Interview With an Expert: Cognitive Impairment and ADT

Alicia Morgans, M.D., M.P.H., Medical Oncologist
Vanderbilt University Medical Center

Does ADT cause cognitive impairment?

This question seems simple, but really, it’s more like opening a medical can of worms.  So let’s ask a different question.

Do men on ADT get cognitive impairment?  Yes, some do.  But many don’t.

It is hard to pin down definitive facts here – like, how many men get it? What’s the risk at one year, two years, five years, and ten years?

Nobody knows the exact statistics, and there are several reasons why.

  • There are probably many more men on ADT with cognitive impairment than we know about. But they don’t spend enough time with their doctors, at 5- and 10-minute follow-up visits to renew their Lupron prescription, for their mental status to be evaluated.  Cognitive impairment doesn’t always show up in casual conversation.
  • Scientists looking to answer this question aren’t using standardized criteria. For example, does hormonal therapy mean only ADT, or ADT plus another drug, like enzalutamide?  Also, are we talking about actual Alzheimer’s disease here, or just an inability to find the right word quickly on a crossword puzzle?

Let’s take yet another tack, and look at men who are actually showing signs of cognitive impairment.  That’s not much easier; there are still more questions:

  • Would they have gotten it anyway?
  • Did they start ADT with some risk factors for dementia already on board?
  • If they are showing signs of dementia, is it because when they got on ADT they stopped exercising, gained weight, and experienced depression – and could one of those those factors actually be the tipping point?

We have reached a crossroads here, and in some ways, it’s actually a sign of progress.  Long, long ago, heart disease wasn’t a big health problem – because people died of other things, like accidents and infections, and diseases that we now get routinely vaccinated for.  Diabetes wasn’t a huge risk for many people; sugar wasn’t widely available, there was no such thing as soda, obesity was rare, and people were more physically active.  Prostate cancer wasn’t that big a deal, either, because most men didn’t live long enough to get it.

Not too long ago, men with metastatic cancer died within months or a few years of their diagnosis.  Today, men with metastatic prostate cancer are living long enough to develop other problems, and doctors – who previously had just been focused on keeping these patients alive – are trying to figure out how best to keep them alive and well.

Alicia Morgans, M.D., M.P.H., Medical Oncologist

What we have here is an issue of survivorship – living with metastatic prostate cancer, and dealing with the side effects and challenges of treatment.   Medical oncologist Alicia Morgans, M.D., M.P.H., of Vanderbilt University Medical Center, is a PCF-funded investigator and a pioneer in studying survivorship.  Cognitive issues have not been much studied in prostate cancer, and scientists are playing catch-up.

“It’s not fair for us just to look at the benefits of treatment anymore,” she says, “now that we are starting to understanding the risks better.”

One easy place to start is to make sure that all men who are put on ADT really need it.   Next, men on ADT need better follow-up to monitor their cognitive function.   Morgans believes cognitive impairment in men on ADT is “underreported, underappreciated, and underdiagnosed.”  In a PCF-funded study, Morgans’ patients are taking brief neuropsychological tests; the tests look for changes in verbal memory, visual memory, attention, and executive function.  She hopes to develop reliable tests that can be done online – tests that could be given to many more patients in clinical trials, so that investigators can get an idea of the scope of the problem.

Family and friends can help:  Someone who is having cognitive impairment may not be aware of changes, or may not be able to articulate them well.  But his family and friends can help bring worrisome symptoms to the doctor’s attention.

Layers of medication:  One of Morgans’ patients, a 76-year-old man, had been doing fine on Lupron for years.  But when his PSA started to rise, Morgans added abiraterone, and then enzalutamide.  For this man, enzalutamide might have been the tipping point, “one thing on top of another thing, on top of another thing.  He was experiencing confusion and forgetfulness,” she says.  The man, a minister, was not able to write or deliver sermons anymore.  “We decided, despite the fall in his PSA, to stop the enzalutamide.”  Four weeks later, his cognitive function had improved, and “he continues to give sermons today.”

For this man, the key to cognitive issues seemed to be enzalutamide.  For another man, it could be something different.  It could be a different kind of domino effect – the higher risk of diabetes and cardiovascular disease, for instance; maybe these other health problems, in turn, affect the vitality of the brain.  “There may be subclinical strokes or cerebrovascular disease that we don’t know about,” Morgans says.

Loss of estrogen?  Morgans suspects that a change in cognitive function might also have something to do with a man’s estrogen levels.  Women aren’t the only ones who make estrogen; men make it, too, at lower levels.  But ADT causes men to have “very low levels of estrogens, lower than postmenopausal women have.”   In studies of women with breast cancer, she points out, “low estrogen levels on their own can be associated with cognitive decline.  It’s not ‘chemo brain,’ it’s something different.”

Men with prostate cancer don’t need to have low estrogen levels in order for their cancer to be treated; it just happens as a byproduct.  Normally, men need some level of testosterone in order to make estrogens.  “Estrogen doesn’t have to fall for us to treat prostate cancer, but it does fall with the method we use – we know testosterone drops to a place it’s never been since puberty.”  Would giving some type of estrogen along with the ADT be helpful?  No one knows.

Depression is a risk factor for dementia; big changes in sleep habits can also be a risk factor.  It may be that addressing each of these separately – with an antidepressant, with exercise, and with melatonin to help with sleeping – could help keep the brain working better.

What about changes in the way ADT is given?  Intermittent therapy may be an option.  This could mean giving ADT, stopping it for a few months, and then starting back up again.  “When men go off ADT, their testosterone comes back, they feel better, think better, their executive function is better – their ability to do a crossword puzzle, or find a synonym, or find the word they’re searching for – and they feel more like themselves again.”  Another approach, as PCF-funded investigator Samuel Denmeade is testing at Johns Hopkins, is “bipolar” hormonal therapy:  alternating ADT with its polar opposite – high-dose testosterone.

Treating the individual:  At the PCF, we talk a lot about precision medicine, treatments based on key genetic differences in cancer.  But personalized medicine is just what it sounds like: taking the person into account.  Some men may develop minor cognitive problems and be okay with it.  “A lot of my patients will tell me they’ve been impaired, but they’re still functioning over the years,” says Morgans.  Other men may not be okay with any loss in their ability to think, no matter how subtle.

Could “brain exercise” help?  Maybe.  Crossword puzzles and mind-challenging games may indeed act as mental push-ups and sit-ups.

The ultimate goal for treatment, scientists and doctors agree, is to find a way around ADT altogether, or to change it somehow so that the prostate cancer is affected, but the brain is not.  Until then, it’s up to doctors to use ADT wisely, only when it is medically appropriate.  “Using hormonal therapy has to be more than just a reflex, like giving people penicillin for a head cold,” says medical oncologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation.  The PCF, in fact, is actively funding research for other ways to treat metastatic cancer that don’t involve hormones at all – better chemotherapy, and better immunotherapy.

It’s also up to you, too, to make sure you start ADT only if and when you need it.  If you are at intermediate- to high-risk of recurrence, or if you have a rising PSA but no evidence of metastatic disease and your doctor wants to put you on ADT, get a second opinion.  You may also be eligible for a clinical trial of a different kind of therapy that does not affect your hormones.

If you do have metastatic disease, right now ADT is the standard of care, and it could put your cancer into remission for many years.  There is a lot you can do to help mitigate the side effects – which, in turn, may help protect your brain.

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Janet Worthington
Janet Farrar Worthington is an award-winning science writer and has written and edited numerous health publications and contributed to several other medical books. In addition to writing on medicine, Janet also writes about her family, her former life on a farm in Virginia, her desire to own more chickens, and whichever dog is eyeing the dinner dish.