Source/Disclosures
Disclosures: Jayadevappa reported no relevant financial disclosures. Please see that study for the other authors’ relevant financial disclosures. Bernard, Patil and Ryan report no relevant financial disclosures.
April 13, 2020
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Researchers explore cognitive effects of hormone therapy for prostate cancer

Source/Disclosures
Disclosures: Jayadevappa reported no relevant financial disclosures. Please see that study for the other authors’ relevant financial disclosures. Bernard, Patil and Ryan report no relevant financial disclosures.
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Charles Ryan, MD
Charles Ryan

Androgen suppression therapy for prostate cancer, although effective, is associated with a host of systemic adverse effects.

Researchers at the University of Minnesota are evaluating the effect of hormone therapy on cognitive function and also looking into how physical activity can help.

Charles Ryan, MD, professor of medicine in the university’s division of hematology, oncology and transplantation, and colleagues are conducting this research using a $500,000 grant from the Th!nk Different Foundation.

“We have a number of projects that we are launching in which we will examine various modalities for improving survivorship for men with prostate cancer,” Ryan said during an interview last year with HemOnc Today. In addition to studying the effect of hormone therapy on cognitive function and ways to mitigate any effect, the researchers planned to examine how to ameliorate the adverse effects through exercise, he said.

Androgen deprivation therapy is administered to men with cancer that has spread too far to be cured by surgery or radiation or to men who cannot undergo those treatments, according to the American Cancer Society. It is also used if the cancer does not respond to surgery or radiation or the patient is at a higher risk for recurrence. Some specialists may use hormone therapy to try to shrink the cancer before attempting radiation.

“The foundation of treatment for prostate cancer is the depletion of testosterone,” Ryan told HemOnc Today. “We are successful in putting the cancer into long-term remission, and sometimes short-term remission, by lowering testosterone levels by 90%. When we talk about the side effects of this treatment, we are really talking about what it is like for a man to live without testosterone, which is a fundamentally important hormone for male life.”

Most common adverse effects

The most common major adverse effects associated with ADT include hot flashes, osteoporosis and fatigue, according to a 2018 study by Patil and Bernard. Depression, gynecomastia, erectile dysfunction and metabolic syndrome also are common. Studies have shown conflicting results regarding risk for dementia, thromboembolic disease and cardiovascular disease, they said.

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Although Jayadevappa and colleagues acknowledged this conflicting evidence, in their 2019 study they found ADT was associated with a subsequent diagnosis of Alzheimer’s disease or dementia among elderly patients over a period of 10 years.

Of the 154,089 men in the study, 62,330 (mean age, 76 years) received ADT within 2 years of prostate cancer diagnosis, and 91,759 (mean age, 74.3 years) did not receive ADT.

Results showed 13.1% of men who underwent ADT received a diagnosis of Alzheimer’s disease compared with 9.4% of those not who did not undergo ADT. Researchers also observed dementia in a greater proportion of men who received ADT vs. those who did not (21.6% vs. 15.8%). These associations were apparent in different treatment groups, according to the researchers, who also saw a dose-response relationship.

Jayadevappa and colleagues said previous studies may have been limited by varying inclusion criteria, the inability to account for the duration of therapy and short follow-up time.

They indicated the possibility that hormone therapy may modify or augment the development of dementia rather than cause it.

Ryan said he and his colleagues planned to evaluate how testosterone depletion and blocking the androgen receptor with other agents can affect cognitive function.

“It has been known for quite some time that men receiving hormone therapy for prostate cancer may have a slowing of their executive function — they may have difficulties with spatial orientation and short-term memory processing,” Ryan said. “However, a lot of these effects do not show up in the clinic because patients adapt to these changes or do not bring them up with their physician because they do not think that they are related to treatment. We are going to approach this from a few different perspectives.”

The researchers planned to conduct tests among clinic patients to assess short-term memory, spatial orientation and executive function, Ryan said. Additionally, they planned to use MRI to examine blood flow in the brain during hormonal therapy and conduct a series of genetic analyses to determine if they can identify which patients may be at risk for cognitive dysfunction related to their hormonal therapy.

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“We have teamed up with Alzheimer’s disease researchers who have been able to identify genetic factors that may put men and women at risk for dementia,” he said. “We will test whether these risk factors for dementia are also risk factors for the cognitive effects of hormonal therapy of prostate cancer.”

“ADT is the cornerstone of management for men with metastatic prostate cancer,” Patil and Bernard wrote. “Ultimately, applying a multidisciplinary care model that incorporates specialists and allied health care professionals to aid in pharmacologic and lifestyle interventions is likely to provide optimal benefit in managing side effects for patients receiving long-term ADT.”

Jayadevappa and colleagues concluded in their study: “Our results suggest that clinicians need to carefully weigh the long-term risks and benefits of exposure to ADT in patients with a prolonged life expectancy and stratify patients based on dementia risk prior to ADT initiation.”

Effects of exercise

Ryan said researchers also are conducting a series of prospective clinical trials to explore exercise among men with prostate cancer.

“Epidemiologists have discovered that men who exercise vigorously several times per week, even after they have been diagnosed with prostate cancer, cut their risk for death by upwards of 40% to 50% relative to those who do not exercise [Kazmi et al],” he said. “Although this is an interesting observation, it is not proven. What we are doing in collaboration with the Movember Foundation is conducting a prospective clinical trial to assess vigorous exercise with a trainer and looking to see if survival is improved in these men. We plan to accrue nearly 900 men across Australia, Europe, North America and elsewhere.”

As men with prostate cancer live longer, clinicians must deal with long-term adverse effects of treatment.

“The fact that oncologists are now focusing on survivorship is a sign of success that we are having in turning advanced cancers into chronic conditions,” Ryan said. – by Jennifer Southall and Nancy Hemphill, ELS, FAAO

Disclosures: Jayadevappa reported no relevant financial disclosures. Please see that study for the other authors’ relevant financial disclosures. Bernard, Patil and Ryan report no relevant financial disclosures.