‘Chemo brain’: An imprecise term for a complex phenomenon

The various cognitive impairments collectively known as “chemo brain” can cause anxiety, frustration and difficulty with everyday tasks for cancer survivors.

Despite what the term suggests, “chemo brain” and its associated mental changes are not necessarily related only to chemotherapy. Other cancer treatments also can have short- or long-term cognitive implications. Additionally, some changes in cognitive function may be associated with the cancer itself.

Ongoing research has been seeking to identify the mechanisms behind cancer-related cognitive decline, as well as ways to manage them.

“The research community has been trying to answer this question for many years now,” Lynne I. Wagner, PhD, professor of social sciences and health policy at Wake Forest School of Medicine, said in an interview with Healio. “It really is multifactorial. One of the pieces of this puzzle is that some people appear to be more affected than others. So, part of the challenge is in identifying the underlying mechanisms and subgroups of patients who are impacted.”

A ‘foggy sensation’

Cancer-related cognitive impairment can manifest in many ways, but the most common symptoms include lack of focus, issues with verbal or visual memory, shortened attention span, difficulty multitasking and an overall feeling of fogginess.

“Most of the time, the foggy sensation related to having cancer will resolve over 6 to 12 months after the cancer is successfully treated,” Peter Cole, MD, chief of pediatric hematology/oncology at Rutgers Cancer Institute of New Jersey, said in an interview with Healio. “However, a portion of survivors, ranging from 20% to 70% depending on the type of treatment, exhibit permanent cognitive deficits.”

Because cognitive impairment among cancer survivors has also been noted in patients treated with hormone therapy, radiation, bone marrow transplantation and surgery, the term “chemo brain” is misleading, according to Arash Asher, MD, director of cancer rehabilitation and survivorship and assistant professor of physical medicine and rehabilitation at Cedars-Sinai Medical Center.

“‘Chemo brain’ was popularized initially in breast cancer survivors, and it’s what our patients use. It’s going to be difficult to combat that term,” Asher told Healio. “However, given the role of inflammation associated with the cancer itself, as well as the effects of hormone and radiation treatment and other variables, I don’t think it’s a medically accurate term.”

The role of inflammation

For some patients, cognitive impairment may emerge before cancer treatment begins. Inflammatory cytokines are thought to be one potential driver of cancer-related cognitive impairment, Asher said.

“Studies show that up to a third of people have cognitive symptoms before they get any cancer treatment, so there’s belief that maybe the inflammatory response to the cancer might be contributing to the cognitive symptoms,” Asher said. “These inflammatory cytokines may be produced in response to the cancer, the chemotherapy, or even psychological symptoms such as depression and anxiety. These may all be synergizing.”

In the pro-inflammatory state that occurs with cancer, inflammatory cytokines, which upregulate inflammation, can cross the blood brain barrier and directly alter neuronal function.

“This may be the basis of the foggy feeling many patients with cancer describe, even when they’re not getting chemotherapy or radiation,” Cole said. “In addition, cancer treatments, including both chemotherapy and radiation, can directly cause damage to the brain through a multitude of mechanisms, including induction of neuroinflammation, oxidative stress and perturbation of normal cellular processes.”

According to Asher, the concept of “chemo brain” historically has been dismissed because many chemotherapy drugs do not readily cross the blood-brain barrier.

“The thought was that ‘chemo brain’ couldn’t be real because many drugs don’t readily get into the brain, so how could that be causing cognitive issues? It was assumed that it must all just be anxiety or distress,” he said. “What the research has shown over the past 10 years is that although the drugs may not readily cross the blood-brain barrier, the inflammatory cytokines that our body produces in response to the chemotherapy — interleukin-1, interleukin-6, tumor necrosis factor-alpha and others — can cross the blood-brain barrier, and we know they can be neurotoxic.”

Not just chemotherapy

Even patients treated with surgery may experience their own version of “chemo brain.” According to Wagner, general anesthesia has been associated with cognitive effects lasting between 4 and 6 weeks.

“There are also many conditions — like anemia, for example — that may result from cancer treatment and are associated with reduced cognitive function,” Wagner said. “Also, comorbid conditions can account for some changes in cognitive function.”

Cognitive impairments can occur after patients with hematologic cancers undergo hematopoietic stem cell transplantation, as shown in a study co-led by Noha Sharafeldin, MD, PhD, MSc, assistant professor in the division of hematology and oncology and member of the Institute for Cancer Outcomes and Survivorship (ICOS) at University of Alabama at Birmingham (UAB) School of Medicine, and Smita Bhatia, MD, MPH, director of the ICOS at UAB. Patients who undergo HSCT often are exposed to conditioning regimens that include total-body irradiation and high-dose chemotherapy.

“We found that allogeneic [HSCT] recipients treated with full-intensity conditioning were the most compromised group when compared with healthy controls,” Sharafeldin, who co-authored a 2018 study of cognitive impairment after HSCT, told Healio. “Non-myeloablative HSCT recipients showed evidence of delayed decline, [whereas] patients receiving an autologous HSCT were generally spared.”

Sharafeldin added that some patients who undergo HSCT seem to be more vulnerable to cognitive impairment and its persistence than others.

“Certain demographic characteristics place some individuals at higher risk [for] impairment,” she said. “We found older age, male gender, low education, low income levels and — most importantly — an individual’s cognitive reserve to be important predictors of cognitive outcomes [after] transplant.”

The role of genetics

Genetics also could play a role in predicting which patients will be most affected by cognitive symptoms after HSCT, as shown by research led by Sharafeldin and Bhatia.

In the 2020 study, the researchers evaluated 277 individuals (58.5% men, 68.6% non-Hispanic white) who underwent HSCT (46.6% allogeneic). The analysis was adjusted for HSCT type, age at transplantation, sex, race/ethnicity and cognitive reserve. Participants underwent neuropsychological testing before HSCT and 6 months, 1 year, 2 years and 3 years after BMT.

The researchers examined approximately 1,000 single nucleotide polymorphisms in 68 candidate genes among the participants.

“We identified certain genes that were associated with post-transplant cognitive impairment,” Bhatia told Healio. “These included the blood-brain barrier genes, meaning that they helped or prevented chemotherapies in going into the brain.”

Additionally, Bhatia and colleagues identified SNPs on DNA repair genes, as well as on genes related to telomere homeostasis.

“We combined the information from these genes, as well as the patient’s clinical characteristics,” Bhatia said. “We were able to create a prediction tool that could help us identify those at highest and lowest risk of developing cognitive impairment. Adding these genetic variants helped us tremendously.”

Bhatia and Sharafeldin are now conducting studies in which patients identified through the tool as being at high risk receive remediation therapy.

“We’re identifying a subgroup of patients who are at the highest risk and having these patients participate in computer games in order to improve their cognition,” she said. “We hope to take this forward and apply it to other cancers, and make it into standard of care if it’s working well.”

Survivors of pediatric cancers

Individuals who have survived treatment for pediatric cancers usually have full, healthy lives ahead of them. However, these survivors often are at crucial stages in their educational and intellectual development and therefore may be especially impacted by cancer-related cognitive impairments.

“The good news is that most survivors of childhood cancers are fine, with no symptoms of cognitive impairment,” Cole, who deals frequently with pediatric cancer survivors, said. “However, a subset will note he said, problems with attention span, short-term memory and/or executive functions, like impulse control or flexibility in switching from one task to another.”

Cole said he and his colleagues are investigating why some survivors of pediatric cancer seem to be disproportionately affected by cancer-related cognitive impairment. To some extent, he said, the variability among patients is related to the type of treatment used.

“High doses of radiation to the brain are particularly damaging, for example,” he said.

Cole also cited possible genetic predispositions to treatment-related cognitive impairment. “There are also host factors, like differences in genetic makeup, that contribute to the variability,” he said. “We and others have identified common genes that make some more susceptible to this side effect of therapy.”

Additionally, Cole said he and his group have been evaluating the possible role of environmental factors, such as poverty, and differences in dietary intake of certain nutrients.

‘Chemo brain’ vs. dementia

Older adults represent another especially challenging group when it comes to cancer-related cognitive impairment. When managing these patients, it may be difficult for clinicians to differentiate cognitive decline linked to cancer from early dementia or age-related memory loss. Additionally, these patients may be taking medications for comorbid conditions that may compromise their cognitive function.

“The picture can be fairly complicated for these patients because, in addition to aging, these patients likely have other medical conditions,” Wagner said. “In these cases, a comprehensive geriatric assessment would be required, ideally by a geriatric oncologist.

Asher said cancer-related cognitive impairment generally is much less severe than dementia.

“Cancer-related cognitive impairment is usually mild; it may be distressing to the patient, but you wouldn’t expect to have things like people getting lost or having agnosia or apraxia or things that are associated with more advanced Alzheimer’s or dementia,” he said. “If you have a patient do a clock draw and they are completely disoriented, that is unlikely to be cancer-related cognitive impairment.”

Sometimes, however, dementia and cancer-related cognitive impairment may be occurring simultaneously in an older patient, Asher said, making the overall situation more complicated.

“Sometimes, it’s confusing,” he said, “In cases where both processes might be going on, I usually consider imaging and/or neuropsychological testing whenever there is a concern for dementia. Also, when patients continue to struggle with significant cognitive concerns and functional re-integration after 6 to 12 months have passed, it may also be time to think about getting neuropsychological testing.”

Wagner said a comprehensive geriatric assessment can also rule out other medical conditions that might be impacting brain function among older patients.

“Neuropsychological assessment and neuroimaging may identify whether there are other medical conditions, such as vascular conditions, that may be affecting the vasculature of the brain,” she said.

Making the assessment

Primary care physicians and other clinicians who treat cancer survivors should be aware of each patient’s case and be watchful for signs of cancer-related cognitive decline. Because many of these symptoms may be attributable to other causes, Asher said it is important to rule out other possible explanations for cognitive issues. He said conditions such as hypothyroidism, anemia, electrolyte imbalance, sleep apnea, depression or B12 deficiency may account for cognitive issues.

“These are things we don’t want to miss,” he said. “I think for any physician assessing cognitive symptoms, these would be the first things to rule out.”

Wagner said PCPs also should be receptive to any concerns a patient might express regarding cognitive impairment, even when it occurs years after cancer treatment.

She added that physicians should not overlook patients who have undergone endocrine therapy as part of their cancer treatment. As part of the TAILORx breast cancer treatment trial, Wagner and colleagues found that at 12, 24 and 36 months, women treated with hormone therapy reported similar loss of cognitive function as those treated with chemotherapy.

Wagner emphasized that although the cognitive deficits patients mention may be mild, providers should take them seriously.

“They are subtle changes yet very distressing to the person who is experiencing them,” she said. “We’ve defined ourselves based on our cognition, our ability to remember things — it’s part of what makes us uniquely human. So, I think primary care providers should keep an ear out about changes in cognitive function, even if it’s a few years after starting treatment.”

Treating ‘chemo brain’

Although research is being conducted in hopes of identifying an effective treatment for cancer-related cognitive impairment, no intervention for these symptoms has been established.

Experts with whom Healio spoke said that because the causes of “chemo brain” are so varied and extensive, effective treatment likely will combine pharmacologic, behavioral and rehabilitative approaches. In many cases, the treatment might need to be tailored to the individual patient.

“There are many different factors that may contribute to cognitive changes in the cancer setting, and so I don’t think there is going to be a singular mechanism for everyone,” Asher said. “There is a need to look at this broadly, to see what factors are playing a role for each person, and to target interventions to that person.”

Learning systems of adaptation and behavior modification may be an effective way for some patients to overcome cancer-related cognitive decline. Wagner discussed a trial underway that is evaluating “compensatory strategies” as a means of offsetting cognitive issues.

“The strategy here is for patients to identify and adapt to their problem areas,” she said. “If these are the cards you’ve been dealt, what can you do? What strategies can you incorporate into your day-to-day life that can make up for these changes, so they are less disruptive?”

Drugs being investigated include psychostimulants, which have yielded mixed results at best. Asher discussed the use of drugs such as Provigil (modafinil, Cephalon), Ritalin (methylphenidate, Novartis) and Adderall (amphetamine and dextroamphetamine, Shire).

“The evidence is rather limited for using these stimulant-type medications,” he said. “Many of these are often habit-forming, as well. I usually use these when someone has metastatic cancer and they are going to be in some sort of treatment indefinitely, or when we’ve tried all nonpharmacologic options and nothing has helped.”

Sharafeldin said agents such as erythropoietin or hormonal treatment have been used, but these may carry increased risk for adverse events among patients with cancer.

“Other approaches include pharmacotherapies for comorbid depression and/or fatigue,” she said.

Wagner discussed REMEMBER, an ongoing trial conducted by the Wake Forest NCI Community Oncology Research Program (NCORP) Research Base at Wake Forest Baptist Comprehensive Cancer Center that is evaluating the use of Aricept (donepezil, Eisai) among breast cancer survivors with cancer-related cognitive impairment.

“They are evaluating whether donepezil, which is approved for Alzheimer’s dementia, might help women with breast cancer to preserve their cognitive function,” she said. “It is important to identify potential pharmacological strategies.”

In recent years, there also has been steady increased interest in nonpharmacological interventions. Sharafeldin is leading a computer-based cognitive training intervention (cTAG) at UAB.

“Patients undergoing allogeneic HSCT receive 12 weeks of online cognitive training, and their cognitive function is measured prior to and after training to evaluate efficacy of the intervention,” Sharafeldin said. “These approaches are mainly restorative, and the premise is that they will subsequently promote improvements in everyday activities.”

Lifestyle strategies

Reasonable lifestyle changes, which most patients can safely make, are another way to potentially combat cancer-related cognitive decline, according to Asher.

He noted that factors such as obesity, insomnia and even loneliness have been found to be associated with cognitive impairment among patients who have survived cancer.

“Insomnia is very common, for example, among [patients with cancer] and cancer survivors,” he said. “I would argue that, depending on which group you look at, the rate is at least 50%. Also, visceral fat is associated with producing more inflammatory cytokines, and so that might also be a mechanism contributing to this.”

Exercise is a powerful lifestyle component that may have an impact on several mechanisms of cancer-related cognitive impairment.

“There is emerging evidence that aerobic exercise supports cognitive recovery,” he said. “Anecdotally, I’ve certainly seen this in my own practice. This benefit may be related to reduced inflammatory cytokines from exercise or other factors such as improving depression or self-efficacy — all of which are important for cognitive function.”

Social factors also may have some effect on cognitive function after cancer treatment.

Asher said he and his colleagues conducted a study (Myers et al.) that showed symptoms of loneliness are highly correlated with symptoms of cancer-related cognitive impairment.

“What was interesting is that when participants went through our group rehabilitation program, the improvements in loneliness these patients achieved paralleled improvements in cognitive symptoms,” he said.

Asher, who helped develop a psychoeducational intervention called “Emerging from the Haze,” said he believes addressing some of these lifestyle factors can bring about improvements in cognitive functioning for cancer survivors.

“There have also been a few studies now looking at mindfulness-based stress reduction programs for improving cognitive symptoms,” he said. “There are pilot studies of things like qigong and other mind/body interventions. Particularly with mindfulness, there is reasonable evidence that it really helps with attention, which is an important part of the memory pathway.”

As researchers continue to search for evidence-based approaches to cancer-related cognitive decline, clinicians can make a difference for patients through one simple step: acknowledging the problem.

“I think simply recognizing that these cognitive changes are real can be tremendously beneficial,” Wagner said. “Cancer-related cognitive impairment hasn’t been taken seriously for a long time. So, I think for a provider to simply say, ‘yes, this is common among people in your shoes,’ is tremendously therapeutic. The patient feels as though their concerns have been heard.” – by Jennifer Byrne

References:

Myers JS, et al. Arch Phys Med Rehab. 2020;doi:10.1016/j.apmr.2020.01.021.

Sharafeldin N, et al. J Clin Oncol. 2018;doi:10.1200/JCO.2017.74.2270.

Sharafeldin N, et al. J Clin Oncol. 2020;doi:10.1200/JCO.19.1085.

Wagner LI, et al. J Clin Oncol. 2020;doi:10.1200/JCO.19.01866.

For more information:

Arash Asher, MD, can be reached at arash.asher@cshs.org

Smita Bhatia, MD, MPH, can be reached at sbhatia@peds.uab.edu.

Peter Cole, MD, can be reached at colepd@cinj.rutgers.edu.

Noha Sharafeldin, MD, PhD, MSc, can be reached at nsharafeldin@peds.uab.edu.

Lynne I. Wagner, PhD, can be reached at lywagner@wakehealth.edu.

Disclosures: Asher, Bhatia, Cole, Sharafeldin and Wagner report no relevant financial disclosures.