COGNITIVE IMPAIRMENT IN ADULTS WITH CANCER

Cancer survivors report more symptoms of cognitive impairment than people without a history of cancer. Formal neuropsychological testing demonstrates a range of objective cognitive deficits in some but not all survivors who report symptoms, compared with healthy controls. These deficits include the following:

Impaired memory.
Reduced concentration.
Slower information processing.
Reduced executive function.

Subjective reports of cognitive impairment often do not correlate with the results of formal neuropsychological testing.[4,5] In addition, the risk factors for subjective or objective cognitive impairment—such as age, preexisting cognitive function, type of cancer, type of chemotherapy, and the natural history of the impairments—remain a matter of active investigation.

The oncology clinician who cares for survivors with objective or subjective cognitive impairment is advised to consider the following:

Because abnormal is defined as a significant deviation from population means, formal neuropsychological testing may be insensitive to subtle changes in cognitive function since cancer diagnosis or treatment.
There is a strong correlation between a patient's subjective reports of cognitive impairment and decreased daily functioning or reduced quality of life.
It is not known whether cognitive impairment influences or is a sign of psychological distress. However, one study of 226 participants (166 patients with newly diagnosed breast cancer and 60 controls) demonstrated that patients with breast cancer scored consistently worse than controls on cognitive tests. This decline was mediated by post-traumatic stress disorder (PTSD), indicating that PTSD may contribute in part to cognitive decline. Studies have also shown that cognitive impairment is associated with negative emotional states such as anxiety and depression, the personality trait of negative affectivity, and self-perceived treatment burden.
Treatments for patients with cancer-related cognitive impairment have shown minimal to modest benefit. For clinicians, compassionate acknowledgment of a patient's concerns and a supportive approach are essential.

Normal Cognition

Cognition is the mental process of acquiring knowledge and understanding through thought, experience, and the senses. The six domains of cognitive function summarized below were proposed in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, to help establish the etiology and severity of neurocognitive disorders.

Attention and concentration: Ability to triage relevant information, thoughts, and actions while ignoring distractions; the ability to maintain attention for an extended period of time.
Executive function: Ability to initiate and generate hypotheses, to plan, and to make decisions.
Information processing speed: Ability to quickly and efficiently process information.
Visuospatial skill: Ability to process and interpret visual information about where things are in space.
Language: Ability to understand and communicate symbolic information, both verbally and in writing.
Learning and memory: Ability to learn new information; ability to store and recall new information, in either the short term or the long term.

The domains are interdependent, and any proposed taxonomy is provisional and will depend on the specific neuropsychological tests used to assess patients. Furthermore, published studies vary in terms of the cutoff for impairment and which scales are combined into a single score. While the domains reasonably capture the range of concerns experienced by people with cancer, it is important to clarify the specific impairment through a careful history and formal testing. In addition, comparisons between studies are hampered by different scales and definitions.

Evaluation of Subjective Reports of Cognitive Impairment

As with all patient-reported symptoms and signs, a thorough evaluation will help determine the cause of cognitive impairment and potential interventions to reverse the symptoms or stabilize the patient. A focused history and physical examination can assess the following:

Measures of baseline cognitive function, such as educational attainment, job-related responsibilities, and premorbid functioning.
Potential risk factors for cognitive impairment such as advanced age, type and stage of cancer, and treatment history, including time since last treatment and drugs used in treatment.
Use or misuse of prescription and over-the-counter medications and supplements.
Focal neurological deficits. Focal motor defects or discrete cortical defects such as aphasia or apraxia are uncommon in cancer-associated cognitive impairment.
Signs of metastatic disease to the brain, meninges, or both.

The routine use of neuroimaging is not warranted unless there are concerns about specific complications from the cancer or its treatment (e.g., metastatic cancer to the brain).

Education About the Risk of Cognitive Impairment

In-depth interviews with cancer survivors revealed that few materials were available to educate them about cognitive problems. The amount of information desired by survivors varied from extensive to brief and general. The optimal method of information delivery was also not clear. Patients and survivors described feeling overwhelmed by the amount of written information about treatment and side effects that they received. Some patients expressed the desire to discuss their preferred method of learning with a health care provider who would provide information in a relaxed, unhurried manner.

One study examined the influence of priming patients to associate chemotherapy treatment with cognitive impairment. Via cancer websites, investigators recruited 150 patients with cancer who were receiving or had received chemotherapy and 86 patients who had no experience with chemotherapy to participate in a study on the effects of cancer therapies on individual patients. Volunteers were randomly assigned to receive a neutral introduction or a priming introduction that stated “some patients treated with chemotherapy experience cognitive problems.”

The study found an association between priming and having had chemotherapy. Patients who had chemotherapy and received the priming introduction reported higher levels of cognitive impairment than those who received the neutral introduction. No difference was found for patients not treated with chemotherapy. The volunteers were highly aware of the relationship between chemotherapy and cognitive impairment, but preexisting knowledge of that relationship had no effect on self-reported cognitive complaints and neuropsychological test performance. These study results raise the possibility that the test environment introduced an artifact.

The optimal means and content for educating patients about cognitive impairment are not established. The principle of informed consent applies: the oncology clinician must inform patients of the risk in a manner that respects personal autonomy.

Screening

No large-scale studies of routine screening for cognitive impairment in people with cancer have been published. In the clinical setting, the Mini-Mental State Exam is often used to assess for cognitive impairment but has varying sensitivities of mild cognitive impairment. The National Comprehensive Cancer Network has identified a series of questions and probes to screen for cognitive impairment and rule out other concerns (e.g., depression or sleep disturbances) that can be treated.[6] One challenge in screening for cognitive impairment is the lack of a brief measure that can accurately assess the multiple cognitive domains. Patient-reported outcome scales (e.g., the Patient-Reported Outcomes Measurement Information System [PROMIS] 8-item and 4-point scales and the Functional Assessment of Cancer Therapy—Cognitive [FACT-Cog] version 3) might prove valuable, but further study is required. PROMIS has two scales based on the FACT-cog, including perceived cognitive impairment and perceived cognitive abilities, which measure different dimensions of cognitive impairment.

An additional challenge is the timing of screening activities, given the variable time to onset and the resolution of concerns without intervention for many patients.

Nonpharmacological Interventions

Evidence-based interventions to manage cognitive impairment in cancer patients and survivors have not been firmly established. Several nonpharmacological approaches have shown promise, including the following:[1]

Cognitive rehabilitation.
Exercise and physical activity.
Psychosocial interventions such as attention-restoring activities and meditation.

Cognitive rehabilitation

Cognitive rehabilitation has shown promise in reducing the impact of cognitive problems on cancer patients and survivors. This approach originated to treat people with brain injuries such as stroke or traumatic brain injury, and it has been adapted for the cancer setting. Several rehabilitation approaches have been blended to varying degrees, including the following:

Psychoeducation provides useful information about brain functioning, cognitive deficits, and their consequences for daily life.
Compensatory training focuses on the acquisition of new behaviors and strategies to compensate for chronic dysfunction. This intervention may include modifying or restructuring the environment by substituting external aids (such as calendars and electronic diaries) so that individuals rely less on their cognitive abilities. It may involve learning new coping strategies (such as pacing cognitive activities and minimizing distractions).
Cognitive training involves the use of repetitive, increasingly challenging tasks (often via computer) to improve, maintain, or restore cognitive function in the areas of attention, memory, and executive function. The modest evidence for the efficacy of cognitive rehabilitation is based on several randomized controlled trials that used a diverse group of objective tests of neuropsychological function and subjective measures of cognitive impairment. Cognitive rehabilitation intervention groups showed greater improvement than controls in self-reported cognitive impairment and objective neuropsychological measures of attention, memory, and processing speed. Other cognitive rehabilitation intervention studies provided similar results but were limited by partial or no randomization, one-group design or secondary analysis.[10]

Exercise and physical activity

There is increasing interest in physical activity and mind-body exercise to address cognitive impairment in cancer survivors. A systematic review of randomized controlled trials using exercise to address cognitive function in cancer survivors identified 29 potentially relevant trials that were published through 2018. Of these trials, 12 (41%) found benefit in perceived cognitive function. In addition, 3 of the 10 studies (30%) that objectively measured cognitive function found some benefit. A number of limitations in these trials were noted; the type of physical exercise varied, and cognitive function was often not the primary outcome of interest.

In one multicenter randomized clinical trial, 181 breast cancer survivors who had received neoadjuvant or adjuvant chemotherapy reported cognitive problems, which were confirmed by lower-than-expected performance on neuropsychological testing. Participants were randomly assigned to an exercise group or a control group. The 6-month exercise intervention consisted of supervised aerobic exercise and strength training (2 h/wk) and Nordic/power walking (2 h/wk). Notably, two-thirds of the participants attended 80% or more of the exercise sessions, and physical fitness significantly improved for participants in the exercise group, compared with participants in the control group (peak oxygen uptake, 1.4 mL/min/kg, 95% confidence interval, 0.6–2.2). No difference was seen in the primary outcome of memory. However, significant beneficial effects were found for self-reported cognitive functioning, fatigue, quality of life, and depression. In addition, subgroup analysis indicated a positive effect of exercise on tested cognitive functioning in highly fatigued patients.

Similarly, the Exercise Program in Cancer and Cognition Study was a randomized controlled trial designed to determine whether 6 months of 150 minutes or more per week of moderate-intensity aerobic exercise, compared with usual-care control, improved neurocognitive function in 153 women with breast cancer receiving endocrine therapy.

Primary outcomes, assessed before baseline and within 2 weeks postintervention, included objective cognitive performance tests of processing speed, learning and memory, verbal memory, and working memory. Secondary outcomes included performance on cognitive tests of attention, executive function, and mental flexibility. Adherence to the exercise intervention was high, with 70.13% of participants who were at least 80% adherent, 67.33% who were at least 90% adherent, and 55.84% who were 100% adherent. However, cardiorespiratory fitness did not differ significantly between treatment groups from baseline to postintervention. Improvements in processing speed were noted for the exercise group compared with the usual-care group, with a significant group-by-time interaction (P = .041) and a trend for the main effect of time (P = .11) for processing speed and no change in the controls. Improvements in processing speed were associated with better intervention adherence (P = .017). In addition, younger women (aged ≤60 years) had a trend for greater processing speed improvements (P = .06), while those with a lower educational level (≤16 years of education) had a significantly greater improvement in processing speed (P = .03).

A randomized controlled trial of qigong—a set of coordinated gentle exercises, meditation, and breathing—demonstrated improved self-reported cognitive impairment in cancer survivors after chemotherapy. Other movement studies used one-group designs, were not randomized, or were secondary analyses.

Attention restoration

An intervention focused specifically on restoring and maintaining the capacity to direct attention, actively focus, and concentrate—components of cognitive function—was developed and tested in breast cancer survivors. The intervention consisted of exposure to the natural environment, including activities such as walking or sitting outdoors, tending plants or gardening, watching birds or other wildlife, and caring for pets. Participants contracted in writing to spend 120 minutes per week engaged in one or more of these activities. Neuropsychological tests of attention demonstrated greater improvement in the capacity to direct attention in the group that participated in attention-restoring activities than in the control group.

Meditation

Mindfulness-based stress reduction (MBSR) is an integrative therapy that focuses on bringing attention and awareness to each moment in a nonjudgmental way. The benefits of MBSR have been evaluated in numerous studies of health conditions such as chronic pain, anxiety, and fibromyalgia. A review of MBSR studies in cancer patients found only two randomized trials with positive results, despite a small sample size. In one large, adequately powered, randomized trial in breast cancer survivors, the MBSR group showed more improvement in self-reported confusion than did the control group at the end of the intervention period, but there were no long-term effects. No objective measures of cognitive function were used in this trial, and evidence of impairment was not a requirement for study eligibility.

A smaller study showed that MBSR participants experienced more positive effects on self-reported attention and working memory than did a control group. The finding was durable at 6 months.[29] An objective measure of accuracy also showed durable improvement in the MBSR group.

A randomized trial of Tibetan sound meditation demonstrated improvement in objective measures of memory, processing speed, and self-reported cognitive function. Although the sample size was small, eligibility for the study required self-reported cognitive impairment.

Pharmacological Interventions

Several classes of agents have been investigated as potential interventions for managing cognitive impairment. In general, the quality of study design, outcomes studied, and variations in doses and schedules of the agents prevent any firm conclusions.

Psychostimulants: Approved by the U.S. Food and Drug Administration primarily for attention-deficit hyperactivity disorder or sleep-wake disorders, psychostimulants are generally well tolerated. These agents have been tested in individuals with drug- or cancer therapy–induced cognitive dysfunction with varying levels of other associated symptoms. Seven phase II trials of different psychostimulants for treating cognitive impairment and associated symptoms were reviewed. Not all agents showed benefit; the symptoms most likely to improve were alertness, attention, and psychomotor speed. Six trials had control arms, and one reported results in a descriptive fashion. Also, some trials were in limited populations that may have had additional confounders such as individuals with central nervous system tumors, making results difficult to extrapolate to other patient groups. Finally, the trials were underpowered, in part because of difficulty with enrollment.

Erythropoietin-stimulating agents (ESAs): The hypothesized mechanism for ESAs in the improvement of cognitive function is the result of preclinical data demonstrating erythropoietin receptors in brain tissue providing a neuroprotective effect and preventing neuronal apoptosis. The potential for cognitive improvement must be weighed against the risks of ESAs, which include cardiovascular and thrombotic events, the potential for causing tumor progression, and decreases in overall survival.

Acetylcholinesterase (AChE) inhibitors: Donepezil, an AChE inhibitor, is approved for Alzheimer disease. It is hypothesized that whole-brain radiation therapy (WBRT) causes neuronal injury that results in a decrease in acetylcholine. This theory is supported clinically by similarities between WBRT cognitive dysfunction and Alzheimer disease. The use of donepezil may increase acetylcholine levels in the brain.