It is not uncommon for women with breast cancer to have multiple surgeries with general anesthesia, chemotherapy, radiation therapy, and then endocrine therapy, which has led us to study how the whole treatment package—not just chemotherapy—affects cognition.
Tim A. Ahles, PhD
Although chemotherapy is often cited as the main culprit for diminishing cognitive function in patients with cancer, ushering the term “chemobrain” into the vernacular, research by Tim A. Ahles, PhD, and his colleagues is showing that multiple factors may contribute to the condition.1 Using breast cancer as the prototype, Dr. Ahles reviewed data from neuropsychological, imaging, genetic, and animal studies that examined pre- and post-treatment cognitive change in patients. He found that age, endocrine therapy (either alone or in combination with chemotherapy), surgery, dosing and timing of treatment regimens, and even the cancer itself likely all contribute to a decline in cognition. That shift in cognition, which can cause problems in attention, concentration, working memory, and executive function, can be persistent, lasting as long as 10 to 20 years in some cases, said Dr. Ahles.
Although earlier reviews of studies found a wide range of between 17% and 75% of women experiencing prolonged deficits in cognition after breast cancer treatment,2-4 Dr. Ahles believes the actual number is probably between 20% and 30%,—but even that estimate, he admits, may be incorrect.
“It is really complicated to determine an accurate number of patients affected by post-treatment cognitive change because we used to think the problem was all due to chemotherapy, but it turns out that some of the endocrine treatments, as well as other factors, may also produce cognitive side effects,” said Dr. Ahles.
The ASCO Post talked with Dr. Ahles, Director of the Neurocognitive Research Program at Memorial Sloan Kettering Cancer Center in New York, about how treatment for cancer, aging, and the level of “cognitive reserve” at diagnosis all contribute to reduction in cognitive function; the potential for cognitive-deficit risk assessment; and what can be done to help patients minimize their risk of cognitive decline.
Please explain some of the factors that contribute to changes in cognitive function in patients with cancer.
Most of the research in this area has been done in women with breast cancer, and whether we can generalize the information to other types of cancer and treatment regimens is unclear. We suspect that androgen ablation therapy for men with prostate cancer may produce cognitive side effects, because testosterone in men, like estrogen in women, is critical for cognitive functioning in specific areas. For example, in women, estrogen is particularly important in verbal and working memory skills; in men, testosterone is critically important in visual-spatial skills.
In breast cancer, when you give women drugs like tamoxifen or an aromatase inhibitor like anastrozole you are dramatically changing the amount of estrogen available in their bodies. Some women may not have had much of a cognitive effect from chemotherapy alone, but then they may be affected by the endocrine therapy. Or it may be an additive effect of a certain amount of decrease in cognitive functioning caused by the chemotherapy, which is then compounded by the endocrine therapy.
General anesthesia from surgery may also contribute to problems in cognition. We used to think the problems stemmed primarily from chemotherapy, but it is not uncommon for women with breast cancer to have multiple surgeries with general anesthesia, chemotherapy, radiation therapy, and then endocrine therapy, which has led us to study how the whole treatment package—not just chemotherapy—affects cognition.
Do psychosocial issues like anxiety, stress, and worry also factor into whether or how much a patient experiences cognitive decline?
Certainly psychosocial conditions, such as depression, anxiety, and stress, as well as physical issues like sleep disturbance and fatigue, all influence cognitive functioning. Part of the reason we see such disparity in the percentage of women affected by cognitive decline is that some research rules out patients with a history of depression or fatigue, which will reveal a smaller number of women affected by the problem. But if you broaden the sample of patients to include those affected by all conditions, including psychosocial issues and comorbidities such as diabetes and cardiac disease—which we know impact cognition—the number of women affected may be much bigger.
Another surprising finding is that when we did pretreatment assessments of women with breast cancer, between 20% and 30% performed lower than expected on neuropsychological tests based on age, education, and occupation. This is confusing because if the only major issue in these women was the breast cancer, they should have been cognitively normal before treatment. That finding has led us to think that perhaps there is something about the cancer itself that influences cognitive change.
There may also be coexisting risk factors that increase the likelihood for cognitive difficulties. For example, we have a lot of genetic factors that can minimize DNA damage in the body, and some people have better repair mechanisms than others based on their genetic profile. If you have a poor DNA repair mechanism, you have a higher risk of developing cancer, and it turns out you also have a higher risk of developing a variety of neurocognitive diseases, including Alzheimer’s disease and Parkinson’s disease. You could have a genomic instability that is contributing to both the diagnosis of cancer and mild cognitive deterioration over a period of years.
What are some of the most common cognition problems that patients with cancer experience?
Almost all patients complain about problems with short-term memory—for example, not being able to remember names or an item they just read in the newspaper. But when we test these patients, we often find that their memory is pretty normal. It is their ability to focus attention and the speed at which they are able to process information that have slowed down. These issues are perceived as memory problems because the information the brain is trying to encode never gets encoded and stored properly.
There is also the concept of cognitive reserve, which is tied to IQ and the level of education and type of career a person has—the more stimulating the better—and not based solely on genetics. People who have higher levels of cognitive reserve tend to be less affected by chemotherapy or trauma to the brain than people with low cognitive reserve.
Are men and women equally affected by cognition difficulties during and after cancer treatment?
Because most of the research in this area has been done in women with breast cancer, we do not exactly know the percentage of men cognitively affected by cancer treatment. That said, researchers have done related studies in lymphoma, leukemia, and prostate cancer, and it does appear that men experience cognitive deficits as well.
Is there a risk assessment test oncologists can perform to determine which patients are more likely to have cognitive difficulties following treatment?
Identifying who is at greatest risk of developing cognition decline and determining whether there is an effective way to treat the cancer and sidestep the problem of reduced cognitive functioning are hot areas of research right now. But at this point, we do not have a good understanding of who is most vulnerable to develop problems or how to avoid damage to the brain.
Are there interventions to treat cognitive changes?
There are studies showing that modafinil, a psychostimulant, is effective in improving memory and attention and reducing fatigue. Older medications like methylphenidate are also effective in improving memory and concentration.
In addition, cognitive rehabilitation approaches are being tested, and the initial results are promising. For example, participating in mind-training games like those offered on the Lumosity website (lumosity.com) may be helpful. And studies examining the impact of diet and exercise on cognitive functioning in patients with cancer are just beginning to be conducted and reported.
There is research underway to investigate advanced imaging techniques, such as high-quality magnetic resonance imaging, to look at memory activation patterns and changes in activation patterns in patients before and after treatment. That information may help us determine how to mitigate cognitive change in patients. These techniques are not ready for clinical use just yet, but as they become more precise and automated, they will be built into clinical care. ■
Disclosure: Dr. Ahles reported no potential conflicts of interest.
Addressing the evolving needs of cancer survivors at various stages of their illness and care, Palliative Care in Oncology is guest edited by Jamie H. Von Roenn, MD. Dr. Von Roenn is ASCO’s Senior Director of Education, Science, and Professional Development Department.