Cancer- and Treatment-Related Cognitive Changes: What Can We Do Now? What Lies Ahead?

The common term “chemobrain” belies the complex nature of the problem of changes in cognitive function experienced by patients with cancer.[1] Multiple factors contribute to these cognitive changes. Moreover, some patients have been found to have poorer cognitive function than their healthy counterparts before they began therapy, pointing to the possibility that factors other than treatment are contributing to the problem.[2,3]

In general, whether an individual has cancer or not, more years of education and a higher IQ are related to better cognitive function, while advancing age is related to poorer or declining objectively measured cognitive function.[4] Cognitive function is also interrelated with mood and functional ability. In particular, if someone reports a significant deterioration in cognitive function, they are more likely to also experience worsening mood. Conversely, individuals who are clinically depressed commonly experience poorer attention, learning and memory, and psychomotor slowing.[5,6] Fluctuations in hormone levels that naturally occur over the course of life may also be related to changes in cognitive function. For example, there is evidence that the hormonal fluctuations that occur during a woman’s reproductive cycle and with menopause are related to variations in cognitive function, and particularly to variations in verbal memory.[7,8]

It is important to recognize that some patients with cancer are at greater risk for changes in cognitive function. The stress, anxiety, or depressive symptoms they experience across the trajectory of the cancer experience may influence their cognitive function, although clinically meaningful deterioration in objectively measured cognitive function would not be expected unless a patient were experiencing clinical depression meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria. It is more common that patient-reported cognitive problems are associated with changes in mood that do not necessarily meet diagnostic criteria for a mood disorder.[5,6] Self-reported cognitive problems may also be associated with other symptoms, such as fatigue, sleep disturbance, and pain.[9-13] Moreover, poorer cognitive function may be related to medications taken to manage these symptoms (eg, analgesics, antiemetics, hypnotics).[14] Factors that may contribute to poorer pretreatment cognitive function in patients with cancer include lingering effects of anesthesia after breast cancer surgery, disease-related factors, comorbidities (eg, diabetes, heart failure), and the medications used to manage comorbid conditions.[1,2]

Patients who have received cancer treatment in the past are at increased risk for developing cognitive impairments with current treatment, particularly those who experienced cognitive problems with past therapy.[15] Patients receiving higher-dose therapy[16] or a longer duration of therapy, particularly with some biologic agents, such as interferon alfa, are also at increased risk for cognitive impairments.[17-19] Similarly, patients receiving concurrent chemoradiation[20] or therapy delivered directly to the central nervous system are at greater risk.[14] Other factors that increase patients’ risk of cognitive impairments include a history of psychiatric illness, substance abuse, neurological disease, or neurotrauma.[4]

When a patient with cancer complains of cognitive problems, clinicians should keep in mind that these complaints may be associated with mood changes rather than neuropsychological changes. Probing more about depressive symptoms or anxiety may lead to appropriate management strategies. However, when there is concern about clinically significant cognitive impairments, referral for a comprehensive neuropsychological assessment may be warranted.

Building on the progress researchers have made in characterizing this complex phenomenon and identifying risk factors, future research has the potential to improve the identification of patients at different levels of risk for cognitive changes so that targeted interventions may be provided to the patients who need them most. To reach this goal of personalized medicine, we must understand the mechanisms underlying cognitive changes. As noted, while the multiple primary procedures and adjuvant therapies provided to cancer patients could contribute to these changes, at least some of the cognitive changes previously attributed to treatment were evident before adjuvant therapy.[21-23] Subgroups of patients are likely at variable levels of risk due to pretreatment factors (eg, mood changes, cognitive reserve, physical fitness, genomic differences that impact inflammatory processes).[23-26] Moreover, these and other unknown factors may influence trajectories of cognitive changes during treatment.

A powerful tool for uncovering the mechanisms underlying cognitive changes in these subgroups is neuroimaging (eg, functional MRI). Imaging studies have the potential to provide substantial insight by uncovering brain biomarkers associated with cognitive changes in different subgroups. These brain biomarkers may identify novel targets for screening and intervention. High costs, and challenges such as claustrophobia, make the widespread use of neuroimaging for research and clinical screening unlikely in the near future. However, technological advances will likely obviate these difficulties with time, much as they are beginning to do for the use of genetics in oncology practice.[27,28] Once costs come down and other barriers begin to abate, the powerful combination of neuroimaging and genomic techniques has the potential to provide the detailed risk profiling needed to enable clinicians to offer targeted education and interventions before cognitive changes manifest, which may prevent or minimize these potentially detrimental changes.

In summary, much of the existing research into the phenomenon commonly referred to as “chemobrain” has been descriptive, and we know enough now to identify some patients at risk for cognitive changes after a diagnosis of cancer. While we can educate patients about the possibility of these changes, we are just beginning to learn about appropriate interventions that may attenuate changes in cognitive function. Few interventions have been tested, and none have yet shown clear benefits that would warrant their implementation in clinical practice. Studies have explored the efficacy of medications such as psychostimulants and erythropoietin with mixed results.[29,30] Studies using interventions such as cognitive behavioral therapy, cognitive training, and physical exercise are showing initial promise for attenuating changes in cognitive function.[31-34] However, more research is needed to determine the efficacy of these interventions and the optimal doses for the management of changes in cognitive function in patients with cancer.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Acknowledgment:Dr. Merriman is a Postdoctoral Scholar supported by the National Institute of Nursing Research funded T32 grant titled “Interdisciplinary Training of Nurse Scientists in Cancer Survivorship Research (TNR011972A).”

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