What Is the Best Approach to Managing 'Chemobrain'?

Kate M. O'Rourke


July 27, 2018

It is nearly as mysterious as it is ubiquitous among survivors of cancer: chemobrain. A little over a decade ago, patients with breast cancer coined the term to describe such cognitive problems as confusion or difficulty concentrating, which they experienced after receiving chemotherapy.[1]

The term is also a misnomer. The phenomenon, now known as cancer-related cognitive impairment or CRCI, is not well understood but is probably caused by a number of factors, including not just chemotherapy but endocrine therapy, radiation therapy and cancer itself.[1,2,3] Recently, Medscape reached out to several experts for insight into CRCI in patients with metastatic breast cancer.

A Multifactorial Problem

"We truly don't know what causes it, but I think we are all in agreement that it is multifactorial," said Janette Vardy, MD, PhD, a medical oncologist working as a clinician researcher at the Concord Cancer Center, University of Sydney, in Sydney, Australia. "CRCI can be caused by a neurotoxicity direct effect from either the cancer or the cancer treatment. There is work suggesting that the inflammatory marker cytokines are involved."

A recent study revealed an association between genetic and behaviorally related variables for inflammation and perceived cognitive function for breast cancer survivors.[4] Studies in colorectal cancer patients and head and neck cancer patients, however, did not find any associations with objective cognitive impairment and inflammatory markers.[5,6]

Common medications that may contribute to CRCI include sedative hypnotics used for sleep and anxiety (antihistamines, benzodiazepines), antinausea agents, and pain medications.[7]

CRCI affects patients with various solid tumors and hematologic malignancies and can occur at any point during the cancer trajectory.[1,2,3] "Across the board, roughly 70%-80% of women who have been through the breast cancer experience will complain of chemobrain at some point along the way, but 30% have more long-lasting concerns," said Jamie Myers, PhD, RN, a research assistant professor at University of Kansas School of Nursing and researcher at the University of Kansas Cancer Center. "We haven't broken it down more specifically to metastatic disease, but I see no reason to believe that group would have a different percentage."

Current research aims to identify which treatments may put some people more at risk of having CRCI and which cognitive domains may be more or less affected. A recent meta-analysis found that in both cross-sectional and longitudinal studies, breast cancer patients treated with chemotherapy had overall cognitive impairment compared with healthy age-matched controls, but the dysfunction in breast cancer patients treated with or without chemotherapy were very similar, with multiple cognitive domains affected.[8] Patients who received chemotherapy performed slightly worse in terms of executive function tests.

"The jury is still out on exactly what the predictors are for why someone is going to have long-lasting effects," said Myers. Older individuals and those with lower cognitive reserves might be at higher risk for having CRCI, said Myers, and some research shows that there might be a genetic predisposition.

According to Myers, a little over 10 years ago, there was still a disconnect between the cognitive symptoms that patients were reporting and what the healthcare community embraced as being a real phenomenon. "We are not where we need to be, but I am happy that 10 years later, the healthcare community has embraced this more as a phenomenon," said Myers.

Vardy said that a big problem is that patients aren't being told that CRCI is a potential side effect, so it comes at them out of left field. "I think people should be warned that it is a possibility, just as they are warned about other side effects," said Vardy.

CRCI can affect memory, attention, concentration, language, multitasking, organizational skills, daily functioning, and quality of life of cancer survivors.[1,2,3] Educating people about CRCI in advance validates their symptoms and doesn't leave them feeling so isolated and alone when they experience a side effect, said Vardy.


Guidelines such as those from the National Comprehensive Cancer Network, which provide assessment, evaluation, and management recommendations for cognitive dysfunction in cancer survivors, state that there is no effective brief screening tool for CRCI.[3] The Mini-Mental State Examination and similar screening tools lack adequate sensitivity for subtle decline in cognitive performance.[3]

According to Lori J. Bernstein, PhD, CPsych, a neuropsychologist in the Department of Supportive Care, Cancer Rehabilitation and Survivorship Program at Princess Margaret Cancer Centre and University of Toronto, a brain scan may be warranted. "If patients with metastatic cancer experience severe or sudden cognitive impairment, then brain imaging like MRI can help rule out the possibility that the cancer has spread to the brain, which is something different from CRCI. Also, blood tests can sometimes reveal reversible causes of cognitive symptoms, such as abnormal thyroid or anemia," said Bernstein. "In older people, even low-grade infections such as a urinary infection can be associated with cognitive impairment, so that should also be ruled out if cognitive symptoms are sudden, because they can be treated."

The standard tools that we have were not designed for the cognitive changes that cancer survivors experience.

Researchers are currently trying to refine methods for assessing cognitive function in survivors of malignancy. "The standard tools that we have, the neuropsychological batteries, were not designed for the cognitive changes that cancer survivors experience. They were more designed for head injuries, stroke, Parkinson's, or Alzheimer's," said Myers. For this reason, some researchers are looking at alternative methods. For instance, Bernstein and colleagues at Princess Margaret Cancer Centre examine variability in reaction time and have found that it may be a more sensitive measure of cognitive dysfunction than overall mean accuracy or mean response time, which are the standard measurements in neuropsychological batteries.[9,10]

In another example, Myers and colleagues are assessing the use of task-evoked pupillary response (TEPR), which has been used in the world of psychology for some time but hasn't made its foray into the oncology world until now. TEPR is a method of evaluating people's pupil size as they are expending cognitive effort. Eye-tracking software measures the cognitive effort that breast cancer patients expend during mental tasks, such as coming up with as many words as they can that begin with a certain letter or remembering complex sequences of numbers and letters. The more effort exerted, the more the pupils dilate.

"TEPR is an area of research that we are moving into right now, to see if we can't make a more fine-tuned assessment of cognitive function that will better help us assess people who are having difficulty, and then, hopefully in the future, help us better assess for intervention research if we are making a difference," said Myers.

Managing Symptoms

Currently, there is no pharmacologic treatment for CRCI. Guidelines recommend nonpharmacologic interventions (eg, instruction in coping strategies; management of distress, pain, sleep disturbances, and fatigue; occupational therapy), reserving pharmacologic interventions as a last line of therapy in survivors for whom other interventions have been insufficient.[3]

"For anyone who is concerned about changes in their thinking abilities during or after cancer treatment, I want them to know that although there is no medical cure for it, there are things that can be done to help reduce symptoms and the impact those symptoms have," said Bernstein. Myers agreed. "The treatments at this point are still under investigation, but there are a number of areas that look promising. Cognitive behavioral training looks promising. Exercise-based regimens look promising," said Myers.

Vardy has used the brain-training program Brain HQ (Posit Science) with patients and seen "definite improvement in cognitive symptoms and quality of life," but these were not accompanied by improvements in actual objective cognitive function. She believes that brain training programs are easily accessible over the Internet and worth trying.

Behavioral changes can be helpful to reduce mistakes in everyday life, which themselves can cause stress. "Tips include things such as using calendars and timers/electronic reminders, writing things down, making notes, organizing one's environment (decluttering), and avoiding multitasking," said Bernstein. "If the patient is suffering from sleep problems, anxiety, or depression, then those issues should be addressed, and referral to psychological counseling may be helpful."

Patient complaints about mental fog provide clinicians with an opportunity to engage patients in brief motivational interviewing for lifestyle changes that may improve cognition.[7] Three simple questions provide a wealth of information and a starting point for interventions: (1) How many hours a night are you sleeping? (2) Do you have a daily exercise plan? And (3) What is a typical lunch or dinner for you?[7] Clinicians can encourage patients to implement a schedule that allows for 7-9 hours of sleep, a plan for safe exercise such as walking, and a focus on a healthy diet, which does not take much time and will likely provide more benefit over time than medication options for CRCI.[7] Practicing oncologists can save time by providing handouts, DVDs, and directions to online resources to patients that can give tips about how to manage symptoms.[7,11]

Anxiety, depression, not sleeping well, and chronic pain can make cognitive deficits in patients with cancer worse, as they make it harder for a person to cope with and adapt to cognitive changes. Improving stress management can help with cognitive function, whether the stress is about the cognitive symptoms or about other things. "It is important for patients who notice that they have cancer-related cognitive dysfunction to look for ways to improve those other symptoms if they have them," said Bernstein.

At the Princess Margaret Cancer Center, patients with self-reported CRCI are offered psychoeducation intended to reduce distress about CRCI symptoms and improve everyday cognitive performance. In a study of 100 breast cancer patients, the single, 1-hour psychoeducational intervention was associated with lasting and improved adjustment to memory symptoms at least 6 weeks after the intervention.[12] "We don't know if there is a 'key ingredient' that made this intervention beneficial, and/or what it is," said Bernstein.

The psychoeducational intervention provided survivors with more knowledge, confidence, and techniques to promote self-management of the cognitive deficits experienced in their everyday life. Strategies fell into one of three categories: compensatory behaviors (ie, writing things down, using alarms, etc.), increasing mental stimulation with problem areas (ie, word-finding homework, journaling), and healthy brain lifestyle activities (ie, keeping physically active, developing healthy stress management lifestyle). About half of the session time involved patient education, with the other half spent discussing strategies the patient could use to improve management of her CRCI symptoms and improve brain health. Patients left the office with specific homework goals.

Myers was involved in a cross-sectional study involving 317 patients with breast cancer and 46 healthy controls, which demonstrated that women who were overweight reported more perceived cognitive impairment than women who were not overweight.[13] "Interestingly, the women who had frequent exercise had better perceived cognitive function than women who did not, regardless of whether or not they were overweight," said Myers. A review of 26 studies concluded that there is a promising trend for the use of exercise as a potential intervention for improving cognitive function following cancer and cancer treatment, but questions remain concerning exercise type, timing of initiation, intensity, frequency, and duration.[14]

"Exercise has multiple benefits," said Bernstein. "It is something that we recommend to cancer survivors, even without the cognitive piece, because one of the other big concerns that people have as they go through the cancer experience is overwhelming fatigue. Exercise has been shown to be helpful in mitigating physical fatigue, and when a patient reports having physical fatigue they usually report mental fatigue as well."

As far as how exercise helps cognitive function, researchers believe that it primarily relates to being able to decrease inflammation. "One of the hypotheses behind why people have cognitive issues following cancer and cancer diagnosis is that there is an oversecretion of inflammatory cytokines," said Bernstein. "One of the things that exercise can do is decrease proinflammatory cytokines in the bloodstream, which we feel probably is one of the reasons why we see some benefit of exercise on CRCI."

Clinical Trials

Myers is currently conducting a three-arm intervention study comparing Qigong, a mindfulness-based exercise combining physical postures and breathing; gentle exercise without the mindfulness component; and a support group specifically tailored to the needs of women who have been treated for breast cancer. "Our hypothesis is that we believe that exercise is helpful, and we are interested to find out whether adding a mindfulness component would add further benefit to exercise," said Myers.

KU Medical Center is also collaborating with Cedars Sinai Medical Center in Los Angeles in a psychoeducational study called "Emerging from the Haze" in which people with a variety of cancers with cognitive challenges attend a weekly course for 6 weeks to learn to improve their cognitive function through guided relaxation, compensatory strategies for attention and memory problems, and behavioral strategies for negative thoughts.[15] Participants have reported positive results, and the researchers are planning a larger study.

We don't have a gold standard for what we can recommend.

"I always encourage clinicians to be aware of the studies that are open in their community, in case their patient might be eligible for something," said Myers. "We don't have a gold standard for what we can recommend that people do. Participating in a study helps everyone. For people who don't have a study that is available to them, I encourage regular exercise as one positive thing that people can do, because we know it is going to help them in many, many different areas beyond cognition."

Vardy agreed that exercise was important. "At this stage, there is nothing I would recommend outside of a treatment trial, because there is just not the evidence for it. At the moment, my main thing for treatment would be (1) informing people about it, and (2) asking people about it down the track to see if it is actually a problem, because I am sure it is more of a problem than what many oncologists think it is," said Vardy. "The best evidence at the moment is probably for the cognitive rehabilitation–type programs for symptoms and for exercise."

Drs Bernstein, Myers, and Vardy have disclosed no relevant financial relationships.


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