in the Perelman School of Medicine at the University of Pennsylvania. The results were published this week in JAMA.
Of the 154,089 men sampled in the study, 62,330 received ADT within two years of their prostate cancer diagnosis and 91,759 did not. Of the patients with prostate cancer who received the hormone therapy, 13 percent were later diagnosed with Alzheimer’s disease, compared to 9 percent who did not receive ADT. For dementia, those numbers widened: 22 percent of prostate cancer patients who received ADT were diagnosed with dementia, compared to 16 percent who did not receive the therapy. This research builds on previous, smaller studies which showed similar correlations between hormone therapy and cognitive risks in patients with prostate cancer. The lifetime risk for Alzheimer’s dementia for men overall is 12 percent, according to data from the Framingham Heart Study.
“To our knowledge, this is one of the largest studies to date examining this association, and it followed patients for an average of eight years after their prostate cancer diagnosis. Our results suggest that clinicians need to raise their awareness about potential long-term cognitive effects of hormone therapy and discuss these risks with their patients,” said the study’s principal investigator Ravishankar Jayadevappa, Ph.D., a research associate professor of Geriatrics and senior fellow in the Leonard Davis Institute of Health Economics.
Prostate cancer is the most commonly diagnosed non-skin cancer in the United States and the second leading cause of cancer death in American men. ADT, or hormone therapy, has been shown to dramatically reduce the spread and progression of the disease. The treatment works by reducing levels of male hormones in the body, called androgens, to stop them from stimulating prostate cancer cells to grow. It is typically used in patients who have an advanced stage of the disease, when the cancer has metastasized, or in those with a high risk of recurrence after their initial treatment.
Despite the benefits of ADT, its use has faced controversy, as some evidence suggests that decreasing androgen levels may increase risk factors for Alzheimer’s and dementia, including loss of lean body mass, diabetes, cardiovascular disease, and depression. Hormone therapy may also affect cognitive function by impairing neuron growth and the regeneration of axons.
After controlling for several factors, such as other medical conditions, disease severity and sociodemographic characteristics — like age and marital status — the Penn researchers determined the hazard ratio for prostate cancer patients who receive hormone therapy. A hazard ratio measures the effect of an intervention over time. With all other factors remaining equal, the research team determined that patients with prostate cancer who receive hormone therapy face a hazard ratio that translates to a 14 percent increased risk of developing Alzheimer’s and a 20 percent increased risk of dementia when compared to other prostate cancer patients who are not exposed to ADT.
The Penn study contrasts with results from several recent papers that have examined the association — or lack thereof — between ADT and dementia. These past studies relied on data from a single institution, while others fail to adjust for cancer stage, ADT dose, and duration. Many examined a small cohort of patients and only for a short amount of time following their treatment.
By contrast, Jayadevappa’s team used data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database of the National Cancer Institute, which brings together Medicare administrative claims data and clinical tumor registry data from 18 different sites, encompassing 28 percent of the U.S. population. For their retrospective study, the Penn researchers collected data from a sample of men ages 66 years and older with localized or advanced prostate cancer who were diagnosed between 1996 and 2003.
The team noted more research is necessary to understand the possible biological mechanisms that underlie the link between dementia and ADT. As to whether physicians should advise their patients regarding the risk of hormone therapy, it may depend on the patient and the severity of his or her disease, cautioned study co-author Thomas Guzzo, MD, MPH, chief of Urology.
“I think we need to look at these patients on an individual level. Certainly, there are patients who need hormonal therapy and benefit from it greatly,” Guzzo said. “There are others where the evidence is less clear, and in these patients, we should strongly consider the risk of hormonal therapy versus the benefit in treating their prostate cancer. This should be a shared decision-making process with the patient.”
Funding: This study was funded by Agency for Healthcare and Research Quality grant 1R01HS024106-01. Additional Penn authors include Sumedha Chhatre, Bruce Malkowicz, Ravi B. Parikh, and Alan J. Wein.
Association Between Androgen Deprivation Therapy Use and Diagnosis of Dementia in Men With Prostate Cancer
Importance The association between androgen deprivation therapy (ADT) exposure and dementia is uncertain.
Objective To analyze the association between ADT exposure and diagnosis of Alzheimer disease or dementia among elderly men with prostate cancer. Design, Setting, and Participants This retrospective cohort study used data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results–Medicare linked database. Participants were 154 089 elderly men newly diagnosed with prostate cancer between 1996 and 2003. The analyses were conducted between November 1, 2018, and December 31, 2018.
Exposure Androgen deprivation therapy.
Main Outcomes and Measures Patients receiving ADT within 2 years of prostate cancer diagnosis were identified. Survival analysis was used to determine the association between ADT exposure and diagnosis of Alzheimer disease or dementia in the follow-up period. Propensity score and instrumental variable approaches were used to minimize measured and unmeasured selection bias. The association by dose of ADT was also examined.
Results Of the 295 733 men diagnosed with prostate cancer between 1996 and 2003, 154 089 met the study criteria. Of these, 62 330 (mean [SD] age, 76.0 [6.0] years) received ADT within 2 years of prostate cancer diagnosis, and 91 759 (mean [SD] age, 74.3 [6.0] years) did not receive ADT. Mean (SD) follow-up was 8.3 (4.7) years. Exposure to ADT, compared with no ADT exposure, was associated with a diagnosis of Alzheimer disease (13.1% vs 9.4%; difference, 3.7%; 95% CI, 3.3%-3.9%; P < .001; hazard ratio [HR], 1.14; 95% CI, 1.10-1.18) and dementia (21.6% vs 15.8%; difference, 5.8%; 95% CI, 5.4%-6.2%; P < .001; HR, 1.20; 95% CI, 1.17-1.24). For 1 to 4 doses of ADT, the HR was 1.19 (95% CI, 1.15-1.24) for Alzheimer disease and 1.19 (95% CI, 1.15-1.23) for dementia. For 5 to 8 doses of ADT, the HR was 1.28 (95% CI, 1.22-1.35) for Alzheimer disease and 1.24 (95% CI, 1.19-1.29) for dementia. For more than 8 doses of ADT, the HR was 1.24 (95% CI, 1.16-1.34) for Alzheimer disease and 1.21 (95% CI, 1.15-1.28) for dementia. The number needed to harm was 18 patients (95% CI, 17-19 patients) and 10 patients (95% CI, 9.5-11 patients) for Alzheimer disease and dementia, respectively.
Conclusions and Relevance Among elderly patients with prostate cancer, ADT exposure was associated with subsequent diagnosis of Alzheimer disease or dementia over a follow-up period of at least 10 years.