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Cognition and Cancer Treatment

Psychologists and oncologists are developing tools and techniques to better diagnose and treat cancer-related cognitive impairment

By Chris Palmer Date created: March 1, 2020 11 min read

https://www.apa.org/monitor/2020/03/cognition-cancer

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Every year more than 650,000 cancer patients in the United States receive chemotherapy. During their therapy, some of them experience confusion, lapses in memory and attention, and difficulty concentrating, a collection of symptoms known colloquially by patients as “chemo brain” or “chemo fog” and more formally by clinicians as cancer-related cognitive impairment. This phenomenon has been studied most extensively in breast cancer patients, and different studies find from 15% to 75% of patients report experiencing it. Most fully recover within a year, but 20% to 35% continue to experience symptoms for months to years after their chemotherapy ends (International Review of Psychiatry, Vol. 26, No. 1, 2014).

Studies consistently find that this impairment can undermine a person’s quality of life, yet for many it is so subtle that it is undetectable by oncologists, as well as close friends and colleagues. So far, treatment options, mostly consisting of medications, cognitive skills training and exercise, haven’t offered much relief. But now, research supported in large part by the National Cancer Institute (NCI) is identifying risk factors and developing diagnostic tools and treatments.

“Our aim is to bring together cognitive psychologists, neuro­scientists and oncologists,” says Todd Horowitz, PhD, a program director at NCI. These interdisciplinary collaborations have generated some novel approaches: Researchers are zeroing in on the genetics of susceptibility to cancer-based cognitive impairment, developing a mouse model to study the impact of different chemotherapies on cognition and harnessing electrical brain stimulation to prime patients to succeed with cognitive skills training.

Meanwhile, as researchers break new ground in the lab, health-service psychologists man the front lines, primarily using cognitive rehabilitation techniques to help patients improve their cognitive functioning.

Subtle but persistent symptoms

The signs of cancer-related cognitive impairment are more understated than those seen in people with Alzheimer’s disease or mild cognitive impairment. They include memory-related deficits, such as having difficulty concentrating to learn new things or organize tasks, and being slower to process information. Other signs include having trouble concentrating on a single task, feeling mentally “slower” than usual and having trouble multitasking. In addition, cancer-related cognitive impairment is often accompanied by anxiety and depression. “It seems to be kind of a cyclical process,” says neuropsychologist Shelli Kesler, PhD, an associate professor at the University of Texas at Austin LIVESTRONG Cancer Institutes. “Cancer and its treatments are inherently stressful and also tend to make patients less resilient overall to stress.”

The medical community has been trying to understand cancer-related cognitive impairment since the late 1990s, though patients, primarily women receiving chemotherapy for breast cancer, had been reporting problems for years before that. However, complaints were often vague—“It’s hard to think,” “I’m slower at work,” “I just can’t do all the things I used to”—and physicians refused to accept that chemotherapy could be causing cognitive issues, because chemo­therapies were not believed to cross the blood-brain barrier. “Many of my patients told me the same story: that their physician said it wasn’t possible, and that they had anxiety or depression, rather than a real physical injury to their brain,” Kesler says.

However, a handful of animal studies in the mid-2000s showed that chemotherapy drugs could get through the blood-brain barrier. Shortly after, a surge of neuroimaging studies provided biological evidence: Brains of chemotherapy patients had to work harder during memory recall than those of cancer patients who did not receive the drugs (Clinical Cancer Research, Vol. 15, No. 21, 2009). “The interpretation was that their neural networks had been altered, making the brain work much harder to do the same tasks,” Kesler says.

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This research confirmed the reality of chemo brain for the medical community and patients. But how exactly chemo­therapy exposure affects the brain is still under investigation. Potential mechanisms involve damage to DNA and DNA repair mechanisms, oxidative damage, inflammation, damage to white matter, reduced blood flow and decreased activity of the hypothalamic-pituitary-adrenal axis (ASCO Educational Book, Vol. 38, 2018).

“There is evidence that chemotherapy ages you faster, including your brain,” Kesler says. “The brains of these middle-aged women that we’ve studied sometimes look more like 60- or 70-year-olds’.” Her studies have shown that the brains of patients who have received chemotherapy have similar connectivity patterns to the brains of women who later develop Alzheimer’s disease (Alzheimer’s & Dementia, Vol. 9, No. 1, 2017). In addition, neuroimaging studies of brain volume—which generally shrinks with age—suggest chemo­therapy leads to a decrease in both gray matter and white matter (Simó, M., et al., Neuroscience & Biobehavioral Reviews, Vol. 37, No. 8, 2013).

Blame for cancer patients’ cognitive problems, however, may not fully rest with chemotherapy. Often patients get some combination of surgery with general anesthesia, chemo­therapy and radiation, and they then may take endocrine therapies that affect estrogen levels for five to 10 years post-treatment. In addition, side effects of cancer treatment, including anemia, fatigue, insomnia, nutritional deficiencies and infection, have all been linked to thinking and memory problems.

A handful of studies with primarily breast cancer patients (but also colon and testicular cancer patients) also suggest that about one-third of patients had subtle cognitive deficits before any treatment began, indicating the body’s physiological response to a tumor—­including inflammatory processes or vascular changes around the tumor—could be disruptive as well (Olson, B., & Marks, D.L., Cancers, Vol. 11, No. 5, 2019).

Who’s at risk?

Because not all cancer patients undergoing chemotherapy experience cognitive decline, researchers are trying to find out who’s most at risk. Not surprisingly, studies point to a combination of genetic and lifestyle factors.

Epidemiological data suggest that multiple demographic and health characteristics are associated with susceptibility to cancer-related cognitive impairment. These include ethnicity, education level, cognitive reserve, psychological conditions such as depression and anxiety, and medical conditions such as diabetes, hypertension, sleep disturbance and fatigue. Tumor size, location and malignancy also play a role.

A major genetic culprit, meanwhile, may be a gene variant that is also implicated in Alzheimer’s disease risk: ApoE4. Jeanne Mandelblatt, MD, MPH, a geriatrician and epidemiologist at Georgetown Lombardi Comprehensive Cancer Center, and colleagues have found cognitive declines among cancer survivors were more pronounced for women with ApoE4 (Journal of Clinical Oncology, Vol. 36, No. 32, 2018).

Paralleling her work with human patients, Mandelblatt is working with colleague G. William Rebeck, PhD, to use a mouse model to explore how chemotherapy can drive cognitive decline. In one study, they gave mice the chemotherapy drug doxorubicin and found that mice with the ApoE4 variant experienced more severe spatial-learning and memory deficits than mice without ApoE4 (Speidell, A.P., et al., Neurotoxicity Research, Vol. 35, No. 2, 2019). Mandelblatt hopes to use the mouse model to test different chemotherapy types, one by one, to determine their effects on cognition and the brain. She and Rebeck would also like to use the model to test drugs that can prevent cognitive decline.

Better diagnosis and treatment

Even if a practioner has a general understanding of who is more likely to experience cancer-related cognitive impairments, symptoms are often so understated that they are difficult to diagnose. If a patient goes from high cognitive functioning to normal cognitive functioning, physicians may not be able to tell, even if the decline is obvious to a patient and their family.

“The syndrome is often discredited when patients referred for neuropsychological testing come out average or normal,” Kesler says. “First, the tests, originally designed to detect focal lesions from stroke rather than diffuse damage, sometimes aren’t sensitive enough to it. And second, patients are usually tested only after the problem has already occurred, so we don’t know what their baseline was.”

NCI has recently funded a study by Michelle Janelsins, PhD, MPH, an associate professor of surgery and neuroscience at the University of Rochester Medical Center, to develop and test a battery of neurocognitive tests to determine if they are useful in identifying cancer-related cognitive decline. These tests will assess three cognitive components that have been shown to be particularly susceptible in cancer-related cognitive impairment—visual working memory, sustained attention and new learning 10 years post-chemotherapy. A preliminary analysis of 450 patients found that chemo­therapy patient scores on the tests significantly declined six months after treatment, while control subject scores did not (Journal of Clinical Oncology, Vol. 36, No. 32, 2018).

Unfortunately, once cancer-related cognitive impairments have been identified, there are no medications approved specifically for treating the syndrome and options to treat symptoms are limited.

Early treatments for improving mental focus included stimulants such as Adderall and Ritalin, but clinical trials have generally shown that the drugs are not very effective, and they have side effects including increasing anxiety and interfering with sleep. The Alzheimer’s drug memantine was found to delay cognitive impairment following whole brain radiation therapy, but only for a short time (Brown, P.D., et al., Neuro-Oncology, Vol. 15, No. 10, 2013). Modafinil has also shown modest short-term benefits (Kohli, S., et al., Cancer, Vol. 115, No. 12, 2009). Studies with other neuroprotective medications, such as methyl­phenidate and donepezil, have been inconclusive (Wartena, R., Journal of Cancer Metastasis Treatment, Vol. 4, No. 59, 2018). Clinical trials are underway for other neuroprotective drugs, including lithium, fluoxetine, pioglitazone, ramipril and docosahexaenoic acid, as are trials for nicotine patches, ibuprofen and a host of antioxidants (Karschnia, P., et al., The Lancet Oncology, Vol. 20, No. 2, 2019).

Results from cognitive skills training have also been disappointing, likely because chemotherapy saps patients of the ability to focus, according to Kevin Krull, PhD, a neuroscientist at St. Jude Children’s Research Hospital in Memphis, Tennessee. To help restore attention so survivors can get more benefit from training sessions, Krull, with a grant from NCI, has been exploring a treatment involving transcranial direct current stimulation (tDCS). Krull’s team uses 15-minute sessions of low-voltage tDCS to stimulate a neural network in the dorsolateral prefrontal cortex that they found was disrupted in previous studies with leukemia patients who had undergone chemo­therapy. That stimulation creates a two-hour window during which the network seems to be primed for cognitive skills training. Krull says this pilot study has produced significant improvements in both objective and subjective indices of executive function after just 10 sessions.

In a separate effort, Kristina Hardy, PhD, a neuropsychologist at Children’s National Hospital in Washington, D.C., is investigating the potential of neural feedback technology to help improve attention problems in cancer patients who have had chemotherapy. The idea is to train patients to reduce their brain’s theta rhythms, which are thought to play an important role in learning and memory, and increase their focus and attention during cognitive training sessions.

Krull says that in lieu of an effective medication, what is needed is a multipronged approach encompassing good sleep, physical activity, balanced nutrition, maintaining a healthy weight, not smoking or drinking, avoiding infection, engaging in cognitive skills training such as attention retraining, and the use of compensatory strategies—the earlier the better.

He recommends that psychologists be standard members of all oncology teams. “Why do we wait until the problems start?” he says. “We should be working from a preventative approach and starting to use these technologies to help enhance the skills and functions in those patients before they start experiencing deficits.”

Psychologists’ role

Currently, cancer patients are usually referred to psychologists only after reporting problems with cognition, says Tamar Press, PsyD, a senior psychologist at Rusk Rehabilitation at New York University Langone Health.

“It’s fairly rare for most community cancer centers, or even the comprehensive cancer centers, to have a psychologist on site,” says Robert Ferguson, PhD, an assistant professor of medicine at the University of Pittsburgh School of Medicine.

Ferguson and Press say the most effective treatment that health-service psychologists offer cancer patients is cognitive remediation, in which an individual is taught alternate, or compensatory, strategies to supplement their current level of cognitive functioning. One typical compensatory approach is using written or digital resources, such as a memory book. “We have patients use an appointment book and check it every day and then write every night in a memory journal—what did they do that day, what did they talk about,” says Press, who typically works with patients for between two to three months and several years.

Ferguson also offers a cognitive-behavioral therapy called Memory and Attention Adaptation Training (MAAT), which consists of compensatory strategies and interventions to promote adaptive emotional coping with cognitive problems. MAAT can be delivered remotely, which is critical for survivors who have used most of their leave time from work to receive cancer treatment or live far from the cancer center.

Ferguson cautions that while cognitive symptoms are often attributed to cancer or cancer treatment, it can be a mistake to ascribe all daily memory and attention failure to cancer. “We want to help survivors entertain the idea that there may be other factors more within their control, such as being attentive, organized, well rested and managing their stress,” he says.

In addition to providing cognitive training or rehabilitation, Press says psychologists should emphasize patients’ emotional lives. “People with a terminal diagnosis need a place to talk about their fears and anticipations, because family members often struggle with these types of conversations.” One way Press supports patients is by offering group psycho­therapy to help them learn how their cognitive functioning can fluctuate based on their emotional functioning. “If we don’t address the emotional distress of this experience, we’re probably not going to get far in improving the patient’s overall adaptive ability,” Ferguson says.

Further reading

Cognitive Rehabilitation for Cancer-Related Cognitive Dysfunction: A Systematic Review
Fernandes, H.A., et al., Supportive Care in Cancer, 2019

Cognitive Effects of Cancer and Cancer Treatments
Ahles, T.A., & Root, J.C., Annual Review of Clinical Psychology, 2018

Cognitive Changes in Cancer Survivors
Hardy, S.J., et al., ASCO Educational Book, 2018

Clinical Characteristics, Pathophysiology, and Management of Noncentral Nervous System Cancer-Related Cognitive Impairment in Adults
Wefel, J.S., et al., CA: A Cancer Journal for Clinicians, 2014