Major advances in cancer treatment in recent decades have allowed patient survival rates to increase.1 Cancer prevalence is also increasing,2 and these trends underscore the importance of managing adverse effects related to cancer therapies. Cognitive impairment is a highly prevalent chemotherapy-related side effect that occurs in up to 75% of patients with non-central nervous system cancers, affecting the domains of attention, memory, executive function, and processing speed.2

The duration of chemotherapy-induced cognitive impairment (CICI), also referred to as “chemobrain,” ranges from a period of months to 10 years after treatment cessation.2 Findings have linked CICI with reduced quality of life, occupational challenges, and reduced treatment adherence — and thus, further side effects and worse survival rates.3

Although the etiologic mechanisms underlying these effects remain unclear, CICI has been proposed to result from structural and functional changes in the brain as a result of peripheral toxicity induced by cancer therapies.4 In a 2017 paper on the topic, researchers reported that, “chemotherapy agents are, in fact, more toxic to healthy brain cells than to the cancer cells they were designed to treat.”2 Additionally, cancer itself is linked with cognitive deficits, hence the term cancer-related cognitive impairment (CRCI) that some experts use to refer to the range of effects that may result from both cancer and chemotherapy agents.3

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The lack of clarity regarding the causes of CICI, along with the complexity of cancer and its associated treatments, has contributed to a general lag in research progress in this area despite ongoing efforts by some investigators focusing on CICI and potential therapies.4 In terms of treatment, findings thus far support the efficacy of cognitive training and psychoeducational interventions for reducing symptoms of CICI.5

To discuss emerging findings and other aspects of CICI, Neurology Advisor spoke with several experts from various backgrounds: D. Allan Butterfield, PhD, the Alumni Association Endowed Professor of Biological Chemistry at the University of Kentucky, where he also serves as associate vice president for research, director of the Redox Metabolism Shared Resource Facility at the Markey Cancer Center, and faculty in both the Spinal Cord and Brain Injury Research Center and the Sanders-Brown Center on Aging; Bryan E. Kolb, OC, PhD, FRSC, a researcher and professor of neuroscience at the University of Lethbridge in Alberta, Canada; and Todd S. Horowitz, PhD, a program director in the Behavioral Research Program’s Basic Biobehavioral and Psychological Sciences Branch, located in the Division of Cancer Control and Population Sciences at the National Cancer Institute (NCI).

Neurology Advisor: What are some of the specific cognitive effects associated with chemotherapy, and what are the proposed underlying mechanisms?

Dr Butterfield: When CICI occurs, cognitive symptoms often involve dysfunction of higher executive functioning — mostly involving the frontal cortex and hippocampus, but other brain regions may be involved as well — manifesting as slow processing of ideas, planning, thinking, task management, and so on. Multitasking becomes arduous for some patients.

The mechanisms underlying symptoms of CICI are not completely known. What is known is that there are changes in white matter in the brain observed by [magnetic resonance imaging].4 Other structural changes in brain also are reported.

Dr Kolb: Chemobrain is associated with a wide range of cognitive problems ranging from deficits in memory, concentration, executive functions, and multitasking, and a general feeling of cognitive fogginess. Although the cause of chemobrain is often believed to be the chemotherapy, it is likely more complex than that. The mere presence of a tumor is likely enough to trigger chemobrain. The mechanism is unclear, but one hypothesis is that it is related to epigenetic changes. Another possibility is that the chemotherapy is producing neuroinflammation in the brain.

Dr Horowitz: A wide range of cognitive effects has been associated with chemotherapy. There is also evidence that other therapies, such as radiation or hormone therapies, may lead to cognitive difficulties.3

In terms of objective neuropsychological tests, impairments have been reported in nearly every domain that has been tested — attention, executive function, processing speed, motor function, language, visuospatial processing, and multiple memory domains. We can also look at the subjective reports of cancer survivors — problems with attention are common. Survivors have reported difficulties with multitasking, feeling foggy or spacy, being unable to stay absorbed in a book, and difficulty participating in conversations involving multiple people or distractions.

Problems with short-term memory are also widely reported, such as misplacing personal items and not being able to remember names and numbers. [People] also report difficulty learning new information, trouble with finding words, and problems with reading comprehension. One important area of daily life that becomes difficult is driving, because people can’t remember where they’re going or figure out directions, which in turn leads them to fear getting lost. They also may have safety issues in terms of being aware of other drivers or signs and signals on the road.

Underlying mechanisms [represent] a more complicated issue. A number of pathways have been proposed, but a lot more work needs to be done. Chemotherapy can lead to deregulation of cytokines and a state of chronic inflammation, which in turn can lead to increased DNA damage. Some chemotherapy agents can cross the blood-brain barrier (BBB) and lead to cell death and reduced cell division in neurons.

Some researchers have proposed that chemotherapy essentially accelerates the cellular aging process, shortening telomeres and impairing DNA damage repair mechanisms. Changes in hormone levels are also known to lead to cognitive difficulties; chemotherapy can lead to early menopause, and of course hormone treatments themselves will directly affect hormone levels.