Cognitive Impairment Linked to Androgen Deprivation Therapy

Alexander M. Castellino, PhD

May 14, 2015

Men with prostate cancer treated with androgen deprivation therapy (ADT) are likely to experience cognitive impairment, a new study suggests.

The finding, from a study that followed 58 men on ADT, was published online May 11 in the Journal of Clinical Oncology.

"Men who received ADT for prostate cancer were more likely to exhibit impaired cognitive performance than men who only received a prostatectomy for prostate cancer and men who had no history of cancer," Brian Gonzalez, PhD, a postdoctoral fellow in the Health Outcomes and Behavior Program at the H. Lee Moffitt Cancer Center, in Tampa, Florida, who is the corresponding author of the article, told Medscape Medical News. The impairment was seen within 6 months and persisted for 12 months; it was observed across multiple cognitive function tests.

Approached for comment, Stacy Loeb, MD, assistant professor of urology and population health at New York University, in New York City, told Medscape Medical News: "There has been a question raised as to whether androgen deprivation therapy causes cognitive dysfunction. This study suggests that some men on ADT develop cognitive impairment."

She stressed that the side effects of ADT are extremely important because many men with prostate cancer receive it along with radiation therapy, including men with localized disease in the prostate, and it is a mainstay of treatment for metastatic disease.

"Since this [ADT] is commonly used and will continue to be used frequently in the management of prostate cancer, the side effects of ADT are extremely important," she said.

The Moffitt Cancer Center Study

Cognitive function was evaluated in 58 men with nonmetastatic or asymptomatic metastatic prostate cancer receiving ADT, as well as 84 men with prostate cancer not receiving ADT and 88 men without prostate cancer.

Men without prostate cancer were matched for age and educational level with those with prostate cancer who received ADT. Men with prostate cancer who were not receiving ADT were also matched to those receiving ADT on time since prostate cancer diagnosis.

For the purpose of the study, men with prostate cancer who were not receiving ADT and men without prostate cancer were combined in order to increase the statistical power of the study; the two groups did not differ with regard to mean cognitive performance or impairment of cognitive performance.

Cognitive function testing was conducted by clinical psychology graduate students who were trained and supervised by experienced clinical psychologists. Tests that have been validated in older individuals were used to evaluate verbal memory, visual memory, attention, executive function, and cognitive reserve.

Self-reported measures included validated instruments used to measure depression, fatigue, and hot flash–related daily interference in men with prostate cancer. Dr Gonzalez told Medscape Medical News: "These were included in the study because we wanted to see if worse pre-ADT symptoms of depression, fatigue, and hot flashes would predict worse cognitive function."

"None of these were associated with cognitive impairment," he added.

As per the International Cognition and Cancer Task Force guidelines, impaired cognitive function was defined as scoring 1.5 standard deviations (SDs) below published norms on at least two tests, or scoring at least two SDs below published norms on at least one test.

To determine genotypes linked to cognitive impairment, genomic DNA was extracted from blood and genotyped using the Illumina GoldenGate assay. An algorithm developed at the Moffitt Molecular Genomics Core was used to link cognitive impairment with genotypes.

On the basis of published evidence of the association of cognitive impairment, depression, fatigue, or circadian rhythm with single-nucleotide polymorphisms (SNPs), 384 SNPs were included in the analysis.

"We expected that men receiving ADT would exhibit a 'hit' to their cognitive functioning, but we also wanted to determine whether men with certain genotypes would experience a 'double hit,' " Dr Gonzalez explained to Medscape Medical News.

Cognitive Impairment and Its Genetic Predictor

As expected, more men receiving ADT had a Gleason score of 8 or higher. Mean comorbidity index was also higher in the ADT group compared with the control groups. Additionally, men in the ADT group were less likely to be white or better educated compared with the control groups.

The researchers reported that men receiving ADT were 70% more likely to show cognitive impairment during a 6-month period compared with the control group (odds ratio [OR], 1.71; 95% confidence interval [CI], 1.01 - 2.89). In addition, at the end of 12 months, men in the ADT group were twice as likely to experience cognitive impairment (OR, 2.42; 95% CI, 1.27 - 4.61).

The study researchers reported that the 44% of men receiving ADT who had a particular variant (rs1047776) of the GNB3 gene were 14 times more likely to exhibit cognitive impairment.

"The GNB3 gene is associated with transporting many different types of signals across the cell membrane, and previous studies have found this gene is associated with cognitive functioning," Dr Gonzalez said.

"Studies like ours show the importance of identifying genetic predictors of cognitive impairment. This information can be used to further personalize cancer care based on patients' unique characteristics and to find patients who may be prone to be intolerant of this standard type of treatment," said Mayer Fishman, MD, PhD, senior member of Moffitt's Genitourinary Oncology Program, in a Moffitt press release.

 
The risk of cognitive impairment should be considered. Dr Brian Gonzalez
 

"The risk of cognitive impairment should be considered when deciding whether or not to receive androgen deprivation therapy for prostate cancer," added Dr Gonzalez.

Dr Loeb told Medscape Medical News: "The concept of genetic factors that modify the response to treatment or that modify the toxicity of treatment is very intriguing. As genetic technology continues to improve, hopefully we can use these new data to move into the era of personalized medicine."

On the basis of genetics, it would be nice to tell a man whether he is more likely to experience toxic effects such as cognitive impairment or whether he is unlikely to respond to one type of treatment.

"The main weakness of this particular study is the very small sample size, particularly to look at genetic factors," Dr Loeb said. Although provocative, comparing 21 men receiving ADT who have the wild-type GNB3 gene with 27 men receiving ADT who have the variant is not sufficient to draw definitive conclusions, she indicated.

Study Limitations and Conclusions

In an accompanying podcast on the Journal of Clinical Oncology website, Susan F. Slovin, MD, of the Genitourinary Oncology Service at the Memorial Sloan Kettering Cancer Center, New York City, indicates that this is one of the largest controlled, prospective longitudinal evaluations of cognitive impairment associated with ADT.

The study was a prospective but observational study with a small study sample. However, other studies that examined cognitive decline lacked a comparator arm or had a shorter follow-up for assessing and evaluating multiple cognitive domains, Dr Slovin indicated.

The researchers noted that another limitation of their study was in the use of a control group of men with prostate cancer who did not receive ADT but who had undergone prostatectomy. Would their observations be different if the control group had been treated with radiation?

They indicate that larger observational studies and randomized trials are required to evaluate more definitively the impact of ADT on cognitive impairment.

But Dr Slovin noted that physicians have been remiss in informing patients of the benefits and risk of ADT.

"These findings may have implications for discussions of risks and benefits of ADT," the researchers note in their discussion. "Clinicians may also consider inquiring about changes in cognitive functioning that may have occurred after starting ADT and refer patients for assessment and treatment as needed," they conclude.

However, Dr Loeb indicated that larger studies will need to be done to follow up on all of these findings before making any clinical recommendations.

Dr Gonzalez, Dr Slovin, and Dr Loeb have reported no relevant financial relationships.

J Clin Oncol. Published online May 11, 2015. Abstract, Podcast

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