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Chemobrain: Research Continues, But No Definitive Answers

Goodman, Alice

doi: 10.1097/01.COT.0000317245.93185.12
Original Article

SAN ANTONIO—Cancer patients treated with chemotherapy often report difficulty in concentration, memory, and cognitive function, the phenomenon now typically called chemobrain. Research has been directed at understanding the problem and exploring cognitive function before and after chemotherapy. A group of poster presentations at the San Antonio Breast Cancer Symposium explored various aspects of cognitive changes in breast cancer patients, but taken together, the findings still do not prove or disprove a relationship between cognitive impairment and chemotherapy.

One study showed that patients slated to undergo adjuvant hormonal therapy reported no more cognitive difficulties than their healthy peers; another found that elderly women who undergo chemotherapy in the modern era are not at greater risk for dementia; and a third showed that among women who received adjuvant chemotherapy, there was a strong association between cognitive function and age, number of years of education, and intelligence.

A researcher in this area who was not connected to the studies, Sanne B. Schagen, PhD, of the Department of Psychosocial Research and Epidemiology of the Netherlands Cancer Institute, said that she was pleased to see this important topic represented at the meeting.



“The evidence is gradually building that certain combinations of cytotoxic chemotherapy are associated with cognitive problems,” she said. “Most of the evidence comes from breast cancer patients treated with adjuvant chemotherapy, but that is because of the availability of large numbers of long-term survivors and not so much because of the characteristics of this patient group or the particular treatments.”

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Cognitive Status Before Hormonal Therapy

Postmenopausal women with breast cancer who are candidates for hormonal therapy following surgery have a similar cognitive status as age-matched healthy controls, according to a substudy of the TEAM trial. The study showed that the prevalence of cognitive complaints was no higher in breast cancer patients than in controls.

The lead author, Christine Schilder, MSc, also of the Netherlands Cancer Institute, noted that the study subjects were interviewed about memory, concentration, thinking, and language in their everyday functioning—“We did not give them cognitive testing batteries,” she explained.

The study did show that higher anxiety/depression scores were associated with more difficulty in concentrating for both patients and controls, but not with more problems with memory, thinking, and language.

No association was found between cognitive complaints and general and physical fatigue, treatment-related factors, age, or intelligence quotient. “Breast cancer patients often report cognitive changes in association with adjuvant therapy, and we wanted to study whether these changes are already present after surgery but before adjuvant therapy,” Ms. Schilder explained.

The study included 205 patients not qualified to receive chemotherapy who were enrolled in the TEAM trial. TEAM was designed to compare exemestane versus tamoxifen as adjuvant therapy. Patients had a mean age of 69 years. The control group comprised 124 healthy female friends or relatives of the patients, with mean age of 66.5.

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Self-Report vs Objective Test

Tim A. Ahles, PhD, Director of the Neurocognitive Research Laboratories at Memorial Sloan-Kettering Cancer Center, called the study interesting and said that the results are consistent with other studies of self-reported cognitive problems in cancer patients evaluated prior to adjuvant treatment.

“However, if you do formal neuropsychological testing, you can identify a subgroup of patients with lower than expected cognitive scores based on age and education after surgery but before chemotherapy,” he said. About 20 to 30 percent of breast cancer patients have lower cognitive scores in this setting—not a trivial number,” he said.

A question for further research is whether this vulnerable subgroup is at greater risk for the development of cognitive problems after chemotherapy. Another question to explore is why women who score more poorly on neuropsychological tests don't self-report cognitive problems, he said. “We need to understand how this relates to post-chemotherapy cognitive effects.”

Dr. Schagen emphasized that these findings reflect women's performance before endocrine therapy and said that it is interesting that patients do not report more cognitive complaints compared with healthy women. “It would be interesting to see whether this holds true for performance on neuropsychological tests,” she commented.

The study by Schilder et al is part of a large ongoing prospective study on the potential effects of endocrine treatments for postmenopausal breast cancer patients, and Dr. Schagen said she awaits the second assessment of the study on the effects of systemic treatment.

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Adjuvant Chemotherapy & Risk of Dementia

A study reported by Nancy Baxter, MD, PhD, Assistant Professor of Surgery at St. Michael's Hospital at the University of Toronto, compared the incidence of dementia in older women who received adjuvant chemotherapy with that in older women who did not and found no effect of chemotherapy on the development of dementia. “Our study suggests that chemotherapy, as currently delivered, does not seem to pose the risk of dementia,” Dr. Baxter said.

She cautioned, though, that the study was confined to dementia and does not address subtle or temporary effects of chemotherapy on cognition.

“Our study used claims data and relied on strict criteria for a diagnosis of dementia, so more subtle changes in cognitive impairment and subclinical dementia could not be evaluated,” she said.

The study used SEER cancer registry data linked to Medicare enrollment records and utilization data. Diagnostic codes were used to identify women who got chemotherapy and Medicare claims data were used to determine a diagnosis of dementia. The database included 20,541 women age 66 to 80 diagnosed with non-metastatic invasive breast cancer from January 1992 through December 1999.

Of the 20,000+ women who met selection criteria, 2,865 (14%) were exposed to chemotherapy. The median age at diagnosis of breast cancer was 72. The median age of women exposed to chemotherapy was 70, and of unexposed women, 73.



Median follow-up time for the entire cohort was 59 months. Dementia developed in 738 (3.6%) women: 2% of women exposed to chemotherapy and 3.8% of women not exposed to chemotherapy.

Still, Dr. Schagen said there are questions: “As the authors point out, dementia is a rather crude endpoint. Cognitive declines different from normal age-related changes have not been examined in this study. More important is that the results should be interpreted with caution, because the incidence of dementia found in this study [a total of 3.6% in the study population] is so much lower than would be expected in women age 71 and older [14%] that the study may be hampered by a selection bias.

“Using claims data as a source of information on the cognitive status of cancer patients treated with chemotherapy may therefore not be an adequate method.”

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Memory Loss After Adjuvant Chemo

Also reported at the meeting was a prospective study of 119 women who received adjuvant chemotherapy and underwent neuropsychological testing to assess cognitive function before chemotherapy and at several time points later. Cognitive function was linked with age, baseline intelligence quotient (IQ), reading level, and years of education.

“This paper validates what has been established in other areas of neuropsychological research—that cognitive function depends on variables such as age and baseline IQ, not on whether or not patients received chemotherapy,” said Geoffrey Beadle, MD, of the Translational Research Laboratory at the Queensland Institute of Medical Research in Brisbane, Australia.

Study participants included women who underwent adjuvant chemotherapy for breast cancer following surgery, with a wide age range—18 to 70—and had been proficient in English since early childhood.

The patients were assessed with a battery of neuropsychological tests for areas including memory, attention, speed of information processing, and executive function. The preliminary analysis of the study presented was based only on Auditory Verbal Learning Test (AVLT) scores for immediate and delayed recall of words, with and without distractor lists.

Age and years of education were found to be significantly correlated with the scores at all time points, Dr. Beadle reported. The investigators also measured quality of life and found that correlations between quality of life and the learning test scores were inconsistent and were not strongly associated with the scores after adjusting for age and years of education.

The outcome findings have the potential to be quite relevant, because it is one of the largest prospective studies in this field, said Dr. Schagen, noting that the study uses a technique for the analysis of the data that is not frequently applied in this area and deals with the complex and interrelated data in a sophisticated way,

Dr. Ahles noted that the study does not specifically address the effects of chemotherapy on cognition, because there is no control group or comparator group.

“In a longitudinal study, most subjects will improve over time. A comparator group would be needed to see if improvement is similar in women who did not get chemotherapy compared to those who did. In this preliminary analysis, the researchers focused on the AVLT, which is one measure of neurocognition. Another pattern might emerge when they look at other measures.”

© 2008 Lippincott Williams & Wilkins, Inc.
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