Cancer survivors report more symptoms of cognitive impairment than people without a history of cancer.[1] 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: [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 who cares for survivors with objective or subjective cognitive impairment is advised to consider the following:
References:
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.[1]
The domains are interdependent, and any proposed taxonomy is provisional and will depend on the specific neuropsychological tests used to assess patients. Furthermore, there is heterogeneity among published studies on which 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 and formal testing. In addition, comparisons between studies are hampered by different scales and definitions.
References:
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.[1] Patients who report symptoms or concerns suggestive of cognitive impairment may benefit from an evaluation of potentially reversible causes and 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: [4]
Survivors expressed frustration with health care providers' lack of acknowledgment of their cognitive changes; they also expressed the need to be informed early about the possibility of developing this problem.[5,6] Patients found it comforting that subtle mental changes have been observed widely in cancer survivors and are to be expected. The least helpful response by practitioners was minimizing the changes or not taking them seriously.[5]
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:
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.
References:
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 screen all patients routinely 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.[1] The amount of information desired by survivors varied from extensive to brief and general.[2] 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.[3] 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 chemotherapy and who 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.[3] 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 [4] but has varying sensitivities of mild cognitive impairment.[5] 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, sleep disturbances, etc.) 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.[7] 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.
References:
This section summarizes the key findings of meta-analyses, systematic reviews, and individual studies of cognitive impairment.
The International Cognition and Cancer Task Force (ICCTF) has identified several methodological differences or shortcomings in published studies:[1,2]
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
One group of researchers identified 27 studies of subjective cognitive impairment in patients with breast cancer that were published between 1960 and April 2009.[3] 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.[3]
In another study of 212 mostly female breast cancer survivors, fatigue and stress were more important than demographic and medical characteristics in self-reported cognitive impairment, whereas other characteristics such as age, smoking history, and number of chemotherapy cycles were more important in objective cognitive impairment in the linear regression models. This finding emphasizes the need to address psychological problems in cancer survivors reporting cognitive impairment.[4]
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.[5] 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 due to methodological differences (e.g., different assessment methods, different definitions of significant impairment) or the possibility that subjective concerns are a sign of psychological distress.
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.[6] 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.[7] 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:
Insignificant effect sizes were observed for the following:
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 cognitive impairment, and longer time since completion of treatment was associated with cognitive improvement.[7]
Subjective and 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.[8] 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.
In the TAILORx trial, 454 women diagnosed with breast cancer were randomly assigned to receive chemotherapy plus endocrine therapy (n = 218) or endocrine therapy alone (n = 236). They also completed the Functional Assessment of Cancer Therapy (FACT)—Cognitive Function-Perceived Cognitive Impairment (FACT-Cog PCI) to assess perceived cognitive function at baseline (pretreatment) and at 3, 6, 12, 24, and 36 months.[9][Level of evidence: I] The FACT-Cog PCI subscale is a well-known, sensitive measure of perceived cognitive impairment and has an empirical-derived, clinically meaningful change score (PCI cutoff, ˃0.5) to assess cognitive impairment. In this study, breast cancer survivors in both groups reported significantly poorer perceived cognitive function at 3, 6, 12, 24, and 36 months compared with baseline. Breast cancer survivors who received chemotherapy plus endocrine therapy had statistically significant and clinically meaningful change in perceived cognitive impairment at 3 and 6 months, compared with those who received endocrine therapy alone, but this difference abated over time. The findings suggest that chemotherapy provides early but not sustained contribution to perceived cognitive impairment, indicating that the underlying etiology may be more multifaceted than just chemotherapy use. In addition, since both groups experienced significant perceived cognitive impairment compared with baseline, more studies are needed in the clinical assessment and management of perceived cognitive impairment over the treatment trajectory.
Objective cognitive deficits in men with prostate cancer receiving androgen deprivation therapy (ADT)
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.[10] 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.
The only significant effect detected was for visuomotor ability. There were no discernible negative effects on the other domains studied:[10]
Individual Research Studies
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.
Using 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 again at 1, 6, and 18 months.[11] 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.[12] 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 the following:[11]
Another group of investigators performed neuropsychological assessments on 60 women younger than 66 years who had early-stage breast cancer.[13] 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 the following:[13]
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.[14] 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 age-matched controls.[15] 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:
Neuropsychological tests of patients with early-stage colon cancer
Researchers administered formal neuropsychological tests to 81 patients with early-stage colon cancer who were scheduled to receive oxaliplatin, leucovorin, and fluorouracil (FOLFOX4). They conducted assessments prechemotherapy (n = 81), postchemotherapy (n = 73), and 6 months after the end of the last cycle of chemotherapy (n = 54).[16] Attention, visuomotor 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.[16]
Neuropsychological tests of patients with early- and advanced-stage colon cancer
Longitudinal changes in neuropsychological test results 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 (n = 173) or did not receive chemotherapy (n = 116). Results in these patients were compared with results in a control population of 72 participants.[17] Salient results included the following:
Neuropsychological tests of men with prostate cancer receiving ADT
Investigators studied 58 men with prostate cancer who received ADT at baseline and 6 and 12 months later. They 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).[18] 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. The following factors did not moderate the effect of ADT on cognitive performance:
Neuropsychological tests of allogeneic stem cell transplant (SCT) recipients
Researchers tested 102 transplant recipients before and at 12 months after SCT.[19] They used a battery of 14 tests to assess the following cognitive domains:
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.[19]
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.[19]
References:
Nonpharmacological Interventions
Evidence-based interventions to manage cognitive impairment in cancer patients and survivors have not been firmly established. Several nonpharmacologic approaches have shown promise, including:[1]
All of the interventions in Table 1 have shown some evidence of efficacy but remain active areas of investigation.
| Intervention | Dose | Comments | References |
|---|---|---|---|
| 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
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.[29] Several rehabilitation approaches have been blended to varying degrees, including the following:
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.[6,7,8,9,11] Cognitive rehabilitation intervention groups showed greater improvement than did controls in self-reported cognitive impairment [6,7] and objective neuropsychological measures of attention,[6] memory,[7,8,11] and processing speed.[11] Other cognitive rehabilitation intervention studies provided similar results but were limited by partial or no randomization,[5,14] one-group design,[3,4] or secondary analysis.[10]
Physical activity
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.[19] Other movement studies used one-group designs,[22] were not randomized,[21] or were secondary analyses.[18,23]
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.[24] 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.[25]
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.[26] 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.[26] 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.[28] 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.[27] 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. The agents, putative mechanisms of action, and summary of results are provided below and in Table 2.
| Agent | Dose | Comments |
|---|---|---|
| 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. | ||
| Psychostimulants | ||
| 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];[36][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.[37][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.[38][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] | ||
| ESAs | ||
| 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.[40][Level of evidence: I];[41][Level of evidence: I];[42][Level of evidence: II];[43][Level of evidence: II];[44][Level of evidence: II];[45] | ||
| AChE Inhibitors | ||
| 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.[46][Level of evidence: I];[47][Level of evidence: I];[48][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.[49] | ||
References:
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.
Research Studies on the Prevalence, Risk Factors, and Natural History of Cognitive Impairment
Added text about the TAILORx trial involving 454 women diagnosed with breast cancer who were randomly assigned to receive chemotherapy plus endocrine therapy or endocrine therapy alone. Participants who received chemotherapy plus endocrine therapy had a greater decline in perceived cognitive function than those who received endocrine therapy alone at 3 and 6 months, but this change abated over time (cited Wagner et al. as reference 9).
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Purpose of This Summary
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 in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
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Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Supportive and Palliative Care Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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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: 2022-03-25
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