'Chemo Brain' May Actually Be Worry and Fatigue, Says Study

Kate Johnson

December 10, 2012

SAN ANTONIO, Texas — New brain imaging research suggests that "chemo brain" is an inappropriate label for the neurocognitive deficits often reported by cancer patients. That's because reduced brain function caused by fatigue and worry is often present even before chemotherapy begins, according to a new study.

However, the research, presented here at the 35th Annual San Antonio Breast Cancer Symposium, was greeted with plenty of criticism.

The lead researcher did not dismiss the concept of chemo brain. "Cognitive changes do occur in women treated with chemotherapy," acknowledged Bernadine Cimprich, PhD, RN, associate professor emeritus at the University of Michigan School of Nursing in Ann Arbor. "But pretreatment-altered neural activation and fatigue can also contribute to cognitive problems," she said during a meeting press conference.

"This is a strong argument, in our estimation, for early intervention.... Existing interventions to reduce stress and fatigue may alleviate neurocognitive problems over the course of breast cancer treatment," Dr. Cimprich explained.

The research involved functional magnetic resonance imaging (fMRI) in breast cancer patients performed 24 to 34 days after surgery and before chemotherapy (n = 29) or radiotherapy (n = 37). The control group consisted of 32 age-matched healthy subjects.

The prechemotherapy group reported more severe fatigue before treatment than the control and preradiotherapy groups (P < 0.01); this increased after chemotherapy, but remained stable in the other groups.

Dr. Cimprich said the study shows a "moderately strong" correlation between fatigue and cognition in all study participants at baseline and at 5 months (P < .001). "The lower the level of activation, the greater the increase in fatigue over time.... This was an interesting finding for us; you rarely see a correlation between level of activation and any kind of affective or experiential measure," she noted.

Women awaiting chemotherapy are more vulnerable to cognitive problems related to worry and fatigue, and these problems can begin before any adjuvant treatment, she said.

Critics Weigh In

Audience member Patricia Ganz, MD, professor of health services and medicine at the University of California, Los Angeles, questioned the study's conclusions.

The chemotherapy patients had larger tumors at baseline and had undergone more extensive surgery — both of which can influence cognitive function, said Dr. Ganz.

"We know that surgery itself can lead to an increase in proinflammatory cytokines," she explained. "It may be that proinflammatory cytokines, which...are associated with fatigue and cognitive dysfunction, are influencing the underlying biology," she noted.

"The chemo patients likely had reconstruction with mastectomy, which causes much more tissue trauma," she told Medscape Medical News. "I am not sure [the researchers] used covariates in the analysis, which could have explained differences in fatigue, and they did not always show P values when they compared groups,” Dr. Ganz added.

Another expert admired the study but also has reservations. "Our field is in need of prospective studies like this, and prospective fMRI studies are especially sparse," Sanne Schagen, PhD, director of psychosocial research and epidemiology at the Netherlands Cancer Institute in Amsterdam, told Medscape Medical News. However, other studies that have reported prechemotherapy cognitive impairment have failed to find a link with fatigue or anxiety, she said, warning against drawing strong conclusions from this study.

The researchers conclude that pretreatment cognitive compromise and fatigue are key contributors to the cognitive impact often solely attributed to chemotherapy. However, Dr. Schagen explained that "it is important to realize that the correlations on which these conclusions are based are very weak."

"Fatigue may be contributory factor, but to conclude that it is a key contributor is, based on the current data, in my opinion, too strong," she added.

Another breast cancer clinician described the issue as a "multifactorial problem." It's "very interesting" that we see fatigue and cognitive dysfunction in breast cancer patients even before treatment, said Kent Osborne, MD, director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine in Houston, Texas.

"I've often wondered whether some of these cognitive dysfunctions that have been reported with all kinds of different medicines for cancer are as much related to this problem of worry, anxiety, and fatigue as they are to the treatment," he added.

Study Details

All of the study participants had noninvasive breast cancer, but more patients in the prechemotherapy group had a higher stage of disease, which is what "you would expect with standard treatment approaches," said Dr. Cimprich.

Specifically, stage II and IIIa disease was more common in the prechemotherapy group than in the preradiotherapy group (82% vs 16%); earlier stages were more common in the preradiotherapy group (18% vs 84%).

In addition, more women had undergone mastectomy in the prechemotherapy group than in the preradiotherapy group (46% vs 5%), whereas more women had undergone breast-conservation surgery in the preradiotherapy group (54% vs 95%).

In the prechemotherapy group, 79% of women received a regimen of doxorubicin and cyclophosphamide followed by docetaxel (AC-T); 18% received a regimen of cyclophosphamide and docetaxel (CT), and 3% received a regimen of doxorubicin and cyclophosphamide (AC).

Brain function was tested while subjects performed a 30-minute verbal working memory task (VWMT) in the scanner. Immediately after that, they were asked to self-report cognitive function (using the Attentional Function Index) and fatigue (using the Functional Assessment of Cancer Therapy-Fatigue).

Subjects were tested again 5 months from baseline (about 1 month after the end of chemotherapy).

The median age of the patients was 50 to 53 years, and 79% of them were white.

Before treatment, all patients were less able than the control subjects to activate the left inferior frontal gyrus — the brain region critical for working memory (P < .05).

"The prechemotherapy group had the lowest level of activation compared to the controls; the preradiotherapy group fell in between," Dr. Cimprich reported.

Before treatment, the patients performed worse than control subjects on the VWMT (error rate, 10.0% vs 6.5%; P < .05).

After treatment, cognition improved to the level of the control group in the preradiotherapy group, but the error rate worsened to about 12% in the prechemotherapy group.

"Women who were less able to perform this working memory task suffered greater fatigue over time, regardless of treatment," she said. "So this low function before treatment predicted severity of fatigue later on," Dr. Cimprich noted.

The study was funded by the National Institutes of Health and the National Institute of Nursing Research. Dr. Cimprich, Dr. Schagen, and Dr. Ganz have disclosed no relevant financial relationships. Dr. Osborne reports being a consultant/advisor for Genentech, Novartis, and AstraZeneca.

35th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S6-3. Presented December 7, 2012.

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