Countering Chemo Brain
About the Lecture
Cognitive complaints are common both during and after cancer treatments. Many cancer patients exposed to a variety of cancer therapies complain of decreased cognitive efficiency that has often been attributed to chemotherapy. This syndrome of cognitive complaints and difficulties is colloquially named ‘chemo brain.’ For a subset of cancer survivors, these complaints are persistent and result in difficulties that impair their everyday activities. For some, the difficulties are disabling. Also presented is an update on potential causes of ‘chemo brain’ and the latest research on strategies and interventions to counter cancer-related cognitive dysfunction.
Linda M. Ercoli, Ph.D., is an Associate Clinical Professor and the Director of Geriatric Psychology in the Department of Psychiatry and Biobehavioral Sciences at the UCLA Semel Institute. She is a clinical psychologist with expertise in neuropsychology, aging, and cognitive remediation. Her research activities involve studying the use of neuropsychological tests in conjunction with brain imaging for the early detection and prediction of dementia. Dr. Ercoli has also been active in developing cognitive enhancement intervention programs for older adults with chemo brain, age-related cognitive decline and mild cognitive disorders.
This is a summary of a lecture presented on October 14, 2014.
Each year more than 1.6 million individuals in the United States are diagnosed with cancer. There are almost 14 million cancer survivors in the United States and more than 25 million worldwide. Cognitive complaints are common for patients during chemotherapy treatment and can persist once treatment ends for many survivors. Addressing cognitive deficits and complaints after treatment is important as it has an impact on cancer survivors’ quality of life as well as their social and occupational functioning.
Cancer and the Risk of Cognitive Impairment. We have identified subgroups of patients who are at definitely at greater risk for developing cognitive complaints and cognitive impairment associated with cancer or cancer treatment. Children and adults who are treated for brain tumors are at high risk. Children and adults who are treated with whole brain radiation are at risk. Leukemia and lymphoma survivors receiving certain intraspinal chemotherapy are another higher risk group. There is also a subgroup of about 25% of patients who do not have a ‘definite’ risk of treatment-related cognitive impairment, but who are vulnerable to post-treatment cognitive changes and persistent complaints. The range of severity of cognitive problems in this subset of patients varies from mild to disabling.
Cognitive complaints. Patients who have cognitive complaints seem to have similarities in the kinds of difficulties that they report. Some of the common complaints include difficulty finishing something that they started, or feeling like they are less efficient in doing well-known tasks. Many patients mention problems with planning and carrying out a plan of action, multi-tasking, and difficulty in managing complex tasks. Other commonly reported complaints are problems concentrating, feeling easily distracted, and having difficulty learning and remembering new things.
There is a difference between cognitive “complaints” and cognitive “impairment.” “Complaints” refer to what people sense and report about their cognition, and “impairment” refers to actual deficiencies found on neurocognitive tests that measure cognitive functions such as memory, attention, reasoning, language, and visuospatial ability. Self-reported complaints are not always corroborated by impairment on neurocognitive testing. These evaluations use either computers or paper and pencil tests to measure cognition. There could be various reasons for the mismatch between complaints and performance on tests. First, many studies do not measure people’s cognitive functioning prior to treatment—thus this makes it difficult to evaluate cognitive change following treatment. The actual pre-treatment cognitive functioning of a person is not known in these situations. Second, lack of impairment on tests does not mean that people have not had a change in cognitive functioning, or that their impressions are inaccurate. Rather, it may be that the neurocognitive tests are not sensitive enough to pick up subtle cognitive problems, or they do not measure the kinds of cognitive abilities that that are most impacted by treatment. Third, although some patients score in the “average” range (i.e. 50th percentile) on cognitive tests after treatment, for patients with above average levels of cognitive functioning before treatment, an “average” score following treatment may represent a decline. Finally, various research studies indicate that for some patients, complaints may be more related to fatigue and depression than to actual cognitive changes. In any event, complaints matter! It is important to listen to patients, and to devise interventions that target both complaints and cognitive functioning.
Chemotherapy and Other Mechanisms of Cognitive Impairment. Recent studies have found new evidence that cognitive changes may not be due to chemotherapy alone, but that there may be other mechanisms causing compromised cognition. For example, cancer treatment may damage the blood brain barrier which then could allow harmful molecules or substances to enter brain tissue and cells. Other mechanisms may be related to having a genetic susceptibility that predisposes some patients to increased cytokine deregulation that may cause a pro-inflammatory response in the body, affecting cognition, sleep, mood, and energy level. Reductions in estrogen or testosterone may have an effect. Finally, chemotherapy may affect an individual’s ability to repair damage to DNA.
There are a variety of risk factors that may be associated with susceptibility or vulnerability to cognitive effects from cancer or cancer treatment. One such factor is age. The brains of older patients may have less reserve, i.e. the ability to compensate for brain damage or brain function losses. There also may be age and medication interactions, as research has shown that tamoxifen has more adverse effects on cognition in older patients than in younger patients. Having co-morbid medical conditions may increase the likelihood of cognitive impairment after treatment. There may be genetic predispositions or vulnerabilities to inflammation, and chemotherapy-related cognitive impairment. Other risk factors include menopause, hormonal therapies, and supportive care medications. Anxiety and depression can negatively impact or thinking and functioning. The impact of surgery and anesthesia may affect the brain and cognitive abilities. Finally, sleep disturbance can be a factor, and many people have continued sleep disturbance after treatment.
The Case of Inflammation. There is growing evidence to support that several factors, including cancer itself, cancer treatments (surgery, radiation, chemotherapy) and psychological stress, affect the regulation of inflammatory cytokines, which are involved in the body’s inflammatory response, to produce the post-cancer treatment symptoms of fatigue, depression, sleep disturbance and cognitive dysfunction. The deregulation of inflammatory cytokines can result in a cascade of processes that ultimately affect neuroendocrine and neurotransmitter systems, circadian rhythms, and cognition. Currently, a significant amount of research is being conducted to better understand this cancer-inflammation connection. This system is a potential candidate for the development and application of interventions that could alleviate or prevent cancer treatment-related symptoms.
What Do the Research Studies Tell Us?
When we think about cognitive complaints and cognitive function, what does that really mean? The list below indicates the areas that can be affected by cancer and cancer treatment. These areas of cognition are often measured in studies by neurocognitive tests:
- Switching attention from one task to another
- Ability to ignore distractions
- Attention to detail
- Mental Processing Speed
- How quickly one can think, respond
- Motor Skills
- Dexterity, coordination, speed
- Short- and Long-term memory
- Learn and recall words, stories
- Remember events versus facts
- Remember designs, faces
- Executive function
- Organizing, planning and carrying out a plan
- Problem solving
- Working memory
- Mentally manipulate information
- Visuospatial functioning
- Copying, make designs, map reading, hand-eye coordination
- Word retrieval
There were very few studies until a decade ago that even looked at cognitive changes after cancer. The initial studies used a cross-sectional design with survivors, meaning the studies looked at people’s functioning only at one point in time—after treatment. More recently, studies are following patients over time, comparing pre-treatment neurocognitive testing with post-treatment test results. Most of the patients studied thus far have been breast cancer survivors because they comprise the largest survivor groups. Other studies have included patients with lymphomas, colon, and testicular cancer. Studies have shown that, during treatment, about 75% of the patients showed cognitive deficits. Some of the studies have documented impairment on neuropsychological tests in cancer patients prior to treatment and upon retesting the impairment does not worsen with the treatment. This occurs in about 20-30% of the patients studied. Sometimes patients have cognitive complaints, but no impairment on testing, as discussed above. The body of literature overall indicates many participants had poorer neurocognitive test performance in association with chemotherapy exposure. There appears to be no “signature” pattern of impairment associated with cancer treatment—rather cognitive deficits can be varied, affecting memory, visual-spatial abilities, attention and brain processing speed, and language. A meta-analysis that pooled the results of many studies found an overall negative effect of cancer treatment on language (e.g. word retrieval and naming) and visuospatial abilities (e.g. building designs, copying). Overall, the results of studies in the literature support that persistent cognitive impairment does occur in about 25% of cancer patients. Post-treatment impairment can last for several months to up to 20 years.
Evidence of the Effects of Chemotherapy on Brain Structure and Function.
Support for the adverse effects of chemotherapy come from human and animal studies. Provocative results from animal studies have shown both short and long-term neural injury from some chemotherapy drugs. Poor memory function and changes in brain structure after chemotherapy exposure in some animal studies has been reported
- A limited number of brain imaging studies assessing the effects of chemotherapy on brain structure and function have been conducted; but, the scientific community has recently launched an initiative to expand brain imaging studies and share data. Brain imaging studies in women with cancer show changes in brain function and brain structure associated with treatment. In this research, study participants undergo brain scanning either while they are at rest or during the performance of mental tasks. Magnetic Resonance Imaging (MRI) scans are used to view the structure of the brain, while functional MRI (fMRI) and Positron Emission Tomography (PET) scans are used to study brain functioning during mental activity. Taken together, the findings suggest that the brain regions most affected by chemotherapy are the prefrontal cortex, the hippocampus, and the precuneus; these areas are responsible for memory, attention, and executive functions. Brain regions may show structural changes, such as in size, or in the loss of specific tissue types, such as gray matter, after chemotherapy, during treatment phases. After treatment, the brains of many patients may return to ‘normal’ (e.g. one year after treatment), although a subset of patients’ brains only partly normalize and show persistent changes. Researchers have also found alterations in brain activity associated with chemotherapy. Several studies have shown that the brains of patients who have had chemotherapy can be overactive or underactive. One study was performed on two sisters who were identical twins– one who had cancer and received chemotherapy and one who did not have cancer. The twins did not differ in how well they performed the task, but, the brain of the twin who had chemotherapy was more active during the mental task. Overall, current research results indicate that Chemotherapy exposed brains may have to work harder and engage different or more regions to compensate for damage to neural networks. Frontal brain areas seem most affected.
Treatments for Cognitive Complaints
Many cancer survivors have to contend with a myriad of symptoms in addition to cognitive difficulties after treatment, including depression, anxiety, fatigue, pain and sleep disturbance. These symptoms can be the source of complaints. The current wisdom is to treat the whole person by first addressing untreated depression, pain, anxiety, sleep difficulties, and fatigue. If complaints continue, the patient may need to have an evaluation by a neuropsychologist familiar with the effects of cancer treatment.
Strategies for treating chemobrain are in its infancy. Some pharmacological treatments have been used to treat fatigue or sleepiness, such as the stimulants d-methylphenidate and modafanil. There is no strong evidence to suggest the methylphenidate is effective while two studies support positive effects of modafanil on speed of processing, attention or memory. There is no evidence to suggest that Gingko Biloba has any effect.
Potential treatments also include anti-inflammatory agents and drugs that affect cytokines, but they have not yet been studied. Cognitive-behavioral therapy is promising for stress reduction and sleep disturbance, but very few studies use CBT to target cognition. Less studied but showing some promise are activities like meditation, exercise, Tai Chi, QiGong, and yoga. These activities may affect a variety of targets, such as pain, anxiety, sleep, depression and inflammation.
Another approach is cognitive training or rehabilitation. Results from studies of pediatric cancer survivors suggest benefits from individualized cognitive rehabilitation. There have been few studies conducted in adults, but some early studies suggest a benefit from computerized training strategies on attention, speed of processing and memory. Cognitive behavioral therapy that uses relaxation, education, enhancement of coping skills and increased self-awareness to manage frustration, is another important and useful approach. Finally, patients can learn strategies to improve memory and attention. These cognitive training strategies use visualization and associative memory techniques, called mnemonics.
At UCLA, our group, led by Patricia Ganz MD, conducted a study using a manualized cognitive rehabilitation intervention to target attention, memory and executive functioning in breast cancer survivors with cognitive complaints. In a randomized controlled trial, 48 female breast cancer survivors were enrolled in either a cognitive training program or were assigned to a wait-list control group. The women were in their mid-50’s and were 18 months to 5 years post-treatment. Neurocognitive tests of cognition (memory, attention, executive function and language), and self-reported measures of health status, and mood were conducted at baseline, then immediately after the five week program and again two months after the post-intervention evaluation. A subgroup also participated in quantitative electro encephalograms (qEEG), a physiological measure of brain activity, in order to test whether qEEG can show response to treatment.
Women in the five-week cognitive training intervention met with the cognitive trainer (psychologists) in small groups for 2 hours per week. They engaged in exercises in class and at home to enhance attention, memory and executive functioning. They learned to set short- and long-term goals involving the completion of daily tasks (e.g. going for a walk, completing something on a to-do list, cleaning out a closet, or planning a party or trip). At the end of the treatment, compared to the wait-list group, the intervention group demonstrated significant improvements in self-reported memory and overall cognitive complaints that were sustained at the 2-month post-intervention follow-up. The intervention group also showed improved memory on standardized memory tests. Brain activity, as measured by the qEEG, appeared to become more normal over the course of the intervention and correlated with the change in cognitive complaints. Survivors also reported improvement in their ability to meet short- and long-term goals and reported that they continued to use the cognitive strategies they were taught in their daily life.
Computerized training also holds promise for countering cognitive problems. In one study, breast cancer survivors who had received chemotherapy participated in 48 sessions of home-based computerized training for20-30 minutes per session, five days a week, for 12 weeks. The women in this study demonstrated improved executive function at the end of the study.
More studies of interventions are needed. So far, the studies conducted show that a variety of interventions can be promising for improving memory, attention, and executive functions. Treatment interventions are not yet offered on a large scale basis, but availability of empirically supported interventions to improve cognition can be expanded with increasing financial support and more training of personnel to implement the treatments.
What can a survivor who is facing cognitive changes do for themselves? Below are some ideas that may be helpful:
- Minimize distraction when you need to concentrate. By turning off the television, eliminating external noises and using a “Do Not Disturb” sign on your door.
- Minimize multi-tasking by focusing on one task at a time. This is especially important when doing something new or when making errors could be a concern.
- Turn off arriving email alarms and ringers.
- Turn off televisions and radios.
- Go to a quiet area.
- Tell others that you need uninterrupted time.
Organize to Improve Cognitive Efficiency
- Organize your time by selecting times of the day to answer emails and phone calls.
- Prioritize your work.
- Use checklists.
- Outline steps of a new or old activity, because this prevents leaving out a step. Keep track of your process while you are performing an activity
Goal Attainment and Use of a Check List
- Define at the start – What is my goal? This could be applied to following a recipe, cleaning a room, or working on a project at work.
- List the steps required to achieve the goal
- Stop and think “What am I doing?” as you do the task.
- Check your progress and check off the steps on the lists as you go along.
- When finished ask yourself if you achieved your goal.
- Check that you completed each step on the checklist.
Set Memory Goals
- Use a day planner with times through the day.
- Write down activities that you want to do, enter them as an appointment and include the time needed to do the task.
Memory refers to process for learning information, storing information and retrieving (accessing) information). Key components of good memory are paying attention, using association and using imagery.
- Visualize what you want to remember.
- Create images and focus on the image for a moment.
- Sometimes using whacky images are easier to remember because the brain likes novelty.
- Categorize or group like items together to remember of list of items.
- Examine the list. Look for relationships among the subgroups of items.
- Group related items together into a category.
- Give a name to the category.
- To remember the list, first remember the category to jog your memory for the items in each category.
- Take two unlike items and imagine them combined in an image.
- Form Stories when you need to remember lists or errands.
- Take your list of errands or items and create a story that uses all of the components. The story does not have to make sense, but you have to remember the story.
- Remembering Faces and Names
- Visualize the person’s face and notice what stands out to you about them, for example, their eyes. Change the name to something meaningful. Associate the name and the face using the image that you create. For instance, suppose you met “Gene”. You notice he has green eyes. Visualize him with large green eyes, and think of him as Gene with the Green Eyes.
- Remember a new name. Repeat the name when introduced and when you say good bye to the person. Associate other biographical information with the name, such as their occupation. Associate the person or object or place with a similar name.
- To remember names of someone you know, try an alphabet search. Remember any fact associated with the name such as where you last saw the person, their occupation, or the name of friends or a relative.
- Other practical tips
- Use special place for things like keys, TV remote, and wallet or purse.
- Use organizers for medications, bills.
- Use reminders including making lists or a daily diary. Use a calendar, appointment book or send yourself an email. Set reminders on your cell phone, watch alarm or use times. Leave messages on your answering machine.
Take Care of Yourself
- Work with yourself to manage your fatigue. Organize your tasks around your peak energy hours. Lighten up or don’t expect as much when you are having a down or bad” day.
- Get support from support groups, psychotherapy and family. Family may need some education about your condition, how they can help, and you may need to delegate tasks to them. A lot of people shoulder cognitive issues without telling anyone, but you need support.
- Be good to yourself, by challenging negative thinking and harsh thoughts. Praise and encourage your efforts. Give yourself a break. Remember that you are only human.