Cognitive Impairment in Adults with Non−Central Nervous System Cancers (PDQ®): Supportive care - Health Professional Information [NCI]

General Information About Cognitive Impairment in Cancer Survivors

Cancer survivors experience more-than-expected symptoms related to cognitive impairment.[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 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:

• Because abnormal is defined as significant deviation from population means, formal neuropsychological testing may be insensitive to subtle changes from prediagnosis or pretreatment cognitive function.
• There is a strong correlation between patient subjective reports of cognitive impairment and decreased daily functioning [6] or reduced quality of life.[7]
• It is not known whether cognitive impairment influences psychological distress 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 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.[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 (DSM-5), 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; and 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, either verbally or in writing.
• Learning and memory: Ability to acquire new information; and 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 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.

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.
• Memory lapses.
• Inability to focus on tasks.
• 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 evaluation of potentially reversible causes and the taking of appropriate measures. Potential contributing factors include the following:

• Age.
• Frailty.[2,3]
• 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.
• Comorbidities.
• Use of alcohol or other agents that alter cognition.

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.[4] 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.[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 define potential interventions to reverse the symptoms or stabilize the patient. A focused history and physical examination will assess the following:

• Measures of baseline cognitive function, such as educational attainment, job-related responsibilities, and premorbid functioning.
• Likelihood of cognitive impairment based on potential risk factors such as 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 neurologic deficits. Focal motor defects or discrete cortical defects such as aphasia or apraxia are uncommon in cancer-associated cognitive impairment.[8]
• Signs of metastatic disease to the brain, meninges, or both.

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.

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. Myers JS: Chemotherapy-related cognitive impairment: the breast cancer experience. Oncol Nurs Forum 39 (1): E31-40, 2012.
5. 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.
6. 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.
7. 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.
8. 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 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.[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 experience with chemotherapy and who received the priming introduction reported higher levels of cognitive impairment.[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 is respectful of personal autonomy.

Screening

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.[4] 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.

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. 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 Prevalence, Risk Factors, and the Natural History of Cognitive Impairment

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 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

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.[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]

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.[4] 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.[5] 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.[6] 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.[6]

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.[7] 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.[8] 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.[8]

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.[9] 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.[10] 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.[9]

Another group of investigators performed neuropsychological assessments on 60 women younger than 66 years who had early-stage breast cancer.[11] 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.[11]

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.[12] 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.[13] 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.

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).[14] 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.[14]

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.[15] Salient results included the following:

• Self-reported cognitive impairment was more common in patients who received chemotherapy (32%) than in patients 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, 6, and 12 months, compared with approximately 15% of controls.
• There were no differences between patients who had or had not received chemotherapy.

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).[16] 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.[17] 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.[17]

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. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. Whalley LJ, Deary IJ, Appleton CL, et al.: Cognitive reserve and the neurobiology of cognitive aging. Ageing Res Rev 3 (4): 369-82, 2004.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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

Nonpharmacologic 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 cognitive rehabilitation, exercise, and psychosocial interventions such as attention-restoring activities and meditation.[1] All of the interventions in Table 1 have shown some evidence of efficacy but remain active areas of investigation.

Table 1. Nonpharmacologic Interventions for Cognitive Impairment

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 (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.[29] Several rehabilitation approaches have been blended to varying degrees in CR interventions:

• 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; or 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 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,[6] memory,[7,8,11] and processing speed.[11] 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.[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 maintaining and restoring 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.

Pharmacologic Interventions

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.

• Psychostimulants. Psychostimulants are approved by the U.S. Food and Drug Administration primarily for attention-deficit hyperactivity disorder or sleep-wake disorders. 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.[33,34,35] 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.[34,35,36] 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, preventing neuronal apoptosis. The potential for cognitive improvement must be weighed against the risks of ESAs, including 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 outside of the WBRT setting.

Table 2. Agents for Managing Cognitive Impairment

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]

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Changes to This Summary (11 / 05 / 2018)

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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The lead reviewers for Cognitive Impairment in Adults with Non−Central Nervous System Cancers are:

• Andrea Barsevick, PhD (Thomas Jefferson University)
• Larry D. Cripe, MD (Indiana University School of Medicine)
• Diane Von Ah, PhD, RN, FAAN (Indiana University School of Nursing)

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Last Revised: 2018-11-05