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Large Meta-analysis Documents Persistent Mild Cognitive Deficits in Breast Cancer Patients Post-Chemotherapy

Samson, Kurt

doi: 10.1097/01.COT.0000423788.57695.06
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Chemotherapy appears to cause cognitive problems in some breast cancer patients for at least six months after treatment, but deficits are limited primarily to just two cognitive domains and are usually mild to moderate, according to the results of a new meta-analysis of all pertinent studies published since 1937.


In the study, published in the Journal of Clinical Oncology (2012:30:3578-3587), Heather S.L. Jim, PhD, a researcher in the Health Outcomes and Behavior Program of H. Lee Moffitt Cancer Center, and colleagues at several institutions reviewed evidence in eight cognitive domains:

  • attention
  • executive function
  • information processing
  • motor speed
  • verbal ability
  • verbal memory
  • visual memory
  • “visuo-spatial” ability.

Only deficits in the verbal and visuo-spatial categories were statistically significant six or more months after treatment, and these typically fell in the small to moderate range. There was also evidence of deficits in executive function, but the differences did not reach statistical significance, the researchers reported.

“While there is evidence that breast cancer patients may experience cognitive problems during chemotherapy, it is unclear the extent to which cognitive problems occur in the post-treatment period,” Jim said in explaining the purpose of the study in an interview.

HEATHER S.L. JIM, PHD: “Earlier meta-analyses have not focused specifically on the post-chemotherapy period and have not incorporated several recent studies.”

“Earlier meta-analyses have not focused specifically on the post-chemotherapy period and have not incorporated several recent studies. What we found is consistent with what many patients report after chemotherapy: that they may have trouble finding the right word, may experience visuo-spatial difficulties such as getting lost more often in unfamiliar locations, and find it more difficult to quickly switch cognitive tasks, or to multi-task.”

The team reviewed 2,751 abstracts culled from major literature databases and, after being independently reviewed, 17 studies met inclusion criteria. These included a total of 807 patients treated with standard-dose chemotherapy who underwent neuropsychological testing six or more months after treatment.

Chemotherapy patients scored lower than non-cancer patients, those not treated with chemotherapy, and their own pre-treatment test scores.

“Verbal deficits were slightly worse in patients who received chemotherapy than in individuals without cancer, while visuo-spatial scores were slightly worse than in patients who did not undergo chemotherapy,” she said. “On average, the deficits were not very large, but there may be a lot of variability and some patients may experience larger deficits.”

Neither age, education, time since treatment, nor endocrine therapy appeared to significantly affect scores, although Jim said that these and other factors could influence cognitive changes.

“Patients who are older and have less education may have less cognitive reserve, or greater vulnerability to cognitive problems during and after chemotherapy,” she explained. “Genetic factors and menopause can also contribute to these cognitive problems.”

She noted that most women who undergo chemotherapy for breast cancer are in their mid-50s, which is a time that many are also experiencing some symptoms associated with menopause. These include fatigue and sleep difficulties, both of which can cause cognitive difficulties.

“We found fewer and smaller cognitive deficits after chemotherapy than previous studies have reported during treatment, so there may be some cognitive recovery that takes place,” she said. “This information can be used to develop interventions to educate patients and their families about potential long-term cognitive changes after treatment. Memory training and some pharmaceutical studies have also shown some benefits.”

Breast cancer patients who experience cognitive problems after six months should be referred for neuropsychological testing, she added.

‘A Real Condition’

“Research into the phenomenon of chemobrain started with complaints by patients, and for a long time these were not taken seriously by everyone,” said Gary M. Rodin, MD, Professor of Psychiatry and Head of the Psychosocial Oncology and Palliative Care Unit at Princess Margaret Hospital and the University of Toronto Health Care Network.

“This study is one more piece of evidence supporting the need for greater awareness and additional research—this is a real condition,” he said. “The good news is that the effects appear to be mild and limited to just two cognitive domains.”

While there has been a lot more research and a growing consensus that chemobrain does in fact exist, available studies have used different designs and patient groups, which makes analyses difficult, he explained in an interview for this article.

“The strength of the study is that at least six months had passed since chemotherapy for all of the subjects. “However as the authors noted, the data on which the meta-analysis was based has limitations.”

Rodin wrote an accompanying editorial (JCO: 2012;30:3568-3569) with Tim A. Ahles, PhD, who established and heads Memorial Sloan-Kettering Cancer Center's Neurocognitive Research Laboratory. They said that the study's findings may not be applicable to a wider range of cancers. In addition, the causative role of chemotherapy in producing the cognitive impairment remains unclear, given that most patients who received chemotherapy typically received other modalities such as surgery, radiation, and/or endocrine therapy.

The editorial also noted that there is consensus among many investigators in the International Cognition and Cancer Task Force (ICCTF) that a specific subgroup of patients may be particularly vulnerable to post-treatment cognitive changes. “I don't think this is specific to just breast cancer, and there may be greater effects in patients where the brain is more vulnerable,” Rodin elaborated.

These include older subjects, those with less education, and persons with other illnesses and health conditions. Most of the reviewed studies included relatively young to middle-aged patients, who tend to be more highly educated, and there may not have been a sufficient number of older and less educated patients to yield significant associations, he noted.

Rodin cited a recent study coauthored by Ahles and Andrew J. Saykin, PsyD, ABCN, Director of the Center for Neuroimaging at Indiana University School of Medicine, demonstrating that both age and cognitive reserve—which is influenced by such factors as education, occupation, and cognitive stimulation—were associated with post-treatment cognitive decline.

“I believe cognitive reserve is a factor,” Rodin said. “Better-educated patients, and those who work in mathematics, science, or finance, may have greater cognitive reserves and therefore experience fewer problems.”

GARY M. RODIN, MD: “This study is one more piece of evidence supporting the need for greater awareness and additional research. The good news is that the effects appear to be mild and limited to just two cognitive domains.”

Future research, he added, should compare different patient populations as well as utilize neuroimaging to better understand any changes in the brain that take place after chemotherapy as well as determine how these changes may contribute to cognitive complaints.

Subjective Deficits May Differ

“The methodology used in the study was particularly well suited for better understanding this common and distressing symptom given discrepant findings in previous research,” said Lynne I. Wagner, PhD, Associate Professor of Psychiatry at Northwestern University Feinberg School of Medicine.

“The findings suggest that most breast cancer survivors treated with standard-dose chemotherapy can expect generally normal cognitive function six months or more after treatment, with the exception of mild impairments in verbal and visuo-spatial abilities.”

For patients, this translates to problems with finding the right word or getting lost more easily, she explained. “However, It is possible that patients may demonstrate only mild impairments on neuropsychological testing, while their subjective experience is very different in that they experience significant disruption in their day-to-day lives related to cognitive problems.”

This discrepancy may be due to a number of factors, and performance on neuropsychological tests may not directly translate to a person's ability to function in day-to-day activities.

“Factors such as work demands, life demands, and other concerns such as fatigue, have a significant effect on a person's daily cognitive functioning, and these factors are not taken into consideration with neuropsychological testing,” Wagner said.

“The key is for cancer survivors to identify their own strengths and weaknesses when it comes to their cognitive functioning, so that they may employ strategies to compensate for areas that are problematic for them, such as making lists, keeping a calendar, taking notes, etc.”

Neuroimaging Correlates

Saykin, who is also the Raymond C. Beeler Professor of Radiology and Imaging Sciences and Professor of Medical and Molecular Genetics at Indiana University School of Medicine, said that although there are limited data from neuroimaging studies to date, what information has emerged seems to point to changes in gray matter density that correlate with observed and self-reported cognitive problems.

“There is some cross-sectional data, but few prospective studies, because it is difficult to recruit patients to participate in imaging studies when they are going through, or about to go through, chemotherapy,” he said.

He and his colleagues recently published two papers in which they reported changes in brain structure in breast cancer chemotherapy patients, using structural magnetic resonance imaging (MRI). A third paper used functional MRI (fMRI) in which “patients were asked to perform cognitive tasks while in the scanner, and we looked for structural and functional correlates with neuropsychological testing data.”

ANDREW J. SAYKIN, PSYD, ABCN, said that although there are limited data from neuroimaging studies to date, what information that has emerged seems to point to changes in gray matter density that correlate with observed and self-reported cognitive problems.

“We found changes in gray matter density on the cortical surface, particularly in frontal regions, using voxel-based morphometry or VBM.” VBM is a technique for analyzing neuroimaging data that uses statistical parametric mapping to investigate structural changes in the brain, he explained.

The researchers used a pre-treatment baseline, followed by testing one month after chemotherapy, and again after one year.

“After both one month and one year, we found structural MRI evidence of a decrease in gray matter density in frontal regions of the brain responsible for executive function. This is interesting because this correlates with the chief complaint of patients: that they have trouble with problem-solving and multi-tasking.”

The greatest change was observed at the one-month point, but partial recovery occurred after one year: “The brain appears to recover,” he said. “Not entirely, but substantially.”

© 2012 Lippincott Williams & Wilkins, Inc.
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