July 29, 2008 — Men with prostate cancer may experience changes in cognitive functioning if they undergo androgen-deprivation therapy (ADT). A review article published in the July 21 Online First issue of Cancer supports evidence suggesting that androgen-ablation therapy is linked to significant cognitive decline in patients with prostate cancer.

"The key point of this paper is for oncologists to be aware that adverse changes in cognitive function can be a side effect of treatment," said lead author Christian J. Nelson, PhD, who is with the Department of Psychiatry and Behavioral Sciences, Memorial Sloan-Kettering Cancer Center in New York City. "If they are aware of these effects, they can monitor them and discuss it with the patient."

In an interview with Medscape Oncology, Dr. Nelson emphasized that these changes are generally subtle. "We are talking about visuospatial abilities and working memory, and not gross changes across all areas. Patients may have problems with memory and difficulty with multitasking."

If a patient does experience a dramatic and pronounced change in cognitive function, then it may be a sign that something else is going on. "The patient should undergo a normal evaluation, as would anyone else experiencing the same symptoms," he said.

ADT is commonly used to treat locally advanced or metastatic prostate cancer, and in some cases, a survival benefit may be associated with the use of ADT in earlier stages of the disease. In addition, the efficacy of ADT use in men with rising prostate-specific antigen (PSA) levels is being studied, and this group of patients may be receiving ADT longer than those with later-stage prostate cancer. Treatment in this population could continue for 5 to 10 years, or even longer.

Significant adverse effects are associated with ADT, Dr. Nelson explained, including osteoporosis, fatigue, sarcopenia, gynecomastia, loss of libido, erectile dysfunction, risks for diabetes and cardiovascular disease, and fatal cardiac events.

"The impact of this therapy on cognitive functioning hasn't been well studied," he said. "With the ablation therapy, there are so many more pronounced symptoms and these are clearly evidenced. This line of research is still fairly new."

The results of early research, conducted in both animals and in older and/or hypogonadal men, suggest that depletion of testosterone may affect the areas of working memory, verbal memory, and visuospatial ability. These findings supported the rationale to investigate the effect of ADT on cognitive functioning in patients with prostate cancer, the study authors note.

In this review, Dr. Nelson and colleagues examined several studies that investigated the relationship between ADT in men with prostate cancer and its cognitive effects. A total of 9 studies met their criteria and were included in the review, with the earliest one dating from 2002.

Table. Results of Reviewed Studies of ADT in Men With Prostate Cancer

*ADT indicates androgen-deprivation therapy; FACT-COG, Functional Assessment of Cancer Therapy-Cognitive.

Studies Small, Data Inconsistent

All of the studies were small, and findings were somewhat inconsistent. There was also significant variability in the types of cognitive tests administered, although most studies used comprehensive neuropsychological batteries. The researchers also observed that only 3 of the 9 studies reviewed defined "cognitive impairment," and the definition was not consistent across studies. Therefore, it was difficult to make comparisons between findings and develop firm conclusions from the literature.

They also note that the reviewed studies have not proved a direct connection between androgen ablation and cognition, although specific mechanisms for testosterone to directly affect cognition appear to exist. However, it is also possible that the associated adverse effects of ADT may also be contributing to cognitive impairment.

"Despite these important considerations, when reviewing this literature as a whole, we conclude from the data that androgen ablation does have implications for cognitive functioning," they write. "From these studies, we can draw the conclusion that androgen-ablation therapy appears to have subtle yet significant negative effects on specific domains of cognition as opposed to inducing gross cognitive changes that sweep across all cognitive domains."

For some men, these changes may only be temporary, but for others, they may be permanent. The results of a recent study that was not included in this analysis showed that when patients are receiving short-term therapy, the cognitive effects were alleviated when treatment was discontinued, Dr. Nelson explained.

"But many patients are on long-term therapy, probably for the rest of their lives," he said. "And if they are able to discontinue treatment, they may have experienced structural changes in the testes and not produce as much testosterone, so side effects will continue."

Larger longitudinal studies are warranted, and these studies should also explore the moderating/mediating implications of the adverse effects of ablation therapy on cognitive functioning. It would also be of value for future studies to attempt to integrate brain imaging as a component of this research.

Cancer. Published online July 21, 2008.

Clinical Context

Study Highlights

• Researchers examined PubMed and the Information Sciences Institute Web of Knowledge–Web of Science to find studies that addressed the effects of hormone therapy on cognition in patients with prostate cancer.
• The authors included 9 studies in their review.
• The collective body of research had significant limitations:
  • The number of participants was small, ranging between 14 and 57 patients.
  • There was significant variability in the cognitive tests used to assess patients, particularly tests that examined specific domains of cognitive function.
  • The definition of cognitive impairment was not stated in most of the included research.
  • It was not clear whether any cognitive decline noted in the body of literature was independent of other adverse events associated with ADT, such as fatigue, anemia, and hot flashes.
• There did not appear to be an effect of ADT in broadly reducing cognition over multiple domains.
• However, 47% to 69% of men had cognitive declines in at least 1 specific area. Specifically, visuospatial ability and executive functioning were most likely to be decreased by ADT.
• There were conflicting results regarding the effects of ADT on verbal memory. In 2 studies, researchers actually demonstrated an increase in verbal and spatial memory in men receiving ADT.
• 1 study demonstrated that immediate verbal memory was improved through treatment with estradiol in a cohort of men treated with androgen deprivation.

Pearls for Practice

• Testosterone levels decline gradually among men older than age 30 years. Low testosterone levels might be related to a decline in working memory, verbal memory, and visuospatial ability, and some research indicates that treatment with exogenous testosterone can improve these deficits.
• The current review finds that ADT for prostate cancer may promote cognitive decline in particular areas, specifically visuospatial ability and executive functioning, but the available scientific research does not support a pattern of broad cognitive decline associated with ADT.

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