‘Chemo brain’ linked to neurobiological mechanism

Pharmacologic treatments remain elusive, but cognitive behavior therapy shows promise.

For many years, cancer survivors have complained about a mental fogginess after chemotherapy that interferes with multitasking, processing speed, concentration and memory.

Health care professionals initially rejected these claims, contending the problems — reported both during treatment and, in some cases, years after — were psychosomatic.

Recent research, however, has shown that these cognitive issues are not imagined. In fact, two studies have demonstrated brain changes in patients who display symptoms of this mental fog, commonly referred to as “chemo brain.”

“Calling it chemo brain is probably a misnomer because patients may have cognitive changes that could come on with just surgery, just radiation, surgery with radiation or chemotherapy, or even some targeted therapies,” Patricia Ganz, MD, director of cancer prevention and control at Jonsson Comprehensive Cancer Care Center and a professor of medicine and health services at UCLA, told HemOnc Today. “It’s more appropriately termed ‘cancer brain.’”

Most of the research into cognitive impairment has focused on patients with breast cancer because they have been the most vocal about this issue. However, there is evidence that these cognitive challenges also plague patients who have been treated for several other types of cancer.

Recent research

Some of the most recent studies have shown that there are measurable changes in the brain after cancer treatment.

Shelli R. Kesler, PhD, and colleagues at Stanford University School of Medicine compared 25 women with breast cancer who were treated with chemotherapy with 19 women with breast cancer who did not receive chemotherapy and 18 healthy female controls. The researchers used functional MRI to determine which part of the brain was activated when the women performed a card-sorting task. In addition, they used questionnaires to evaluate the patients’ perceptions of their cognitive abilities.

The results showed that women with breast cancer who were treated with chemotherapy had significantly reduced function in the prefrontal cortex, the area of the brain responsible for skills such as problem-solving, working memory and multitasking.

Additionally, the chemotherapy group showed more perseverative errors and reduced processing speed. There was a significant correlation between reduced left caudal lateral prefrontal cortex activation and higher disease severity and increased subjective executive dysfunction in the women treated with chemotherapy.

“[This study] contributes to the growing body of literature [showing] that there are measurable changes in brain functioning following chemotherapy for breast cancer,” said Kesler, an assistant professor of psychiatry and neuropsychologist at Stanford University Medical Center in Palo Alto, Calif. “This was a study focused on breast cancer, but there is some evidence that other cancers that are treated with chemotherapy may be at risk for similar problems. It tells us that this is a real issue in cancer survivorship, and we need to come up with some treatments for those patients who are reporting these problems.”

White matter changes

Sabine Deprez, MD, and colleagues at the University Hospital Gasthuisberg of the Katholieke Universitet Leuven in Leuven, Belgium, evaluated cerebral white matter integrity before and after chemotherapy with magnetic resonance diffusion tensor imaging (DTI). Participants also completed a detailed cognitive assessment.

In all, 34 premenopausal women with early stage breast cancer underwent DTI testing and cognitive assessment before chemotherapy and 3 to 4 months after treatment. Sixteen patients with cancer who were not exposed to chemotherapy and 19 age-matched healthy controls underwent the same testing.

After treatment, the chemotherapy group had significantly worse scores on tests of attention, psychomotor speed and memory. In addition, they had significant decreases of white matter fractional anisotropy — a DTI measure that indicates white matter tissue organization — in frontal, parietal and occipital white matter tracts after treatment. The researchers saw no changes in the other groups.

The results also showed that changes in attention and verbal memory correlated with mean regional fractional anisotropy changes in the chemotherapy group.

Long-term effects

Previous research indicated that cancer-treatment induced cognitive dysfunction may last up to 2 years; however, findings published recently in the Journal of Clinical Oncology indicate these issues can persist much longer.

In a case-cohort study, Sanne B. Schagen, PhD, of the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital in Amsterdam, evaluated the cognitive performance of patients with breast cancer who were treated with a regimen of cyclophosphamide, methotrexate and fluorouracil (CMF) chemotherapy.

Although the CMF combination is no longer widely used, two agents — cyclophosphamide and fluorouracil — are used often in current breast cancer regimens, Schagen told HemOnc Today.

Schagen and colleagues evaluated 196 patients with breast cancer, and the average time since treatment was 21 years. The researchers compared these women with a population-based sample of 1,509 women who were never diagnosed with cancer.

 The results showed that the chemotherapy group performed significantly worse on cognitive tests of immediate and delayed verbal memory, processing speed, executive functioning and psychomotor speed.

“It is the first study that shows that many years after completion of chemotherapy for breast cancer, subtle differences between former patients with breast cancer treated with chemotherapy and women without a history of cancer in cognitive performance are still present,” Schagen said.

Unanswered questions

Many questions about cognitive dysfunction after cancer treatment remain.

For example, researchers do not know how many patients are affected. The best estimates are that about 20% of patients have lasting cognitive deficits after chemotherapy.

“Estimates range widely because different studies have used different populations and different approaches to measuring and defining cognitive impairment,” said Lynne I. Wagner, PhD, associate professor in the department of medical social sciences and a member of the Robert H. Lurie Comprehensive Cancer Center at the Northwestern University Feinberg School of Medicine in Chicago.

It is not clear which patients are most at risk, Ganz said.

“We know that more intensely treated patients — those who undergo bone marrow transplant, high-dose chemotherapy and whole-body radiation — probably are at higher risk,” Ganz said.

Older women, as well as those who were less physically and mentally active before their diagnosis, are much more vulnerable to the effects of chemotherapy, Kesler said.

Researchers also are trying to determine what causes cognitive impairment after cancer treatment.

“The causes are not known,” Ganz said. “Some of the chemotherapy treatments may get into the brain and cross the blood-brain barrier.”

Chemotherapy can be extremely toxic to neural stem cells, Kesler said.

“If even a small amount gets in, that can likely do quite a bit of damage,” she said.

Inflammatory response

There also is a possibility that cancer treatment may stimulate an inflammatory response in the body that causes problems with memory and concentration, Ganz said.

She is studying the pattern of single nucleotide polymorphisms in the promoter region of the tumor necrosis factor (TNF)-alpha gene (TNF-alpha 308) to determine whether some individuals may be predisposed to develop post-treatment increases in pro-inflammatory cytokines and associated symptoms.

“These are not genes that cause brain damage,” she said. “They’re just genes that are involved in inflammation, and people who may have one variant or another may have more inflammation.”

Increased blood levels of TNF-alpha, as well as other pro-inflammatory cytokines, can lead to fatigue and other symptoms that, in animal models, are called “sickness behavior,” which causes loss of interest in usual activities, Ganz said. This is similar to how a person feels when they have the flu or a bad cold.

“We can see elevations of this in patients who get cancer therapies,” she said. “This might be one of the mechanisms by which patients are having fatigue and these cognitive complaints.”

Inflammation also is increased simply by having a tumor, Kesler said.

“There are several things that are probably playing a role, with the chemotherapy being a toxin that gets into the brain and does some damage,” she said.

Genetics may affect the development of cognitive issues. Some research has been done on apolipoprotein E-4 gene, a genetic SNP linked to Alzheimer’s disease.

“There is some concern that patients with that polymorphism may be more susceptible to this,” Ganz said.

Other factors

Other factors such as fatigue and secondary medical conditions could negatively influence cognitive function.

“It’s a complicated picture,” Wagner said. “When someone is going through chemotherapy, they have a lot of other symptoms related to treatment, fatigue being most common.

“We must evaluate the patient to see if there are any medications that are compromising cognitive function and, if so, whether they are necessary,” Wagner said. “Can other medications be used? Or perhaps, if it’s a short-term medication, then everybody understands that once you’re off this medicine, things should get better.”

Other medical conditions that could lead to cognitive impairment, such as anemia, should be ruled out or treated if present, Wagner said.

“Anemia is commonly associated with chemotherapy,” she said. “We have an abundance of research in patients with end-stage renal disease demonstrating that anemia is associated with significant impairment of cognitive function.”

Diagnosing cognitive dysfunction is difficult because the standard neurological tests available are not sensitive enough to detect the cognitive changes.

“One of the problems is, we’re talking about subtle changes,” Ganz said.

“The first challenge is finding a good measure that can be used in the clinic easily that can discriminate between who has it and who doesn’t,” Kesler said. “The standard psychological testing is not super-practical in the clinic because it takes multiple hours and you have to have a specialist [administer it], and it’s not always sensitive. The biggest challenge is to develop some measure that correlates with brain function and also with outcomes that occur several years down the road.”

Treatment options

There currently are no reliable pharmacologic treatments for cancer therapy-induced cognitive impairment.

The narcolepsy treatment modafinil (Provigil, Cephalon) appears promising, but there have been no large randomized clinical trials demonstrating its effectiveness, Wagner said.

“Modafinil has been studied for cancer-related fatigue,” Wagner said. “In that study, [the researchers] looked at cognitive function as a secondary endpoint and they found that some patients improved on only a few subscales out of many on cognitive function. It may be that modafinil, in improving fatigue, may improve cognitive function, but we don’t have a solid evidence base yet.”

Researchers at Wake Forest University have studied whether donepezil (Aricept, Eisai) would improve cognitive function in patients with primary brain tumors or brain metastases, Wagner said.

“In their early phase trials, they have found that the drugs we use for Alzheimer’s may play a role, but this is in a different population than your breast cancer survivor who is post-treatment and has no evidence of cancer,” Wagner said.

Some small studies have been done on attention-deficit/hyperactivity disorder drugs, but no drug has stood out as a good option, Ganz said.

A few studies have examined erythropoietin, which is typically used to treat anemia. Erythropoietin had some moderate effects but also reduced survival, Kesler said.

“Finding the right pharmacology is going to be challenging,” she said.

Nonpharmacologic strategies

Currently, the most exciting research is being conducted on nondrug strategies such as cognitive behavioral therapy, Wagner said.

Robert J. Ferguson, PhD, a clinical health psychologist at the Eastern Maine Medical Center in Bangor, Maine, and colleagues are studying a cognitive rehabilitation tool called Memory and Attention Adaptation Training (MAAT), which they designed specifically for mild cancer treatment-related impairment.

Unlike typical cognitive rehabilitation, in which the patient performs a repetitive task to recreate brain circuitry, this approach emphasizes the acquisition of new behaviors and cognition to compensate for the impairment.

“Our approach is more behaviorally adaptive,” Ferguson said. “We probably aren’t going to improve memory functioning per se, but [we will] help the person improve behaviors in daily performance for which memory is used.”

With MAAT, the patient practices compensatory strategies, such as keeping a daily planner and verbal rehearsals. They also practice self-instruction training, which requires them to talk through a task to improve attention and procedural performance. Patients can use that skill in the event of a memory failure.

Results of a single-arm pilot study in patients with breast cancer yielded high patient satisfaction and improvements in verbal memory.

A subsequent randomized trial included patients with breast cancer who were 5 to 7 years post-chemotherapy. The researchers randomly assigned patients to a waitlist group, with normal follow-up cancer care, or the treatment group. Both groups’ pretreatment and post-treatment testing occurred at the same interval.

The results showed a robust effect in verbal memory performance.

“We weren’t expecting that,” Ferguson said.

There also was an increase in quality of life as measured by a spiritual subscale.

“We were kind of puzzled by that, but when we looked at the items in that spiritual scale, it has a lot to do with optimism and acceptance of cancer survivorship and the problems,” Ferguson said.

In the end, the best way for physicians to treat cognitive dysfunction in cancer survivors is to recognize it.

“Know that it is real,” Kesler said. “There is a neurobiological mechanism that is associated with the complaints patients have. Currently, the best treatment plan is to get a referral to neuropsychology for an evaluation and recommendations for dealing with cognitive difficulties.” – by Colleen Owens

Does chemotherapy have a direct, organic effect on the brain that causes cognitive dysfunction?

We do not know the answer yet.

Some patients have reported that they are unable to think and function as well when they have chemotherapy. For a small portion of them, the problems persist for quite some time after the chemotherapy is stopped.

These complaints led to investigations of cognitive function. Essentially, those investigations found that the cancer diagnosis itself is associated with cognitive deficits. The chemotherapy may add to that in a small portion of patients.

There is not a very strong relationship between the people who self-report cognitive dysfunction and their formal testing. That may be because the tests are not sensitive enough to pick up subtle differences in cognition. It may be that patients are initially high functioning and, even though that level of function decreases and is noticeable to them, it is still within normal range. It also may be that people feel very anxious, and they report changes that perhaps are not real.

There clearly are patients who both immediately and long term demonstrate deficits in cognitive functioning. Documented changes in brain imaging, both on PET and MRI, lend support to this being a real phenomenon.

It has taken some time for these cognitive impairments to be recognized. In the early days of chemotherapy, the overwhelming problems were things like nausea, vomiting, fatigue and infection. Those acute effects were so dominant; they tended to mask the rather subtle cognitive changes that we now recognize.

Only since the beginning of the last decade have well-designed studies begun to investigate this area, and most studies have shown an effect.

The early studies were not well controlled. You cannot ethically do a randomized trial to compare chemotherapy with no chemotherapy. These trials require two types of controls. First, it is necessary to have a control group of healthy people. Second, researchers must compare chemotherapy-treated patients with people who have cancer but who do not receive chemotherapy.

We have done this in a very large study of colorectal patients, which includes both men and women. We have not published these data yet, but, at least initially, we found an effect of the cancer itself to cause cognitive dysfunction. There was not a big difference between the chemotherapy group and the non-chemotherapy group.

Ian F. Tannock, MD, PhD, DSc, is Daniel E. Bergsagel Professor of Medical Oncology at Princess Margaret Hospital in Toronto. Disclosure: Dr. Tannock reports no relevant financial disclosures.

There is no proof that chemotherapy leads to cognitive impairments.

 

One theory is that chemotherapy may have a direct organic effect on the brain and, therefore, lead to cognitive dysfunction. A second theory, supported in part by data from our own institution, is that cognitive dysfunction may be the result of the conflict and confusion the patient experiences.

Bernadine Cimprich, PhD, RN, FAAN, of the University of Michigan School of Nursing, has performed functional MRI and cognitive functioning testing in women at the time of diagnosis — before they received treatment — and compared them to otherwise normal controls who have not been told they have breast cancer. She found cognitive function drops dramatically in women diagnosed with cancer.

It makes perfect sense to me. If you are told you have had some major catastrophe in your life, your ability to concentrate takes a hit.

It is easy to blame a decline in cognitive functioning on treatment when, in fact, it may be related to everything else going on in the patient’s life.

The trouble is that most of the research has been a cross-sectional analysis of a population without serial follow-up or without proper controls.

Researchers in Canada, as well as Dr. Cimprich, have been monitoring a cohort of chemotherapy-treated patients vs. a control group of patients who did not receive chemotherapy. They have found that the cognitive function of chemotherapy-treated women drops while they are getting treatment. In the studies I have seen, their cognitive function usually returns to baseline within a few months of stopping chemotherapy.

That could be a now-resolved direct organic effect of the chemotherapy on the brain, or it could be that chemotherapy is tough to take. Patients experience fatigue, nausea, vomiting and hair loss. If they have breast cancer, they may have had a mastectomy. A number of things are going on, all of which could affect cognitive function.

I do not want women to perceive that chemotherapy will cause long-term cognitive dysfunction and, therefore, walk away from potentially life-saving therapies. Breast cancer mortality has plummeted over the last 30 years. Part of the decline is due to screening, but a lot of it is from widespread application of adjuvant and systemic therapies, chemotherapy, anti-estrogen therapy and anti-HER-2 therapy.

We need good studies with proper controls to determine whether women who undergo chemotherapy really have persistent cognitive dysfunction and whether chemotherapy is an organic cause. I want to be sure we apply good scientific principles to this to find out what is wrong. We need to prove the mechanism first before we start treating a presumed mechanism.

Daniel F. Hayes, MD, is clinical director of the breast cancer oncology program and Stuart B. Padnos Professor in Breast Cancer at the University of Michigan Comprehensive Cancer Center in Ann Arbor, Mich. Disclosure: Dr. Hayes reports no relevant financial disclosures.

References:

• Deprez S. J Clin Oncol. 2012;30:274-281.
• Kesler SR. Arch Neurol. 2011;68:1447-1453.
• Koppelmans V. J Clin Oncol. 2012;30:1080-1086.

Disclosures:

• Drs. Ferguson, Ganz, Kesler, Schagen and Wagner report no relevant financial disclosures.