ADT

More Evidence Linking ADT for Prostate Cancer to Adverse Neurocognitive Effect

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Meta-analysis shows increased risk of dementia, Parkinson’s, depression

A computer rendering of prostate cancer.

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 Diseasesopens in a new tab or window. “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-analysisopens in a new tab or window 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 consistencyopens in a new tab or window among studies, many of which were retrospective. Authors of yet another reviewopens in a new tab or window 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 trialopens in a new tab or window, 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.”

First-line ADT alone ‘too weak’ for advanced prostate cancer

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A more aggressive first-line regimen is needed to replace current standard treatment with androgen deprivation therapy (ADT) alone for advanced prostate cancer, experts suggest. [Cancer Lett 2015, doi:10.1016/j.canlet.2015.06.021]

“The fundamental problem with ADT for advanced prostate cancer is that virtually all patients show disease progression at a median of 18-24 months after the beginning of treatment. Despite innumerable studies on ADT in the past decades, no one was cured from the disease with this treatment option,” wrote Dr. Arndt Katzenwadel and Dr. Philipp Wolf from the Department of Urology, University of Freiburg, Germany, in a recent review titled ‘Androgen deprivation of prostate cancer: Leading to a therapeutic dead end’.

As the title of their review implies, the two experts believed first-line ADT was the main culprit for patients’ nonresponsiveness to subsequent lines of treatment. “Present second-line treatments bring only slight success in improving quality of life and overall survival,” they noted.

“ADT promotes alteration of signalling, gene expression and cellular outcomes with regard to survival, growth, proliferation, migration and invasion. This promotes the selection of tumour cells, which show an aggressive behaviour and an enhanced propensity to metastasize. These molecular changes can lead to therapeutic failure of drugs targeting these pathways,” they wrote. “It seems to be time for a fundamental paradigm shift in the first-line treatment of advanced prostate cancer.”

Their call for a more aggressive first-line regimen is supported by results of the recent phase III CHAARTED (Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extended Disease) study. In this study, adding docetaxel to ADT significantly improved overall survival (OS) of patients with metastatic hormone-sensitive prostate cancer vs ADT alone (median, 57.6 vs 44.0 months). [N Engl J Med 2015, doi:10.1056/NEJMoa1503747]

More importantly, in subgroup analyses, patients with high volume metastatic disease had an even greater OS improvement of 17 months with docetaxel plus ADT vs ADT alone. “This is in strong contrast to docetaxel-containing regimens in patients with castration-resistant prostate cancer, where the mean OS improvement was 2 to 3 months only,” Katzenwadel and Wolf remarked.

They were in agreement with Dr. Christopher Sweeney, lead investigator of the CHAARTED study, who stated, “Treating castration-resistant disease is a little bit defeatist [because it has already become resistant]. Let us try and start treatment early when it is more at risk of being cured – let us go forward by moving backward.”

Men on ADT Skipping Out on Bisphosphonates

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Few men in Canada receiving androgen deprivation therapy (ADT) for prostate cancer have simultaneous bisphosphonate treatment to prevent fractures, researchers found.

Only 3.4 per 100 men on ADT also had bisphosphonates in 2010-2012, Shabbir Alibhai, MD, of University Health Network in Toronto, and colleagues wrote in a letter in the Journal of the American Medical Association.

“As the most widely used class of prescription drugs for osteoporosis, this suggests limited awareness among clinicians regarding optimal bone health management,” they wrote.

Canadian guidelines have recommended bisphosphonates for men on ADT since 2006 because the prostate cancer therapy carries adverse effects including bone loss and increased fracture risk. Since 2002, Canadian guidelines also have generally recommended bisphosphonates for men with osteoporosis or fragility fracture.

To assess whether bisphosphonates were being used as recommended in this population, Alibhai and colleagues looked at data on 35,487 men, ages 66, and up from the Institute for Clinical Evaluative Sciences in Ontario and the Ontario Cancer Registry, who had ADT for prostate cancer between January 1995 and December 2012.

Bisphosphonate prescription claims in this population did rise over time, but rates were still low by the end of the study period, jumping from 0.35 per 100 in 1995-1997 to 3.40 per 100 in 2010-2012 (P<0.001).

Rates were higher among men with prior osteoporosis, rising from nearly nothing at study start to nearly 10 per 100 in 2010-2012. But rates of bisphosphonate prescriptions remained low even among men with prior fragility fracture, the researchers said.

Peak bisphosphonate claims occurred in 2007-2009, at about five per 100, and these were highest among men with prior osteoporosis at 11.89 per 100.

The fact that rates fell after that time point may have had to do with media reports about the association of bisphosphonates with rare side effects such as osteonecrosis of the jaw and atypical femoral fractures, the researchers said.

“This is appropriate for groups at low risk for fractures, but the decrease in use for high-risk patients is concerning,” they wrote, concluding that it’s “reasonable that most men with prior osteoporosis or fracture should be taking a bisphosphonate or other effective bone medication.”

Calcium, vitamin D supplements failed to prevent BMD loss.

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Calcium and vitamin D supplementation during androgen deprivation therapy did not prevent loss of bone mineral density among men with prostate cancer, according to study results.

Bone mineral density (BMD) loss is an adverse effect of ADT for men with prostate cancer. Doctors routinely recommend 500 mg to 1,000 mg calcium and 200 IU to 500 IU vitamin D per day as a supplement, according to background information in the study.

“Calcium and/or vitamin D supplementation to prevent loss of bone mineral density in these men seems so logical that no one had questioned whether it works,” Mridul Datta, PhD, a postdoctoral fellow at Wake Forest Baptist Medical Center, said in a press release.

Datta and colleagues reviewed guidelines for calcium and vitamin D supplementation.

They also analyzed the results of 12 clinical trials that evaluated a combined 2,399 men with prostate cancer who were undergoing ADT. Those trials compared the effects of calcium supplements, vitamin D supplements and other drugs on BMD.

Only one of the 12 trials showed an increase in BMD in the lumbar spine (0.99% in 12 months). The largest decrease in BMD in the lumbar spine was –4.9% in 12 months.

The trial results indicated that calcium supplementation of about 500 mg to 1,000 mg and vitamin D supplementation of 200 IU to 500 IU did not prevent BMD loss.

“It wouldn’t be so bad if there were simply no obvious benefit,” researcher Gary G. Schwartz, PhD, MPH, associate professor in the departments of cancer biology, urology, and epidemiology and prevention at Wake Forest Baptist Medical Center, said in the release. “The problem is that there is evidence that calcium supplements increase the risk of cardiovascular disease and aggressive prostate cancer, the very disease that we are trying to treat.”

Further studies are needed to evaluate the safety and efficacy of calcium and vitamin D supplementation in this patient population, the researchers wrote.

“Clinical trials to determine the risk-benefit ratio of calcium and vitamin D supplementation in men undergoing ADT for prostate cancer are urgently needed,” they concluded.

Source: Endocrine Today.

Prostate Cancer Trials Show No Link between Androgen-Deprivation Therapy and Cardiac Deaths

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Several studies have suggested that men who receive androgen-deprivation therapy (ADT) to treat prostate cancer may face an increased risk of dying from cardiovascular causes. But a new analysis of clinical trial results has found no evidence that ADT increases cardiovascular deaths among men with high-risk, nonmetastatic prostate cancer.

The findings, from a meta-analysis of eight randomized clinical trials, appeared in the December 7 issue of JAMA. Androgen-deprivation therapy, which suppresses the production of male hormones, is a mainstay of prostate cancer care. A form of ADT known as gonadotropin-releasing hormone agonist therapy has been linked to heart disease in some, but not all, studies.

Citing these studies, the Food and Drug Administration last year issued a safety warning for this class of drugs. Several medical societies have also issued a science advisory stating that there may be a relationship between ADT and cardiovascular events and death.

To explore this question further, Dr. Paul Nguyen of Dana-Farber Cancer Institute and his colleagues analyzed data on more than 4,000 participants in ADT trials. Among 2,200 men treated with ADT, there were 255 cardiovascular deaths (an overall incidence rate of 11.0 percent); among 1,941 men in the control groups, there were 252 deaths (11.2 percent).

The study also showed a benefit: Men who received ADT had a lower risk of dying from prostate cancer and other causes of death than men who did not. “Our study should be reassuring to most men with high-risk prostate cancer considering ADT,” noted Dr. Nguyen.

The main caveat of the study is that the researchers could not assess the risk of cardiac death for specific subgroups of patients, including those at highest risk for cardiovascular disease. Therefore, Dr. Nguyen said, “our study could not rule out the possibility that men with a history of cardiac disease could still be harmed by ADT.”

For men with significant underlying cardiac disease, the study authors recommend a careful examination by a cardiologist and a discussion of the risks and benefits of ADT.

Although ADT is not new, doctors are still learning about its risks and benefits, noted the authors of an accompanying editorial. Some research, for example, has suggested that ADT may shorten the time before a cardiovascular event occurs. (The current study could not address this question.)

To answer such questions, future prospective trials involving ADT should classify patients according to cardiovascular risk factors at the beginning of a study, noted the study’s senior author, Dr. Toni Choueiri of Dana-Farber Cancer Institute.

“While it is important to raise awareness of the possible cardiac side effects of ADT, it may be the case that the pendulum had swung too far away from the use of ADT, even for men with high-risk disease in whom ADT has been shown to save lives,” Dr. Choueiri wrote in an e-mail.

Source:NCI