General Information About Cognitive Impairment in Cancer Survivors

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 the following: [1,2,3]

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

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:

• Because abnormal is defined as 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 [6] or reduced quality of life.[7]
• It is not known whether cognitive impairment influences or is a sign of psychological distress.[4] However, one study of 226 participants (166 patients with newly diagnosed breast cancer and 60 controls) demonstrated that breast cancer patients 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.[8] Studies have also shown that cognitive impairment is associated with negative emotional states such as anxiety and depression,[6,9,10] the personality trait of negative affectivity,[11] and self-perceived treatment burden.[9]
• Treatments for patients with cancer-related cognitive impairment have shown minimal to modest benefit. Therefore, compassionate acknowledgment of the concerns and a supportive approach are essential.

References:

1. Jean-Pierre P, Winters PC, Ahles TA, et al.: Prevalence of self-reported memory problems in adult cancer survivors: a national cross-sectional study. J Oncol Pract 8 (1): 30-4, 2012.
2. Vardy JL, Dhillon HM, Pond GR, et al.: Cognitive Function in Patients With Colorectal Cancer Who Do and Do Not Receive Chemotherapy: A Prospective, Longitudinal, Controlled Study. J Clin Oncol 33 (34): 4085-92, 2015.
3. Scherwath A, Schirmer L, Kruse M, et al.: Cognitive functioning in allogeneic hematopoietic stem cell transplantation recipients and its medical correlates: a prospective multicenter study. Psychooncology 22 (7): 1509-16, 2013.
4. Pullens MJ, De Vries J, Roukema JA: Subjective cognitive dysfunction in breast cancer patients: a systematic review. Psychooncology 19 (11): 1127-38, 2010.
5. Hutchinson AD, Hosking JR, Kichenadasse G, et al.: Objective and subjective cognitive impairment following chemotherapy for cancer: a systematic review. Cancer Treat Rev 38 (7): 926-34, 2012.
6. Shilling V, Jenkins V: Self-reported cognitive problems in women receiving adjuvant therapy for breast cancer. Eur J Oncol Nurs 11 (1): 6-15, 2007.
7. Von Ah D, Habermann B, Carpenter JS, et al.: Impact of perceived cognitive impairment in breast cancer survivors. Eur J Oncol Nurs 17 (2): 236-41, 2013.
8. Hermelink K, Bühner M, Sckopke P, et al.: Chemotherapy and Post-traumatic Stress in the Causation of Cognitive Dysfunction in Breast Cancer Patients. J Natl Cancer Inst 109 (10): , 2017.
9. Hermelink K, Küchenhoff H, Untch M, et al.: Two different sides of 'chemobrain': determinants and nondeterminants of self-perceived cognitive dysfunction in a prospective, randomized, multicenter study. Psychooncology 19 (12): 1321-8, 2010.
10. Hermelink K, Untch M, Lux MP, et al.: Cognitive function during neoadjuvant chemotherapy for breast cancer: results of a prospective, multicenter, longitudinal study. Cancer 109 (9): 1905-13, 2007.
11. Watson D, Pennebaker JW: Health complaints, stress, and distress: exploring the central role of negative affectivity. Psychol Rev 96 (2): 234-54, 1989.

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.[1]

• 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 comprehend 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, 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:

1. Sachdev PS, Blacker D, Blazer DG, et al.: Classifying neurocognitive disorders: the DSM-5 approach. Nat Rev Neurol 10 (11): 634-42, 2014.

Responding to Patient Reports of Cognitive Impairment

Cancer patients may experience the following difficulties:

• Difficulty multitasking; must focus on one thing at a time.
• Trouble concentrating; inability to focus on tasks.
• Memory lapses.
• Difficulty following instructions.
• Decreased ability to handle personal finances.
• Disorganized behavior or thinking.
• Loss of initiative.
• Difficulty remembering common words and recalling names.
• Inability to recognize familiar objects.
• Altered perception.
• Difficulty finding words.

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:

• Advanced age.
• Frailty.[2,3]
• Certain medications and their side effects.
• Hormone status and menopause status.
• Emotional distress and/or depressive symptoms and anxiety.
• Symptom burden such as pain, fatigue, and sleep disturbance.[4][Level of evidence: II]
• Comorbidities.
• Use of alcohol or other agents that alter cognition.
• Higher stage of disease, larger tumor size, and markers of tumor aggressivity (e.g., HER2 positivity in breast cancer).[5]
• Increased levels of C-reactive protein or other proinflammatory cytokines (e.g., interleukin 6).[6,7]

Validation of the Survivor Experience

The experience of cognitive changes after cancer treatment has been documented in qualitative research.[8,9,10,11] Concerns reported by survivors include the following: [8]

• Memory problems.
• Inability to concentrate.
• Decreased ability to function in daily activities, including employment.

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.[9,10] 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.[9]

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.[12]
• 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).

References:

1. Mandelblatt JS, Stern RA, Luta G, et al.: Cognitive impairment in older patients with breast cancer before systemic therapy: is there an interaction between cancer and comorbidity? J Clin Oncol 32 (18): 1909-18, 2014.
2. Mandelblatt JS, Jacobsen PB, Ahles T: Cognitive effects of cancer systemic therapy: implications for the care of older patients and survivors. J Clin Oncol 32 (24): 2617-26, 2014.
3. Mandelblatt JS, Clapp JD, Luta G, et al.: Long-term trajectories of self-reported cognitive function in a cohort of older survivors of breast cancer: CALGB 369901 (Alliance). Cancer 122 (22): 3555-3563, 2016.
4. Huang V, Mackin L, Kober KM, et al.: Distinct sleep disturbance and cognitive dysfunction profiles in oncology outpatients receiving chemotherapy. Support Care Cancer 30 (11): 9243-9254, 2022.
5. Root JC, Zhou X, Ahn J, et al.: Association of markers of tumor aggressivity and cognition in women with breast cancer before adjuvant treatment: The Thinking and Living with Cancer Study. Breast Cancer Res Treat 194 (2): 413-422, 2022.
6. Mandelblatt JS, Small BJ, Zhou X, et al.: Plasma levels of interleukin-6 mediate neurocognitive performance in older breast cancer survivors: The Thinking and Living With Cancer study. Cancer 129 (15): 2409-2421, 2023.
7. Carroll JE, Nakamura ZM, Small BJ, et al.: Elevated C-Reactive Protein and Subsequent Patient-Reported Cognitive Problems in Older Breast Cancer Survivors: The Thinking and Living With Cancer Study. J Clin Oncol 41 (2): 295-306, 2023.
8. Myers JS: Chemotherapy-related cognitive impairment: the breast cancer experience. Oncol Nurs Forum 39 (1): E31-40, 2012.
9. Boykoff N, Moieni M, Subramanian SK: Confronting chemobrain: an in-depth look at survivors' reports of impact on work, social networks, and health care response. J Cancer Surviv 3 (4): 223-32, 2009.
10. Von Ah D, Habermann B, Carpenter JS, et al.: Impact of perceived cognitive impairment in breast cancer survivors. Eur J Oncol Nurs 17 (2): 236-41, 2013.
11. Munir F, Burrows J, Yarker J, et al.: Women's perceptions of chemotherapy-induced cognitive side affects on work ability: a focus group study. J Clin Nurs 19 (9-10): 1362-70, 2010.
12. Wefel JS, Witgert ME, Meyers CA: Neuropsychological sequelae of non-central nervous system cancer and cancer therapy. Neuropsychol Rev 18 (2): 121-31, 2008.

Proactive Approaches to Cognitive Impairment

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 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.[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:

1. Myers JS: Chemotherapy-related cognitive impairment: the breast cancer experience. Oncol Nurs Forum 39 (1): E31-40, 2012.
2. Boykoff N, Moieni M, Subramanian SK: Confronting chemobrain: an in-depth look at survivors' reports of impact on work, social networks, and health care response. J Cancer Surviv 3 (4): 223-32, 2009.
3. Schagen SB, Das E, Vermeulen I: Information about chemotherapy-associated cognitive problems contributes to cognitive problems in cancer patients. Psychooncology 21 (10): 1132-5, 2012.
4. Folstein MF, Folstein SE, McHugh PR: "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12 (3): 189-98, 1975.
5. Mitchell AJ: A meta-analysis of the accuracy of the mini-mental state examination in the detection of dementia and mild cognitive impairment. J Psychiatr Res 43 (4): 411-31, 2009.
6. Denlinger CS, Ligibel JA, Are M, et al.: Survivorship: cognitive function, version 1.2014. J Natl Compr Canc Netw 12 (7): 976-86, 2014.
7. Wefel JS, Vardy J, Ahles T, et al.: International Cognition and Cancer Task Force recommendations to harmonise studies of cognitive function in patients with cancer. Lancet Oncol 12 (7): 703-8, 2011.

Research Studies on the Prevalence, Risk Factors, and Natural History of Cognitive Impairment

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]

• Whether patients enrolled in the study had presented with subjective concerns or were recruited to undergo formal testing.
• Assessment of pretreatment cognitive impairment and interstudy differences in how baseline function was accounted for.
• Variations in objective neuropsychological testing, including instruments selected, definitions of cognitive domains, and definition of impairment.

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:

• Executive function (effect size, –0.27).
• Memory (effect size, –0.21).
• Verbal function and language skills (effect size, –0.17).

Insignificant effect sizes were observed for the following:

• Construction (the ability to draw and build).
• Concept formation.
• Reasoning.
• Perception.
• 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 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 endocrine 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. However, findings were limited by the methodical heterogeneity of included studies and relatively short follow-up periods (3 months to 2 years).

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.

In the Tamoxifen and Exemestane Adjuvant Multinational Trial, breast cancer survivors received 5 years of exemestane treatment (n = 114) or sequential treatment of 2.5 years of tamoxifen treatment, followed by 2.5 years of exemestane treatment (n = 92).[10] Neuropsychological performance was assessed before endocrine therapy, after 1 year (short-term [ST] follow-up), and at 5 years (long-term [LT] follow-up). A control group of 120 healthy participants were assessed with parallel intervals. After controlling for age, intelligence quotient, attrition, menopausal symptoms, anxiety and/or depression, and fatigue, the sequential group showed ST and LT decline, compared with control participants, on verbal memory (effect size [ES] = 0.26, P = .01; ES = 0.34, P =.003) and executive function (ES = 0.27, P =.007; ES = 0.38, P = .002). In addition, compared with the exemestane group, the sequential group demonstrated ST decline on information processing speed (ES = 0.33, P = .01) and executive function (ES = 0.32, P = .01) and LT decline on verbal memory (ES = 0.33, P = .02). The exemestane group showed no cognitive decline compared with control participants. The apparent cognitive adverse effects of tamoxifen alone and after switching to exemestane suggested that tamoxifen may have a carryover cognitive effect.[10] These findings, if confirmed, suggest that tamoxifen may have more adverse cognitive effects than exemestane.

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.[11] 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:[11]

• Attention/working memory.
• Executive functioning.
• Language.
• Verbal memory.
• Visual memory.
• Visuospatial ability.

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.[12] 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.[13] 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:[12]

• Verbal memory.
• Visual memory.
• Working memory.
• Sorting.
• Distractibility.
• Reaction time.

Another group of investigators performed neuropsychological assessments on 60 women younger than 66 years who had early-stage breast cancer.[14] 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:[14]

• Working memory.
• Processing speed.
• Verbal memory.
• 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.[15] 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.[16] 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:

• At baseline, patients with breast cancer had lower overall quality-of-life scores (on the Functional Assessment of Cancer Therapy: General, or FACT-G) than did controls.
• Mean FACT-G scores declined in patients postchemotherapy but remained stable in controls.
• Almost half of the patients experienced decline in cognitive function, compared with only 10% of controls.
• Predictors for decline on the overall FACT-Cog scale included lower reading scores, higher depression, and higher anxiety.
• Predictors for decline in specific subscales varied.

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).[17] 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.[17]

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.[18] Salient results included the following:

• Self-reported cognitive impairment was more common in patients who received chemotherapy (32%) than in those who did not receive chemotherapy (16%) or in controls (12.5%) (P = .007) at 6 months. There were no differences at 12 months.
• Patient self-reported cognitive impairment was moderately associated with fatigue, quality of life, and anxiety/depression.
• Correlation between neuropsychological test results and self-reported impairment was weak.
• Based on ICCTF criteria, cognitive impairment was present in approximately 50% of patients with colorectal cancer at baseline and 6 and 12 months later, compared with approximately 15% of controls.
• There were no differences between patients who had or had not received chemotherapy.

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).[19] 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:

• Age.
• Cognitive reserve.
• Depressive symptoms.
• Fatigue.
• Hot flashes.

Neuropsychological tests of allogeneic stem cell transplant (SCT) recipients

Researchers tested 102 transplant recipients before and at 12 months after SCT.[20] They used 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.
• 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.[20]

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.[20]

References:

1. Wefel JS, Vardy J, Ahles T, et al.: International Cognition and Cancer Task Force recommendations to harmonise studies of cognitive function in patients with cancer. Lancet Oncol 12 (7): 703-8, 2011.
2. Joly F, Giffard B, Rigal O, et al.: Impact of Cancer and Its Treatments on Cognitive Function: Advances in Research From the Paris International Cognition and Cancer Task Force Symposium and Update Since 2012. J Pain Symptom Manage 50 (6): 830-41, 2015.
3. Pullens MJ, De Vries J, Roukema JA: Subjective cognitive dysfunction in breast cancer patients: a systematic review. Psychooncology 19 (11): 1127-38, 2010.
4. Gutenkunst SL, Vardy JL, Dhillon HM, et al.: Correlates of cognitive impairment in adult cancer survivors who have received chemotherapy and report cognitive problems. Support Care Cancer 29 (3): 1377-1386, 2021.
5. Hutchinson AD, Hosking JR, Kichenadasse G, et al.: Objective and subjective cognitive impairment following chemotherapy for cancer: a systematic review. Cancer Treat Rev 38 (7): 926-34, 2012.
6. Jim HS, Phillips KM, Chait S, et al.: Meta-analysis of cognitive functioning in breast cancer survivors previously treated with standard-dose chemotherapy. J Clin Oncol 30 (29): 3578-87, 2012.
7. Hodgson KD, Hutchinson AD, Wilson CJ, et al.: A meta-analysis of the effects of chemotherapy on cognition in patients with cancer. Cancer Treat Rev 39 (3): 297-304, 2013.
8. Bakoyiannis I, Tsigka EA, Perrea D, et al.: The Impact of Endocrine Therapy on Cognitive Functions of Breast Cancer Patients: A Systematic Review. Clin Drug Investig 36 (2): 109-18, 2016.
9. Wagner LI, Gray RJ, Sparano JA, et al.: Patient-Reported Cognitive Impairment Among Women With Early Breast Cancer Randomly Assigned to Endocrine Therapy Alone Versus Chemoendocrine Therapy: Results From TAILORx. J Clin Oncol 38 (17): 1875-1886, 2020.
10. Lee Meeuw Kjoe PR, Kieffer JM, Small BJ, et al.: Effects of tamoxifen and exemestane on cognitive function in postmenopausal patients with breast cancer. JNCI Cancer Spectr 7 (2): , 2023.
11. McGinty HL, Phillips KM, Jim HS, et al.: Cognitive functioning in men receiving androgen deprivation therapy for prostate cancer: a systematic review and meta-analysis. Support Care Cancer 22 (8): 2271-80, 2014.
12. Ahles TA, Saykin AJ, McDonald BC, et al.: Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: impact of age and cognitive reserve. J Clin Oncol 28 (29): 4434-40, 2010.
13. Whalley LJ, Deary IJ, Appleton CL, et al.: Cognitive reserve and the neurobiology of cognitive aging. Ageing Res Rev 3 (4): 369-82, 2004.
14. Collins B, MacKenzie J, Tasca GA, et al.: Cognitive effects of chemotherapy in breast cancer patients: a dose-response study. Psychooncology 22 (7): 1517-27, 2013.
15. Pullens MJ, De Vries J, Van Warmerdam LJ, et al.: Chemotherapy and cognitive complaints in women with breast cancer. Psychooncology 22 (8): 1783-9, 2013.
16. Janelsins MC, Heckler CE, Peppone LJ, et al.: Cognitive Complaints in Survivors of Breast Cancer After Chemotherapy Compared With Age-Matched Controls: An Analysis From a Nationwide, Multicenter, Prospective Longitudinal Study. J Clin Oncol 35 (5): 506-514, 2017.
17. Cruzado JA, López-Santiago S, Martínez-Marín V, et al.: Longitudinal study of cognitive dysfunctions induced by adjuvant chemotherapy in colon cancer patients. Support Care Cancer 22 (7): 1815-23, 2014.
18. Vardy JL, Dhillon HM, Pond GR, et al.: Cognitive Function in Patients With Colorectal Cancer Who Do and Do Not Receive Chemotherapy: A Prospective, Longitudinal, Controlled Study. J Clin Oncol 33 (34): 4085-92, 2015.
19. Gonzalez BD, Jim HS, Booth-Jones M, et al.: Course and Predictors of Cognitive Function in Patients With Prostate Cancer Receiving Androgen-Deprivation Therapy: A Controlled Comparison. J Clin Oncol 33 (18): 2021-7, 2015.
20. Scherwath A, Schirmer L, Kruse M, et al.: Cognitive functioning in allogeneic hematopoietic stem cell transplantation recipients and its medical correlates: a prospective multicenter study. Psychooncology 22 (7): 1509-16, 2013.

Interventions for Cognitive Impairment

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.
• 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.

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:

• Psychoeducation provides useful information about brain functioning, cognitive deficits, and their consequences for daily life.[4]
• 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).[8]
• 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.[9,13,30]

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

There is increasing interest in physical and mind-body exercise to address cognitive impairment in cancer survivors. [17,19,22,31] 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.[32]

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.[33][Level of evidence: I] 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.

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.[28,34] 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.

• 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.[35,36,37] 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.[36,37,38] 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.
• N-methyl-D-aspartate (NMDA) receptor antagonists: By inhibiting the NMDA receptor with the antagonist memantine, radiation-induced neuronal stimulation and excitotoxicity may be reduced, thus preventing WBRT-induced cognitive decline. Memantine has not been studied for reducing cognitive dysfunction in cancer patients outside of the WBRT setting.

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15. Poppelreuter M, Weis J, Mumm A, et al.: Rehabilitation of therapy-related cognitive deficits in patients after hematopoietic stem cell transplantation. Bone Marrow Transplant 41 (1): 79-90, 2008.
16. Rottmann N, Dalton SO, Bidstrup PE, et al.: No improvement in distress and quality of life following psychosocial cancer rehabilitation. A randomised trial. Psychooncology 21 (5): 505-14, 2012.
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18. Derry HM, Jaremka LM, Bennett JM, et al.: Yoga and self-reported cognitive problems in breast cancer survivors: a randomized controlled trial. Psychooncology 24 (8): 958-66, 2015.
19. Oh B, Butow PN, Mullan BA, et al.: Effect of medical Qigong on cognitive function, quality of life, and a biomarker of inflammation in cancer patients: a randomized controlled trial. Support Care Cancer 20 (6): 1235-42, 2012.
20. Schmidt T, Weisser B, Dürkop J, et al.: Comparing Endurance and Resistance Training with Standard Care during Chemotherapy for Patients with Primary Breast Cancer. Anticancer Res 35 (10): 5623-9, 2015.
21. Baumann FT, Drosselmeyer N, Leskaroski A, et al.: 12-week resistance training with breast cancer patients during chemotherapy: effects on cognitive abilities. Breast Care (Basel) 6 (2): 142-3, 2011.
22. Schwartz AL, Thompson JA, Masood N: Interferon-induced fatigue in patients with melanoma: a pilot study of exercise and methylphenidate. Oncol Nurs Forum 29 (7): E85-90, 2002.
23. Schmidt ME, Wiskemann J, Armbrust P, et al.: Effects of resistance exercise on fatigue and quality of life in breast cancer patients undergoing adjuvant chemotherapy: A randomized controlled trial. Int J Cancer 137 (2): 471-80, 2015.
24. Cimprich B: Development of an intervention to restore attention in cancer patients. Cancer Nurs 16 (2): 83-92, 1993.
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26. Hoffman CJ, Ersser SJ, Hopkinson JB, et al.: Effectiveness of mindfulness-based stress reduction in mood, breast- and endocrine-related quality of life, and well-being in stage 0 to III breast cancer: a randomized, controlled trial. J Clin Oncol 30 (12): 1335-42, 2012.
27. Milbury K, Chaoul A, Biegler K, et al.: Tibetan sound meditation for cognitive dysfunction: results of a randomized controlled pilot trial. Psychooncology 22 (10): 2354-63, 2013.
28. Johns SA, Von Ah D, Brown LF, et al.: Randomized controlled pilot trial of mindfulness-based stress reduction for breast and colorectal cancer survivors: effects on cancer-related cognitive impairment. J Cancer Surviv 10 (3): 437-48, 2016.
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31. Lee CE, Kilgour A, Lau YK: Efficacy of walking exercise in promoting cognitive-psychosocial functions in men with prostate cancer receiving androgen deprivation therapy. BMC Cancer 12: 324, 2012.
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Latest Updates to This Summary (05 / 08 / 2024)

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.

Meta-Analyses and Systematic Reviews

Added text about the results of the Tamoxifen and Exemestane Adjuvant Multinational Trial, which assessed the neuropsychological performance of breast cancer survivors who received either 5 years of exemestane treatment or sequential treatment of 2.5 years of tamoxifen treatment, followed by 2.5 years of exemestane treatment, compared with healthy participants. The results suggested that tamoxifen may have a carryover cognitive effect and may have more adverse cognitive effects than exemestane (cited Lee et al. as reference 10).

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About This PDQ Summary

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 adults 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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This summary is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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• Diane Von Ah, PhD, RN, FAAN (The Ohio State University)

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Last Revised: 2024-05-08