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Cognitive Effects of Chemotherapy May be Long Lasting

Fitzgerald, Susan

doi: 10.1097/
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Investigators reported that breast cancer patients who had received a regimen of cyclophosphamide, methotrexate and fluorouracil (CMF) on average 21 years earlier performed worse on several neuropsychological tests than a group of healthy women used as controls for the study.

Cancer patients undergoing chemotherapy often complain of mental fogginess or so-called “chemo-brain,” but it's not clear how long the condition persists after treatment. Now a new study of breast cancer survivors suggests that certain chemotherapy drugs may have an effect on cognitive function that remains even decades later.



That finding emerged from a study in the Netherlands that examined the cognitive function of breast cancer patients who had received a regimen of cyclophosphamide, methotrexate and fluorouracil (CMF) on average 21 years earlier. The breast cancer survivors performed worse on several neuropsychological tests than a group of healthy women used as controls for the study.

“The pattern of cognitive problems is largely similar to that observed in patients shortly after cessation of chemotherapy,” the researchers reported in the Feb. 27 online edition of the Journal of Clinical Oncology. “This study suggests that cognitive deficits following breast cancer diagnosis and subsequent CMF chemotherapy can be long-lasting.”

Sanne Schagen, PhD, one of the principal investigators for the study, told Neurology Today that “up to now we only had information on the effect of chemotherapy up to about five years.”

“We are the only study that has looked at these very late effects of chemotherapy,” said Dr. Schagen, a clinical neuropsychologist who is a group leader in the division of psychosocial research and epidemiology at the Netherlands Cancer Institute in Amsterdam.

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To test the question of whether cognitive deficits are long-lasting, the Dutch researchers compared two groups of women — 196 survivors of breast cancer between the ages of 50 and 80 who had undergone adjuvant chemotherapy at either of two specialty cancer clinics in the Netherlands, and a reference group of 1,509 non-cancer survivors who were part of a population study, called the Rotterdam Study, that is ongoing in the Netherlands.

Participants underwent neuropsychological examinations and an interview identical with those used in the Rotterdam Study. They also had had an MRI of the brain, ultrasound imaging of the carotid arteries, and an electrocardiogram. Only the neuropsychological testing results are reported in this paper; MRI and other results have been published elsewhere or will be published later, Dr. Schagen said.

Participants were given a battery of seven neuropsychological tests to yield 17 outcomes in these domains: processing speed, verbal learning, memory, inhibition and word fluency as elements of executive functioning, visuospatial ability, and psychomotor speed. The Mini-Mental State Examination (MMSE) was given to screen for dementia, and the women also were asked if they had more problems remembering things than they used to.

The breast cancer survivors who had chemotherapy performed significantly worse than the control group on cognitive tests of immediate (p=.015) and delayed verbal memory (p=.002); processing speed (p<.001), executive function (p=.013), and psychomotor speed (p=.001). The differences remained after the researchers made adjustments for age, education level and depression. (The control group reported more depression than the survivors.) While the cancer survivors were more apt to report in the interview that they had memory problems, the complaints did not correlate with test results.



“Strengths of our study are the large sample size, the long interval since chemotherapy, the homogeneous study population regarding cytotoxic agents (regimen, cycles), and the large population-based reference group without cancer,” the researchers reported.

The researchers noted that “because tamoxifen was not part of standard treatment in the Netherlands until the 1990s, it was not possible to include a comparison group of long-term tamoxifen-exposed survivors.” Also, “because of our design we were unable to distinguish the effect of chemotherapy on cognition from the possible effect of breast cancer itself,” the researchers noted. Some research suggests that breast cancer patients may have cognitive changes even before the start of chemotherapy.

The cognitive deficits noted among the breast cancer survivors were subtle, and such changes would not necessarily make a difference in daily living. Still, Dr. Schagen said it was important for researchers to better understand the cognitive impact of cancer treatment because the population of survivors is growing due to better treatment, and many cancer survivors are living to old age.

The study on breast cancer survivors is not the final word on the long-term effects of chemotherapy, and the study itself has limitations. The study was not prospective — following patients from diagnosis and treatment on forward — but instead looked at cancer patients at a single point after treatment. Without baseline and intermittent testing results to serve as comparisons, it's impossible to say whether a patient's cognitive function stayed the same, got worse or even improved over time. The study focused on a drug combination, CMF, that is no longer the standard in breast cancer treatment, though cyclophosphamide and fluorouracil are still used in modern adjuvant regimens for breast cancer, Dr. Schagen said.

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Neuro-oncologist Lisa Rogers, DO, professor of neurology at University Hospitals Case Western Medical Center, told Neurology Today that the focus of cancer care has rightly expanded in recent years from a sole emphasis on treating the cancer to include attention to the many physical, emotional, mental and social ramifications of the disease and its treatment.

Dr. Rogers, who is chair of the AAN Neuro-oncology Section, said that a better understanding of the condition is critical, given that there will be more than 20 million cancer survivors in the US by 2020. The cognitive impact of chemotherapy is particularly significant when it comes to breast cancer because the disease is so common. More than 200,000 cases of breast cancer are diagnosed each year in the US.

“The cognitive effect of chemotherapy is a very important health issue,” Dr. Rogers said. It's not understood precisely how chemotherapy damages the brain, she said. Potential causes include a direct toxic effect of a drug, the generation of free radicals or a dysregulation of cytokines.

Dr. Rogers said this latest study is of interest because neuropsychological testing was performed so many years after chemotherapy. But due to methodological problems common in such studies, she said, the testing results were more suggestive than conclusive of a significant impact of chemotherapy in long-term survivors.

“Nevertheless, it's important for clinicians to be aware that cognitive problems in a patient treated for cancer many years before could stem from the persistent effects of chemotherapy,” Dr. Rogers said.

Jeffrey Raizer, MD, associate professor of neurology at Northwestern University, said the results of the study certainly should not influence a patient's decision to undergo chemotherapy. He noted that the cognitive deficits reported in the study are quite subtle when compared to a control group, and are not a measure of an individual's changes over times. The differences might not be clinically relevant. “The changes are seen during higher-level neuropsychological testing. Does that affect their functioning day to day?” Dr. Raizer asked. “That is not really clear.”

Dr. Schagen's group is continuing to study the issue, in particular looking at whether certain subgroups of patients are more susceptible to cognitive decline following chemotherapy than others. Knowing that could help doctors tailor treatments to minimize or prevent those side effects.

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• Koppelmans V, Breteler MMB, Schagen SB, et al. Neuropsychological performance in survivors of breast cancer more than 20 years after adjuvant chemotherapy. J Clin Oncol 2012; E-pub 2012 Feb. 27.
    ©2012 American Academy of Neurology