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

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.

Neurology Advisor: What do your recent findings add to our understanding of the cognitive impact of chemotherapy?

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Dr Butterfield: In rodent studies, there are deficits in cognitive performance following administration of chemotherapeutic agents that do not reach the brain. Our laboratory and those of our University of Kentucky colleagues showed that there is significant elevation of free radical damage in rodent brain following administration of chemotherapy using doxorubicin, which does not enter the brain.4 Among oxidative damages found were decreased function of mitochondria associated with modification and dysfunction of a major free radical scavenger in brain mitochondria and with brain cell apoptosis.

Our research showed that when the gene for tumor necrosis factor-alpha (TNF-alpha) was deleted in rodents, such changes did not occur, including oxidative damage.4 Other brain changes were also prevented when this gene was deleted. We hypothesize that the systemic administration of free radical-associated chemotherapy agents leads to elevation of TNF-alpha that crosses the BBB by well-known mechanisms, and once in the brain leads to more TNF-alpha production with consequent death of neurons involving free radical damage. More research is needed to flesh out these mechanisms further, and that is the subject of an NCI grant obtained by myself and 2 of my colleagues here at University of Kentucky.

We also reported that treatment of the mice with an antibody to TNF-alpha prevented some of the underlying free radical damage to the brain, and treatment with the [US Food and Drug Administration-approved drug, MESNA, which does not interfere with cancer chemotherapy, prevented the cognitive dysfunction observed following doxorubicin administration.

Dr Kolb: We showed that the presence of an implanted piece of human breast tumor in a mouse induced epigenetic changes in the brain, and these changes varied by area.2 Adding chemotherapy also induced epigenetic changes, which differed somewhat from those in animals that only had the tumor, and it appears that both tumors and chemotherapy alter molecular networks in the brain.

Neurology Advisor: What are the top takeaways or treatment implications you would like to convey to clinicians regarding this topic?

Dr Butterfield: Currently in the [United States], there are approximately 15 million cancer survivors,6 expected to reach 18 million persons in the relatively near future. Most of these survivors would have been treated with chemotherapy as part of their cancer survival. While there is a large range of percentage of participants in CICI clinical studies reporting symptoms of “chemobrain,” the approximate average of this percentage is 30%, although some studies suggest much higher percent involvement in CICI. That means that, of the current 15 million American cancer survivors, at least 5 million would be expected to report some level of cognitive dysfunction — an enormous number that rivals that of some of the major age-related neurodegenerative disorders in this country.

Our studies in rodent models are providing new insights into potential molecular mechanisms and therapeutic targets to modulate and hopefully prevent symptoms of CICI. Considerably more research is needed to fully elucidate mechanisms of CICI, but we are highly encouraged by our findings to date.

Dr Kolb: It is likely that changes in cognition that are often reported by patients before a cancer diagnosis should be taken seriously as being a potential symptom of cancer. Very often such complaints are taken as evidence of depression, but this is not the only possibility.

Dr Horowitz: The first thing that clinicians should know is that CRCI, chemobrain, chemofog, or whatever you want to call it, is a real phenomenon. A wealth of evidence from patient reports, neuropsychological testing, and structural and functional brain imaging shows changes to brain function that can last months or years after chemotherapy. Not everyone gets CRCI. Some patients find that their problems clear up after therapy is complete, while others do not. Probably about a third of patients will experience cognitive impairments 6 months after therapy is complete. Some may experience lasting effects that can be measured years later. Older patients and those with lower cognitive reserve seem to be at greater risk for CRCI developing. Preexisting fatigue, depression, and anxiety can make things worse.

Patients should be prepared for this, as for any other potential late effect. I have heard from several cancer survivors that their clinicians ignored or denied the cognitive difficulties that they were experiencing — one said that his oncologist said he was “crazy.” That’s not helpful. If patients know what to expect and feel that their oncologist supports them, they will be better able to cope and more likely to stick to their treatment regimens.

In terms of treatments for CRCI, we do not really have a lot of options yet. A number of pharmacologic therapies have been tested, with limited success. At the moment, the best option is nonpharmacologic treatments, especially cognitive training programs.

Neurology Advisor: What should be the focus of future research on this topic?

Dr Butterfield: Under the aegis of the above-mentioned NCI funding, we will continue to investigate the role of oxidative damage and its biochemical and cognitive sequelae in the brain associated with chemotherapeutic agents that do not cross the BBB.  

Dr Kolb: The next step is to determine [whether] there are differences in the extent of cognitive change in people with tumors alone or tumors and chemotherapy. Then we need to determine [whether] treatments such as those used for people with neurologic diseases such as stroke would be effective. In our animal studies, we have shown that these agents can be effective in animals with exposure to doses of irradiation typical in cancer treatment, so we suspect that the same logic is sensible in laboratory animals and patients with chemobrain. Another possible treatment is the use of compounds to reduce neuroinflammation, even when the tumor is distal from the brain.

There is little known about the role of age in the study of chemotherapy-related side effects. The molecular changes in the brains of children, adolescents, and aging adults may be very different, as might the possible treatments.

Dr Horowitz: One important next step is determining the risk factors for CRCI, beyond age and cognitive reserve. There is some evidence that certain genetic factors (apolipoprotein E and catechol-O-methyltransferase) may confer vulnerability. Development of a biomarker for vulnerability to CRCI and/or its presence would be a big breakthrough.

In my division at NCI, we are promoting research to develop new ways of testing for CRCI. Current neuropsychological tests were originally developed to diagnose focal brain lesions and are less appropriate for the more diffuse problems faced by cancer survivors. Paradigms adopted from cognitive psychology and neuroscience may prove more sensitive.

And of course, we would like to have more effective countermeasures. It’s important to consider CRCI in the context of other, similar impairments, such as Alzheimer’s and other age-related dementias. They may have disparate causes, but better cognitive treatment plans may be able to help everyone.

References

1. Gutmann DH. Clearing the fog surrounding chemobrain. Cell. 2019;176(1-2):2-4.

2. Kovalchuk A, Kolb B. Chemo brain: From discerning mechanisms to lifting the brain fog—an aging connection. Cell Cycle. 2017;16(14):1345-1349.

3. Horowitz TS, Suls J, Treviño M. A call for a neuroscience approach to cancer-related cognitive impairment. Trends Neurosci. 2018;41(8):493-496.

4. Keeney JTR, Ren X, Warrier G, et al. Doxorubicin-induced elevated oxidative stress and neurochemical alterations in brain and cognitive decline: protection by MESNA and insights into mechanisms of chemotherapy-induced cognitive impairment (“chemobrain”). Oncotarget. 2018;9(54):30324-30339.

5. Bernstein LJ, McCreath GA, Nyhof-Young J, Dissanayake D, Rich JB. A brief psychoeducational intervention improves memory contentment in breast cancer survivors with cognitive concerns: results of a single-arm prospective study. Support Care Cancer. 2018;26(8):2851-2859.

6. American Cancer Society. Cancer Treatment & Survivorship Facts & Figures 2016-2017. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/cancer-treatment-and-survivorship-facts-and-figures/cancer-treatment-and-survivorship-facts-and-figures-2016-2017.pdf. 2016. Accessed February 20, 2019.