Cancer survivors experience more-than-expected symptoms related to cognitive impairment. 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 faulty memory, deficits in concentration, decreased rates of information processing, and reduced executive function.[1,2,3] Furthermore, subjective reports of cognitive impairment often do not correlate with the results of formal neuropsychological testing.[4,5] Finally, 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 will care for survivors with objective or subjective cognitive impairment and is advised to consider the following:
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 (DSM-5), to help establish the etiology and severity of neurocognitive disorders.
The domains are interdependent, and any proposed taxonomy is provisional and will depend on the specific neuropsychological tests employed in assessment. Furthermore, there is heterogeneity among published studies on what scales are combined into a single score and the cutoff for impairment. 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 or formal testing. In addition, comparisons between studies are hampered by different scales and definitions.
Cancer patients may experience the following difficulties:
Before a patient is referred for formal neuropsychological testing, the oncology clinician can perform a complete assessment of the potential contribution of medications and medical comorbidities to the patient's experience. It is well established that preexisting illness may contribute to cognitive impairment before a patient is diagnosed with or treated for cancer. Patients who report symptoms or concerns suggestive of cognitive impairment may benefit from evaluation of potentially reversible causes and the taking of appropriate measures. Potential contributing factors include the following:
Validation of the Survivor Experience
The experience of cognitive changes after cancer treatment has been documented in qualitative research.[4,5,6,7] Concerns reported by survivors include memory problems, inability to concentrate, and decreased ability to function in daily activities, including employment. Survivors expressed frustration with the lack of acknowledgement by health care providers and expressed the need to be informed early about the possibility of developing this problem and for validation when they experience it.[5,6] Patients found it comforting that these subtle mental changes have been observed widely and are to be expected. The least helpful response by practitioners was minimizing the changes and/or not taking them seriously.
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 define potential interventions to reverse the symptoms or stabilize the patient. A focused history and physical examination will assess the following:
The routine use of neuroimaging is not warranted unless there are concerns for specific complications from the cancer or its treatment, e.g., metastatic cancer to the brain.
In addition to responding respectfully and compassionately to patients' concerns about cognitive impairment, the oncology clinician faces questions on how best to inform patients about the risks of cognitive impairment and whether to routinely screen all patients, or limit screening to patients at higher risk.
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 the experience of cognitive impairment. Via cancer websites, investigators recruited 150 cancer patients who were receiving or had received chemotherapy and 86 patients who had no experience with chemotherapy. Volunteers were asked to participate in a study on the effects of cancer therapies on individual patients and 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 experience with chemotherapy and who received the priming introduction reported higher levels of cognitive impairment. 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 is respectful of personal autonomy.
No large-scale studies of routine screening for cognitive impairment have been published. One challenge is the lack of a brief measure of cognitive function that can accurately assess the multiple domains. Patient-reported outcome scales (e.g., the Patient-Reported Outcomes Measurement Information System 8-item scale; and the Functional Assessment of Cancer Therapy—Cognitive) might prove valuable, but further study is required. 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.
Multiple research studies of cognitive impairment have been published. This section summarizes the key findings of meta-analyses, systematic reviews, and individual studies published subsequently.
The ICCTF has recommended that investigators define a priori cognitive endpoints, use a core of validated neuropsychological tests, adopt common criteria for cognitive impairment, employ a longitudinal design, and use a control population.[1,2]
Meta-Analyses and Systematic Reviews
Subjective cognitive concerns in breast cancer patients
Twenty-seven studies of subjective cognitive impairment in patients with breast cancer published between 1960 and April 2009 were identified by one group of researchers. Only eight studies were high quality. The percentage of patients reporting subjective concerns ranged from 21% to 90%. There was no correlation between subjective concerns and objective findings, and no conclusive information about timing and the contribution of disease versus treatment received.
Subjective concerns were related to health status, fatigue, and psychological distress. The authors pointed out that those subjective concerns may be a marker of anxiety or depression rather than objective cognitive impairment.
Relationship between subjective concerns and objective findings
A comprehensive screen for studies comparing rates of subjective cognitive concerns and objective cognitive impairment published between 1980 and 2012 yielded 24 studies. Only 8 of the 24 studies demonstrated a significant correlation, and 6 of these involved patients with breast cancer. The authors pointed out that the lack of correlation may be methodologic (different assessment methods, different definitions of significant impairment) or explained by the possibility that subjective concerns are a sign of psychological distress.
Meta-analysis of cognitive impairment in breast cancer survivors
A group of investigators performed a meta-analysis of data from studies that reported the results of neuropsychological tests in women with breast cancer who were treated for more than 6 months before the study. The investigators identified 17 studies with 807 patients; the mean time since completion of chemotherapy was 2.9 years. Weighted average effect sizes for the studied cognitive domains demonstrated modest impairment in verbal ability (effect size, –0.19; 95% confidence interval [CI], –0.30 to –0.07; P = .002) and visuospatial ability (effect size, –0.27; 95% CI, –0.45 to –0.08; P = .006).
Chemotherapy and cognitive impairment in patients with cancer
A group of researchers calculated effect sizes on the basis of data from 13 high-quality studies published in 2010 and earlier. Key criteria for study inclusion were reports with primary data, statistics to allow calculation of effect sizes, and a control group; studies with patients who had psychological distress were excluded.
Although several domains were affected, the effect sizes were small. The affected domains included executive function (effect size, –0.27), memory (effect size, –0.21), and verbal function and language skills (effect size, –0.17). Insignificant effect sizes were observed for construction (the ability to draw and build), concept formation, reasoning, perception, and orientation and attention.
The authors noted a consistent but not universal trend of worse performance by patients who received chemotherapy compared with groups who received other types of treatment, received no treatment, or were healthy. Furthermore, longer time in treatment was associated with increased impairment, and longer time since completion of treatment was associated with improvement.
Objective cognitive deficits in breast cancer survivors receiving endocrine therapy
Researchers identified 12 high-quality studies (including 2,756 patients) published between 1966 and 2015 that examined the impact of endocrine therapy on cognitive functioning. Study eligibility criteria included all prospective and retrospective observational cohort studies and randomized controlled trials that reported the impact of hormonal therapy, including selective estrogen modulators and aromatase inhibitors, on cognitive performance. Cognitive assessments were examined in breast cancer patients over time, from baseline to 6 months to 1 year and/or 2 years.
Treatment with endocrine therapy was accompanied by deficits in verbal memory, verbal fluency, motor speed, attention, and working memory, but not psychomotor speed. Findings were limited by the methodical heterogeneity of included studies and relatively short follow-up periods (3 months to 2 years); thus, more research is needed.
Objective cognitive deficits in men receiving androgen deprivation therapy for prostate cancer
Researchers identified 14 high-quality studies among 157 potentially relevant articles published between 1950 and June 2012 by searching PubMed, Medline, PsycINFO, Cochrane Library, and Web of Knowledge/Science. Criteria for study inclusion were an appropriate control group, baseline measurements, and the use of objective neuropsychological tests. Eleven studies were longitudinal; the authors included three cross-sectional studies.
Effect sizes were calculated for the results. The only significant effect detected was for visuomotor ability. There were no discernible negative effects on the other domains studied: attention/working memory, executive functioning, language, verbal memory, visual memory, and visuospatial ability.
Individual Research Studies
Formal neuropsychological tests of patients with early-stage breast cancer receiving adjuvant treatment
Several studies are relevant to an understanding of cognitive impairment in women with early-stage breast cancer who receive chemotherapy.
Employing a battery of neuropsychological and psychological tests, investigators assessed healthy controls and women with early-stage breast cancer who were treated with chemotherapy (n = 60) or who did not receive chemotherapy (n = 72), before treatment and then at 1, 6, and 18 months. The primary outcome of interest was processing speed. Results demonstrated that women aged 60 years or older with lower baseline cognitive reserve who received chemotherapy scored lower on processing speed than did healthy controls or women who did not receive chemotherapy. These results are consistent with results from studies of aging. There was also an effect on verbal ability that resolved by 6 months. There were no demonstrable interactions between time, age, and cognitive reserve for verbal memory, visual memory, working memory, sorting, distractibility, or reaction time.
Another group of investigators performed neuropsychological assessments on 60 women younger than 66 years who had early-stage breast cancer. The subjects were tested before and after each cycle of adjuvant chemotherapy. The goal was to determine whether there was progressive decline suggesting a dose-response relationship. A control cohort of 60 healthy women matched for age and education was tested at appropriate intervals. The authors observed a dose-related decline in working memory, processing speed, verbal memory, and visual memory.
Subjective reports by patients with early-stage breast cancer receiving adjuvant treatment
Investigators compared subjective cognitive functioning (measured by the Cognitive Failures Questionnaire) and satisfaction with subjective cognitive functioning (measured with the cognitive functioning facet of the World Health Organization Quality of Life instrument) at two times in women with breast cancer—before chemotherapy and 3 months later—and at comparable times in women with benign breast disease. The frequency of subjective concerns did not differ, but women with breast cancer were less satisfied with their cognitive functioning. Psychological factors and diagnosis influenced satisfaction with cognitive functioning.
Self-reported neurocognitive symptoms in women with breast cancer
Investigators conducted a longitudinal study of 581 patients with breast cancer recruited from community cancer clinics and compared the results with age-matched controls. Patients and controls completed the Functional Assessment of Cancer Therapy—Cognitive Function (FACT-Cog) before receiving chemotherapy, 4 weeks postchemotherapy, and 6 months after the second assessment. Controls were tested within the same time windows as patients. Relevant findings were as follows:
Longitudinal formal neuropsychological tests of patients with early-stage colon cancer
Researchers administered formal tests to 81 patients with early-stage colon cancer who were scheduled to receive oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX4) and conducted assessments prechemotherapy (n = 81), postchemotherapy (n = 73), and 6 months after the end of the last cycle of chemotherapy (n = 54). Attention and visual-motor ability, executive function, verbal memory, and verbal learning were evaluated.
Results demonstrated that more than one-third of patients (37%) had cognitive impairment in processing speed and executive functioning before receiving chemotherapy. More than half of patients (56%) had a decline in verbal memory. At 6 months, 54% of patients had improved, but 33% had worsened. In an exploratory analysis, older age and fewer years of education were risk factors for cognitive impairment. Conversely, quality of life, anxiety, depression, or fatigue levels did not correlate with cognitive dysfunction.
Longitudinal formal neuropsychological tests of patients with early- and advanced-stage colon cancer
The longitudinal changes in neuropsychological tests and patient self-reported measures of cognitive symptoms (FACT-Cog version 2) were studied in a cohort of 362 patients with colorectal cancer (289 early-stage and 73 advanced-stage patients) who received chemotherapy (173) or did not receive chemotherapy (116). Results in these patients were compared with results in a control population of 72 participants. Salient results included the following:
Longitudinal neuropsychological tests of men with prostate cancer receiving androgen deprivation therapy
Investigators studied 58 men with prostate cancer who received androgen deprivation therapy (ADT) at baseline, 6 months, and 12 months and compared their results to those of age-matched and education-level–matched patients with prostate cancer who did not receive ADT (n = 88) and men without prostate cancer (n = 84). The groups were similar at baseline, but at 6 and 12 months, ADT-treated men were more likely to have impaired cognitive performance according to ICCTF criteria, which combine results from individual tests. Rates of impaired cognitive performance on individual tests, however, were not significantly different at 12 months between ADT-treated patients and controls. Age, cognitive reserve, depressive symptoms, fatigue, and hot flashes did not moderate the effect of ADT on cognitive performance.
Longitudinal neuropsychological tests of allogeneic stem cell transplant (SCT) recipients
Researchers tested 102 transplant recipients before and at 12 months after SCT. They employed a battery of 14 tests to assess the following cognitive domains: verbal working memory/fluency, fine motor function, visuospatial working memory, verbal learning and retrieval, and reaction time. The investigators chose to report the frequency of below-normal test scores for individual tests rather than define domain-specific performance, so comparison with other studies is not possible.
Some evidence of impairment in at least one domain was present in 47% of patients at baseline and 41% of patients at follow-up. Age and premorbid intelligence level were associated with performance. Finally, 16% of patients demonstrated a decline in cognitive function.
Evidence-based interventions to manage cognitive impairment in cancer patients and survivors have not been firmly established. Several nonpharmacologic approaches have shown promise, including cognitive rehabilitation, exercise, and psychosocial interventions such as attention-restoring activities and meditation. All of the interventions in Table 1 have shown some evidence of efficacy but remain active areas of investigation.
|RCT = randomized controlled trial.|
|Cognitive rehabilitation||4–96 h||Multiple RCTs and non-RCTs showed improvement in some components of subjective/objective cognition.||Positive results:[2,3,4,5,6,7,8,9,10,11,12,13]|
|Included psychoeducation, compensatory training, and cognitive training.||1 RCT and 2 non-RCTs showed no benefit.|
|Most RCTs had small samples (<50 participants).||Negative results:[14,15,16]|
|Wide variation in components of intervention, dose, and measures.|
|Movement therapy||6–36 h||Several small RCTs and non-RCTs showed improvement in some components of subjective/objective cognition.||Positive results:[2,17,18,19,20,21]|
|Included various types of exercise, yoga, qigong, and tai chi.||2 studies showed no benefit.|
|Wide variation in type of movement therapy, dose, and measures.||Negative results:[22,23]|
|Attention restoration and meditation||12–22 h||2 large RCTs and 3 small RCTs showed improvement in some components of subjective/objective cognition.||Positive results:[24,25,26,27,28]|
|All therapies involved quiet, focused attention in the present moment.|
Cognitive rehabilitation (CR)
CR has shown promise in reducing the impact of cognitive problems on cancer patients and survivors. CR originated to treat populations 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 in CR interventions:
The modest evidence for the efficacy of CR is based on several randomized controlled trials using a diverse group of objective tests of neuropsychological function and subjective measures of cognitive impairment.[6,7,8,9,11] CR intervention groups showed greater improvement than did controls in self-reported cognitive impairment [6,7] and objective neuropsychological measures of attention, memory,[7,8,11] and processing speed. Other CR intervention studies provided similar results but were limited by partial or no randomization,[5,14] one-group design,[3,4] or secondary analysis.
Despite interest in movement therapies to treat cognitive impairment,[17,19,22,31] only a few clinical trials have been completed. 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.[18,23]
An intervention focused specifically on maintaining and restoring 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.
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.[28,32] 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. 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.
Several classes of agents have been investigated as potential interventions for managing cognitive impairment. In general, the quality of study design, the outcomes studied, and variation in dose and schedules of the agents prevent any firm conclusions. The agents, putative mechanisms of action, and summary of results are provided below and in Table 2.
|AChE = acetylcholinesterase; bid = twice a day; ESA = erythropoietin-stimulating agent; NMDA = N-methyl-D-aspartate; qd = every day; RCT = randomized controlled trial; WBRT = whole-brain radiation therapy.|
|Methylphenidate||10–30 mg/d for ≥2 d||Phase II studies with varying levels of benefits for different cognitive parameters (alertness, attention, memory, psychomotor speed, and executive function).|
|Small trials, not always randomized, did not always meet accrual goals; results should be interpreted with caution.[33,34];[Level of evidence: II]|
|D-methylphenidate||5–10 mg bid||Small, underpowered, placebo-controlled experience showed no benefit in verbal learning.|
|N = 57|
|Placebo controlled.[Level of evidence: II]|
|Modafinil||200–400 mg/d for 4 d–6 wk||Phase II studies with varied trial designs.|
|Benefit seen in psychomotor speed, memory, executive function, and attention, with largest study showing sustained benefit.[Level of evidence: II]|
|Interpret with caution: accrual problems, short study duration, and inadequate power.|
|No benefit seen in study in which patients served as their own controls.[34,35,39][Level of evidence: I]|
|Erythropoietin||40,000 U/wk||Multiple clinical trials demonstrated conflicting results; no intervention effect on improvement in subjective cognitive function.|
|Results difficult to generalize: varying assessment tools, small sample sizes, and differences in dosing and length of treatment.[Level of evidence: I];[Level of evidence: I];[Level of evidence: II];[Level of evidence: II];[Level of evidence: II];|
|Donepezil||5 mg qd; may increase to 10 mg qd||Studied in patients 1–5 y postchemotherapy and >6 mo post-WBRT.|
|Mixed results of no treatment effect and some improvement in some measures of attention, concentration, and memory in each trial.[Level of evidence: I];[Level of evidence: I];[Level of evidence: II]|
|NMDA Receptor Antagonists|
|Memantine||20 mg qd||One RCT; primary endpoint of improvement in delayed recall not statistically significant.|
|Treatment resulted in better cognitive function over time; delayed time to cognitive decline; and reduced rate of decline in memory, executive function, and processing speed.|
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Cognitive Impairment in Cancer Survivors
Added text to state that one study of 226 participants demonstrated that breast cancer patients experienced overall cognitive decline and scored consistently worse on cognitive tests, which was mediated by post-traumatic stress disorder (PTSD), indicating that PTSD may contribute in part to cognitive decline (cited Hermelink et al. as reference 8).
Research Studies on Prevalence, Risk Factors, and the Natural History of Cognitive Impairment
Added Objective cognitive deficits in breast cancer survivors receiving endocrine therapy as a new subsection.
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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about expert-reviewed information summary about causes and management of cognitive impairment in people with cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
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PDQ® Supportive and Palliative Care Editorial Board. PDQ Cognitive Impairment in Adults with Non−Central Nervous System Cancers. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/treatment/side-effects/memory/cognitive-impairment-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 29112351]
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Last Revised: 2018-11-05
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