More Evidence Linking ADT for PCa to Adverse Neurocognitive Effects -Meta-analysis shows increased risk of dementia, Parkinson's, depression

[cujoe]

As if we needed more reasons to dislike or avoid ADT, here is additional evidence of negative neurocognitive effects. This MedPage Today article will expecially be of special interest to those of us well into our "Golden Years" and on or considering ADT.

More Evidence Linking ADT for Prostate Cancer to Adverse Neurocognitive Effects - Meta-analysis shows increased risk of dementia, Parkinson's, depression, by Charles Bankhead, Senior Editor, MedPage Today January 9, 2024.

Men treated with androgen deprivation therapy (ADT) for prostate cancer had a significantly higher risk of dementia and other neurocognitive disorders, according to a meta-analysis of more than 2.5 million patients.

The magnitude of excess risk ranged from 20% for dementia to 66% for depression. The risk of Alzheimer's disease, vascular dementia, and Parkinson's disease were all significantly increased among men exposed to ADT versus those who did not receive the hormonal therapy, including those with and without prostate cancer.

"The increased risk of dementia is observed regardless of the treatment modality and duration; however, quantitative analysis is needed to assess the differences between treatment modalities and durations accurately," concluded David E. Hinojosa-Gonzalez, MD, of Massachusetts General Hospital in Boston, and colleagues in Prostate Cancer and Prostatic Diseases "It is important to note that some studies may have used similar databases and overlapping patient cohorts, which could introduce potential bias or duplicate data in this analysis."

"Clinicians should be vigilant in monitoring prostate cancer patients undergoing ADT for symptoms of cognitive decline and other neurodegenerative disorders," they added.

The findings add to a large volume of data on the relationship between ADT and neurocognitive functioning. Dozens of studies and reviews have examined the relationship without producing definitive answers. For example, another recent systematic review and meta-analysis included 31 studies, 16 of which showed no association between ADT and cognitive function; 11 of which showed a negative effect on one or more outcomes; and four that yielded inconclusive results.

Another systematic review showed no consistency among studies, many of which were retrospective. Authors of yet another review published just last year concluded that "studies continue to illustrate the varied outcomes in terms of the association of ADT and other systemic treatments for [prostate cancer] with cognitive decline, despite similar methodologies and design. Patient selection, varied neuropsychological testing, and varied duration of ADT probably account for the differences seen."

Numerous individual studies have yielded suggestive evidence of negative impact of ADT on cognitive function. A review of a national drug-safety databaseopens in a new tab or window showed that men treated with ADT had a 47% higher likelihood of cognitive impairment versus men who did not receive hormonal therapy. The risk was even higher in men treated with newer androgen receptor signaling inhibitors (ARSIs), but the association was not consistent across the ARSI class: increased risk with enzalutamide (Xtandi) and apalutamide (Erleada) but decreased risk with abiraterone (Zytiga).

Prostate cancer specialists note that consideration of the potential adverse effects of ARSIs on cognition should be balanced by consideration of potentially significant clinical benefits. In the landmark ENZAMET trial, enzalutamide was associated with a significant decline in cognitive function but also with a significant improvement in survival for men with metastatic hormone-sensitive prostate cancer, which "outweighed early deterioration in [health-related quality of life]."

Noting the inconsistent and sometimes conflicting evidence reported to date, Hinojosa-Gonzalez and colleagues performed a systematic review of contemporary studies examining the relationship between ADT and neurocognitive function, including dementia, Alzheimer's disease, vascular dementia, and Parkinson's disease.

The analysis included studies published through April 2023. Beginning with an initial list of 305 studies, the authors trimmed the number to 27. The studies involved a total of 2,543,483 patients, including 900,994 with prostate cancer treated with ADT, 1,262,905 with prostate cancer not treated with ADT, and 334,682 men without prostate cancer or exposure to ADT.

The data showed that treatment with ADT was associated with significantly increased hazard ratios (HRs) for:

Dementia: HR 1.20 (95% CI 1.11-1.29, P<0.00001)

Alzheimer's disease: HR 1.26 (95% CI 1.10-1.43, P=0.0007)

Depression: HR 1.66 (95% CI 1.40-1.97, P<0.00001)

Parkinson's disease: HR 1.57 (95% CI 1.31-1.88, P<0.00001)

Additionally, ADT conferred an increased risk of vascular dementia (HR 1.30, 95% CI 0.97-1.73, P<0.00001)

"All analyzed treatment modalities showed an increased risk of dementia," the authors noted in their discussion. "Orchiectomy had the highest estimated risk; however, it is important to note that this treatment modality also had the least evidence. Furthermore, the employed methodology does not differentiate whether there are statistical differences between types of ADT. Future studies should incorporate comparisons of treatment modalities into the results using network analysis or similar approaches."

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Below is link to the MedPage Article:

More Evidence Linking ADT for Prostate Cancer to Adverse Neurocognitive Effects - Meta-analysis shows increased risk of dementia, Parkinson's, depression, by Charles Bankhead, Senior Editor, MedPage Today January 9, 2024.

medpagetoday.com/hematology...

There are a number of research papers hyperlinked in the MedPage article. The one below is to the abstract (full paper is behind a paywall) of the referenced research:

Androgen deprivation therapy for prostate cancer and neurocognitive disorders: a systematic review and meta-analysis, Prostate Cancer and Prostatic Diseases, 2024 Jan 2. doi: 10.1038/s41391-023-00785-w. Online ahead of print.

pubmed.ncbi.nlm.nih.gov/381...

Let's see . . . why was a posting this?🤔

Y'all stay Safe & Well (I can still remember that!)

Ciao - Captain K9

[MateoBeach]

Thank you for highlighting this issue Cujoe. It provides some foundation for accepting that neuro-cognitive impairment from ADT (and certain ARSIs) is real. It validates individual experiences that many will recognize or at lest suspect. Noted well that enzalutamide and apalutamide have increased adverse cognitive effects vs. abiraterone and darolutamide which apperantly do not. This should inform choices and discussions with doctors.

I recently posted here about some possible interventions that may help with mild cognitive impairment and possibly risks for AD and Parkinson's. For those who may have some movement component (tremor or rigidity) or are at greater risk for Alzheimer's (family history and blood test for APO-E4 gene) should consult a neurologist for assessment.

[cujoe in reply to MateoBeach]

MB - Thanks for providing a concise summary of the take-home message. In addition to the well-considered suggestions in your post, linked below:

Treatment and Prevention Strategies for Cognitive Function in PCa - MateoBeach

healthunlocked.com/fight-pr...

I recommend that those of us in our "golden years", and especially those on WFPB diets that eliminate or restrict meat and dairy, consider supplementing with Taurine, which declines with aging and is mostly absent in plant foods. This world-class paper suggests possible multiple benefits.

Taurine deficiency as a driver of aging, Science, Published online 2023 Jun 9. doi: 10.1126/science.abn9257

ncbi.nlm.nih.gov/pmc/articl...

Live Long & Prosper. Ciao - Capt'n K9

[KocoPr]

That’s depressing lol pun intended!

Even though apalutamide shows no cognitive decline most patients are taking an ADT anti androgen drug along with the ARSi’.

Daro doesn’t cross the BBB so i wonder if what little testosterone available (after ADT anti androgen) is in use in the brain and converted to estrogen E2.

Without testosterone you can’t make estrogen.

Estrogen Effects on Cognitive and Synaptic Health Over the Lifecourse

ncbi.nlm.nih.gov/pmc/articl....

Abstract

Estrogen facilitates higher cognitive functions by exerting effects on brain regions such as the prefrontal cortex and hippocampus. Estrogen induces spinogenesis and synaptogenesis in these two brain regions and also initiates a complex set of signal transduction pathways via estrogen receptors (ERs). Along with the classical genomic effects mediated by activation of ER α and ER β, there are membrane-bound ER α, ER β, and G protein-coupled estrogen receptor 1 (GPER1) that can mediate rapid nongenomic effects. All key ERs present throughout the body are also present in synapses of the hippocampus and prefrontal cortex. This review summarizes estrogen actions in the brain from the standpoint of their effects on synapse structure and function, noting also the synergistic role of progesterone. We first begin with a review of ER subtypes in the brain and how their abundance and distributions are altered with aging and estrogen loss (e.g., ovariectomy or menopause) in the rodent, monkey, and human brain. As there is much evidence that estrogen loss induced by menopause can exacerbate the effects of aging on cognitive functions, we then review the clinical trials of hormone replacement therapies and their effectiveness on cognitive symptoms experienced by women. Finally, we summarize studies carried out in nonhuman primate models of age- and menopause-related cognitive decline that are highly relevant for developing effective interventions for menopausal women. Together, we highlight a new understanding of how estrogen affects higher cognitive functions and synaptic health that go well beyond its effects on reproduction.

[Justfor_]

No mention of Bicalutamide. No serious money in it, so who cares.

[pakb]

I'm hoping my husband is like my grandfather as far as cognitive issues. My grandfather was on Lupron for almost 23 years and golfed, did the NYT crossword (in pen!) and was an avid reader until he passed away at 88. My husband has been on it for 7 years. My grandfather was in one of the very first trials with lupron. Agree- it's a balance to weigh the positives and negatives.

[Cooolone]

It so hard to keep up with all the angles and divergent paths we may stumble down while in this fight! I can absolutely attest to reduced cognitive function, subtle, but it's there. Worrisome as I'm in a younger cohort of you will and currently just 59 and been in this fight over 5 years now. But on the subject, is one reason why I went for 2nd Feb 'lutamide' with Daro, when suspect resistance began. Felt from readings it was a better option. Now that all said, I'm not sure if the relaxed brain can also be attributed to the fact that I retired and no longer subject to the daily grind of work. Super stressful and engaged environment that required being on point every minute of the day, just think stress to the upteenth variable! Lol... But there's moments now, can't remember shyt! Think about something, the thought pops out of mind and can't recall it. Weird stuff like that, and it's scary!

But what are the options when this path is the main course fed to patients by most Oncologist? And what are the drawbacks of those paths? In any event, always compelling and a matter of choice. But knowledge allows that, and I'm thankful for posts like this that allow us to be exposed to expanding our knowledge base and help shape our paths! Thank you for posting!

[mrssnappy]

Thank for sharing. My husband was diagnosed with Parkinson's after starting Zoladex, but before adding Zytiga. We both have wondered if there's any connection but when I tried to find some studies I gave up after looking at so many that were inconclusive. I'm glad someone is looking at this question. The neurologists specifically put in the notes for my husband that there are no other features clinically to suggest a secondary cause of Parkinson's. They don't even consider a connection to ADT. All they have to offer for Parkinson's is another drug that has its own set of negative side effects. On a positive note though, he does get physical therapy paid for by Medicare which helps both the Parkinson's and the effects of ADT. Also, there are a lot of really good alternative groups that are helping those with Parkinson's find ways to slow the progression and help with the symptoms, many of which are the same as the side effects of ADT.