Improving Cognitive Function of Older Adults With a History of Cancer Using Nonpharmacologic Interventions: A Systematic Review : Rehabilitation Oncology

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Improving Cognitive Function of Older Adults With a History of Cancer Using Nonpharmacologic Interventions: A Systematic Review

Simone, Abigail SPT, MS1; Blackwood, Jennifer PT, PhD2

Author Information
Rehabilitation Oncology 41(1):p 14-22, January 2023. | DOI: 10.1097/01.REO.0000000000000313


Currently, in the United States, the fastest-growing subset of the population is people older than 65 years.1 Within this demographic, cancer incidence increases 11-fold compared with younger individuals, with the median age at the time of diagnosis being 68 years.1 As more older adults are being diagnosed with cancer and receiving treatment, modern medicine advances in oncology have allowed people to live years past a cancer diagnosis; however, cancer-free living may come with additional sequelae due to side effects of cancer treatment itself.2 The main treatment options across all ages include surgery, radiation therapy, and chemotherapy, with the latter being a common choice. Chemotherapy has been well documented to be associated with a multitude of side effects, both transient and long-lasting, including hair loss, fatigue, anemia, nausea, vomiting, neuropathy, and cognitive dysfunction.3

Cancer-related cognitive dysfunction (CRCD) refers to the mental cloudiness or changes in cognitive function that occur before, during, and after cancer treatment.4 The exact cause of CRCD is unknown but reportedly is the result of various interventions to address cancer, including radiation treatments, hormonal therapies, surgery with anesthesia, and most often, chemotherapy treatments.5 CRCD is a prevalent side effect of chemotherapy, particularly among the young and adult populations, with up to 75% of patients reporting CRCD during treatment and 35% of patients reporting CRCD present 10 or more years following the cessation of treatment.6–10 Additionally, CRCD is prevalent in older adults, those 65 years and older, with a history of noncentral nervous system cancers.11

Age-related changes in cognition reported in the literature include a slowing of processing speed,12 reduced efficiency of inhibitory control, impaired executive function, and decreased recall in both working13 and episodic memory.14 As a result, older adults may experience consequences such as increased distractibility, difficulty with multitasking, and information processing delays.14 Cancer-related chemotherapy treatments are believed to exacerbate cognitive decline in those with preexisting cognitive issues, including in those with aging-associated losses in cognition.15

Studies describing the outcomes of nonpharmacologic interventions on cognitive dysfunction have been performed and have included cognitive rehabilitation, meditation, and physical activity or exercise-based interventions. Cognitive rehabilitation interventions include methods such as cognitive training or compensatory strategy training. Cognitive training is the repetitive practice of specific cognitive functions to improve or modify cognition through structured tasks or activities and can be either computer-assisted or noncomputerized.16,17 Cognitive training can address a specific cognitive domain (ie, recall) or multiple cognitive domains (ie, recall, attention, and set-shifting), whereas compensatory strategy training uss learned techniques to manage or cope with present cognitive impairments.18 Meditation or relaxation-based interventions include mental exercises aimed at reaching a focused state of mind, such as visualization and breathing exercises.19 Physical activity interventions have included aerobic, resistive, or general exercises.

Several nonpharmacologic interventions have been used to address cognitive dysfunction in older adults without a history of cancer. With regard to cognitive training interventions, the parameters and populations in which they have been used differ along with the cognitive functions targeted.20 For example, in older adults with mild to moderate Alzheimer's disease, a group-based cognitive training intervention performed for five 1-month cycles (1 cycle: 20 sessions, 2 hours per day, 5 days per week) with a 4-week break between each cycle elicited improvements in executive function, memory, verbal fluency, and perceptual-motor skills compared with controls. However, in older adults with Parkinson's disease, improvements in verbal fluency and memory were reported after completing twelve 1-hour computerized cognitive training sessions twice per week for 6 weeks.21

Preliminary evidence is emerging in the oncology population identifying the benefits of cognitive training on CRCD. In younger survivors of breast cancer, significant improvements in processing speed, executive function, cognitive flexibility, language, and both delayed and immediate recall were reported after completing a 13-weeklong computerized cognitive training program (20-30 minutes/week 4 times/week). Additionally, study participants reported improvements in subjective cognitive function and mental well-being demonstrating both objective and subjective outcomes of this type of intervention.22

Recent studies have identified changes in physical structures related to cognition as well as improved cognitive functions with regard to physical exercise as a nonpharmacologic intervention to address cognitive decline.23–26 In older adults with mild cognitive impairment, improvements in verbal memory and learning were reported after completing a 6-monthlong aerobic exercise intervention performed at 70% to 80% of heart rate reserve twice weekly for 1-hour sessions.27 A 6-monthlong resistance training program significantly improved selective attention and associative memory in a group of older adults with undiagnosed cognitive impairment.28 Improvements in executive function were reported in older adults with mild cognitive impairment after completing 6 weeks of a 3 times per week combined walking (30 minutes at moderate to vigorous intensity) and tai chi intervention.29 Other studies reporting improvements in global cognitive function have found similar results in older adults with mild deficits in cognition after completing high-intensity aerobic or resistance exercise.30,27

In addition to cognitive training, promising evidence has emerged describing the benefits of physical exercise as a nonpharmacologic intervention for CRCD in adult survivors of cancer (<65 years). Significant improvements in executive function and verbal fluency were reported in a group of adult survivors of breast cancer after completing a 24-weeklong aerobic exercise program (150 minutes per week at 60%-70% heart rate reserve).31 Additionally, improved processing speed and reaction time were reported in younger survivors of cancer after completing at least 45 minutes or more of moderate to vigorous physical activity per day.32

Previous systematic reviews by Treanor et al33 and Syed Alwi et al34 described the outcomes of several nonpharmacologic interventions used to address CRCD. However, both reviews included only younger survivors of cancer and it is not known whether older adults with a history of cancer have the same outcomes from the interventions. While the effects of nonpharmacologic interventions on cognition have been reported in both young survivors of cancer (<65) and in the older adult population (≥65), limited information is available to describe the outcomes of these interventions on CRCD found in older adults. Therefore, the purpose of this systematic review is to describe the current nonpharmacologic interventions for older adults with CRCD.


Data Sources and Searches

This systematic review was registered with PROSPERO (CRD42021232942), and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) standards were followed. The primary search was conducted in April 2021 using the following databases: PubMed, CINAHL, Embase, and MEDLINE. Search terms included (“neoplasms”) AND (“chemotherapy”) AND (“cognitive function”) AND (“non-pharmacological interventions”). Additional “hand search” was conducted by reviewing references, using the “related articles” feature, and locating other publications by authors of identified articles. This additional search was completed in May 2021. A detailed description of the search strategy is found in Supplemental Digital Content Appendix 1 (available at:

Study Selection

Inclusion criteria for articles were as follows: (1) study designs were quantitative, including randomized controlled trials, quasirandomized controlled trials, cohort studies, case-control, and cross-sectional studies; (2) participants were 65 years or older; (3) participants had a history of any type of noncentral nervous system cancer; (4) nonpharmacologic interventions were used; and (5) cognitive function was assessed before and after the intervention. Exclusion criteria were: (1) animal populations; (2) populations younger than 65 years; (3) populations without a history of cancer; (4) populations with a known non-cancer-related cognitive impairment; and (5) studies not published in English.

Two reviewers independently screened the titles and abstracts of articles found from the search. After initial screening, full-text articles were independently appraised for eligibility by the same 2 reviewers. Any disagreements regarding article inclusion were discussed between reviewers to resolve the discrepancy. In the event a consensus could not be met, a third reviewer was assigned.

Data Extraction, Quality Assessment, and Analysis

Two research team members independently extract the data from included studies. Extracted data were compared and discussed with relevant information included. The Cochrane “Risk of Bias 2” (RoB 2) tool was used to assess the quality of included studies.35 Within this tool, quality is rated in different domains of the study including study design, conduct, and reporting. RoB 2 uses a series of questions known as signaling questions to identify risk of bias within areas of the study with potential responses to the signaling questions of “low” or “high” or that “some concern” is present regarding risk of bias. RoB 2 uses an algorithm to generate a risk of bias for each domain of the study based on responses to the signaling questions and also creates an overall assessment of risk of bias. The quality review of included studies was performed by 2 research team members reaching consensus and another researcher served as a tie-breaker. No articles were removed from this review based on study quality.


A total of 5473 titles were identified from electronic searches (Figure), and an additional 10 titles were identified from other methods, including citation lists of included papers and related articles identified using PubMed. Following the removal of duplicates, 3441 titles remained. Titles were screened against inclusion/exclusion criteria resulting in the exclusion of 3191 articles. The abstracts of the remaining 250 articles were examined for inclusion, and 230 of these were excluded. Twenty full-text articles were obtained and thoroughly screened for eligibility. Four of these met eligibility requirements. Reasons for excluding the 16 studies were as follows: study design (n = 5), younger than 65 years (n = 8), inclusion of central nervous system cancers (n = 2), and cognitive function not assessed (n = 1). A summary of the outcomes can be found in Table 1.

PRISMA flow diagram.
TABLE 1 - Summary of Outcomes
Author Primary Outcome Measure(s) Neuropsychological Test(s) Neuropsychological Results (Effect Size)
Andersen et al36 EORTC QLQ-C30
  • Global cognition:


No significant improvement
Wu et al37 CNSVS
  • Perceptual motor:


  • Memory—verbal and visual memory:


  • Complex attention—reaction time:


  • Executive function:

    CNSVS and Frontal Systems BehaviorScale

  • Global cognition:

    Patient Assessment of Own Functioning

No significant improvement
Significant improvement in verbal memory postintervention
  • d = 0.63

Significant improvement postintervention
  • d = 0.70

No significant improvement
No significant improvement
McDougall et al38 Not reported Memory
  • Verbal memory:

    Hopkins Verbal Learning Test-Revised(HVLT-R)

  • Everyday memory:

    Rivermead Everyday Behavioral MemoryTest (REBMT)

  • Visual memory:

    Brief Visuospatial Memory Test-Revised

  • Memory strategy use:

    Metamemory In AdulthoodQuestionnaire (MIAQ)

  • Memory complaints:


  • Memory self-efficacy:

    Memory Self-Efficacy Questionnaire

No significant improvement measured byHVLT-R or REBMT
Significant improvement in visual memory postintervention
  • η 2 = 0.33

Significant improvement in internal memory strategy use postintervention
  • η 2 = 0.15

Significant improvement in number of memory complaints postintervention
  • η 2 = 0.42

Significant improvement in memory self-efficacy postintervention
  • η 2 = 0.23

Miki et al39 Frontal Assessment Battery (FAB)
  • Executive function:


Significant improvement postintervention
Abbreviations: CNSVS, Central Nervous System Vital Signs; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients Questionnaire.

A total of 184 participants were included across all 4 studies. Three studies included cancer survivor control groups that received either usual care, comparison, or no treatment. The usual care control group received standard care during the study.37 The comparison group participated in health promotion training consisting of educational lectures on successful aging.38

The study conducted by Wu et al37 included only male survivors of prostate cancer. The remaining 3 studies included both male and female participants. Andersen et al36 included patients with lung cancer, Miki et al39 included both patients with prostate and breast cancer, and McDougall et al38 included patients with prostate, breast, uterine, lymphoma/leukemia, throat, lung, and facial/basal cell cancers. The number of participants in any single study ranged from 22 to 78, with a mean age of 69.83 years (SD = 4.16).36–39 Studies were conducted in 3 countries: 1 study in Denmark,36 1 in Japan,39 and 2 in the United States.37,38 All studies provided information regarding cancer type. Three studies (75%) reported the cancer treatment type36,37,39 and 2 studies (50%) reported whether participants received treatment during the intervention.36,39 Miki et al39 reported the time from initial diagnosis but no studies reported time since cancer treatment. Further details regarding the characteristics of the included studies can be found in Table 2.

TABLE 2 - Study Characteristics
Author Intervention Design Control Participants, n Cognitive Function Measured Intervention Procedure Assessments
Andersen et al36 Aerobic exercise Prospective single-group clinical trial None
  • Intervention group: n = 24 (14 male, 10 female), mean age = 66, lung cancer

Global cognition
  • Aerobic exercise based on COPD rehabilitation exercise protocol focused on walking training and dyspnea coping

  • 90 min of aerobic exercise at 85%

    V ˙
    o 2max during group sessions 2 d/wk and home sessions 5 d/wk for 7 wk

  • Dyspnea coping exercises included stationary biking, step training, and chair-to-stand exercises performed 2 times for 2 min at near max exercise intensity

  • T1: Baseline

  • T2: Postintervention

Wu et al37 CCT RCT Usual care
  • Intervention group: n = 40 (male), mean age = 66.5, prostate cancer

  • Control group: n = 20 (male), mean age = 66.7, prostate cancer

Executive function, memory
  • Home-based computer training program using BranHQ consisting of 5 cognitive exercises

  • 60 min of individual training, 5#x00A0;d/wk for 8 wk

  • T1: Baseline

  • T2: 4 wk

  • T3: Postintervention

McDougall et al38 CT Secondary analysis RCT Comparison
  • Intervention groupa: n = 8, mean age = 73.9, mixed cancer types

  • Control groupa: n = 14, mean age = 73.9, mixed cancer types

  • In-person group memory training classes covering memory and health, memory functions and mechanisms, factors affecting memory for people of all ages, memory beliefs and aging, and use of internal and external memory strategies

  • 20 h of classes over 12 classroom sessions for 12 mo

  • T1: Baseline

  • T2: 2 mo

  • T3: 6 mo

  • T4: 14-mo follow-up

Miki et al39 Aerobic exercise RCT No treatment
  • Intervention group: n = 38 (17 male, 21 female), mean age = 73, prostate cancer (n = 17) and breast cancer (n = 21)

  • Control group: n = 40 (18 male, 22 female), mean age = 75.5, prostate cancer (n = 18) and breast cancer (n = 22)

Executive function
  • In-person speed feedback therapy with a bicycle ergometer designed to improve cognitive functions

  • 60-min sessions, 1 d/wk for 4 wk

  • T1: Baseline

  • T2: Postintervention

Abbreviations: CCT, computerized cognitive training; CT, cognitive training; COPD, chronic obstructive pulmonary disease; RCT, randomized controlled trial.
aSex, cancer type, and mean age were not broken down for the secondary analysis for either intervention or control groups, but rather reported as part of the overall RCT population: female 59%, male 41%; prostate (n = 5), breast (n = 8), uterine (n = 2), lymphoma/leukemia (n = 1), throat (n = 1), lung (n = 1), and facial/basal cells on nose (n = 3).

Quality Assessment

Results from the quality assessment for the 4 studies included in this review are found in Supplemental Digital Content Table 3 (available at: Based on RoB 2, 75% of the studies were considered to have some concern for bias. The study conducted by Andersen et al36 was rated as high risk for bias due to the randomization process. Despite the concern for bias—all 4 studies were included in the review—all 3 reviewers determined that the inadequacies of the study details were not significant enough to disqualify them from the review process. All 4 studies included an extensive description of the intervention protocol and the method of randomization.

Nonpharmacologic Interventions

Andersen et al36 reported the effects of a 7-weeklong aerobic exercise intervention that was previously performed in adults with chronic obstructive pulmonary disease on quality of life and cognitive function in a group of older adults with lung cancer. Wu et al37 reported the feasibility, acceptability, and preliminary efficacy of an 8-week home-based computerized cognitive training program for treating CRCD in male patients with prostate cancer. McDougall et al38 described the effects of a cognitive-behavioral memory training intervention on memory self-efficacy, metamemory, memory performance, and instrumental activities of daily living performance in a group of mixed survivors of cancer. Miki et al39 reported the effect of a 4-weeklong aerobic cycling program on cognitive function in individuals with a history of breast or prostate cancer.

Cognitive Assessments and Outcomes

In terms of the evaluation, each study used different outcome measures, but all measures used were standardized and validated for the assessment of cognitive performance. Four cognitive domains were studied: executive function,37,39 attention,37 memory,37,38 and perceptual motor.37 In addition, Andersen et al36 and McDougall et al38 included a measure of global cognitive function. All studies reported baseline and postintervention data.

Three studies included follow-up data: Miki et al39 reported 4-week follow-up data, Wu et al37 reported 8-week follow-up data, and McDougall et al38 reported 14-month follow-up data. Comprehensive statistical results were reported in all 4 studies, including the means, standard deviations or range, and P values of the neuropsychological test scores,36–39 while McDougall et al38 and Wu et al37 reported effect size.

Executive function was measured across 2 studies.37,39 These studies used different measures of executive function: the Central Nervous System Vital Signs (CNSVS) assessment,37 the Frontal Systems Behavioral Scale,37 and the Frontal Assessment Battery.39 Both studies reported improvements in executive function; however, only those following the speed-feedback therapy intervention were significant.39

Wu et al37 measured complex attention using the CNSVS and reported significant improvements in reaction time following computerized cognitive training (effect size, d = 0.70). Other aspects of complex attention were measured in the study (processing speed and simple attention) but were not found to improve significantly.37

Memory was assessed by both Wu et al37 and McDougall et al38 via the CNSVS assessment, using the Hopkins Verbal Learning Test-Revised,38 the Brief Visuospatial Memory Test-Revised,38 the Rivermead Everyday Behavioral Memory Test,38 the Metamemory in Adulthood Questionnaire,38 and the Memory Self-Efficacy Questionnaire.38 Verbal memory was reported to improve in both studies. Visual memory had mixed results with improvement in one study38 and decline in the other.37 While a significant time-by-group improvement in verbal memory (effect size, d = 0.63) in the intervention group was reported by Wu et al,37 it should be noted that the usual care control group, also consisting of survivors of prostate cancer, improved their mean verbal memory scores to a greater extent compared with the intervention group.

McDougall et al38 reported a nonsignificant improvement in verbal memory in the intervention group and a significant time-by-group improvement in visual memory (effect size, η2 = 0.33). However, the noncancer control group's visual memory scores actually improved to a greater extent than that of the intervention group. McDougall et al38 reported improvements in everyday memory, metamemory, memory complaints, and memory self-efficacy for the intervention group. Of these, only memory self-efficacy (effect size, η2 = 0.23) and internal strategy use (effect size, η2 = 0.15), a subcomponent of metamemory, were significant between groups.

Wu et al measured perceptual-motor skills using the CNSVS assessment and reported an improvement in the intervention group; however, the improvement was not statistically significant.37

Wu et al37 and Andersen et al36 measured global cognition via the Patient Assessment of Own Functioning Inventory or the European Organization for Research and Treatment of Cancer Quality of Life of Cancer Patients Questionnaire (EORTC QLQ-C30). Although all reported improvements, the results were not significantly different between groups.


In young survivors of cancer and the older adult population, promising evidence exists describing the effects of nonpharmacologic interventions on improved cognition including memory, executive function, language, and complex attention.17,19,20–23,29–35 However, despite positive outcomes from the studies within this systematic review, an unequivocal recommendation supporting the interventions could not be made due to heterogeneity of the populations, variable methods and outcome measures, and differences in intervention parameters and targeted cognitive functions.

Two studies applied an exercise intervention,36,39 and the remaining 2 used a form of cognitive training.37,38 Exercise parameters varied widely across interventions in duration, intensity, and dosage. The exercise interventions ranged in duration from 4 to 7 weeks, and individual sessions were not consistent in mode and intensity across studies. Between the 2 studies using exercise, 2 cognitive domains were assessed: global cognition and executive function. Significant improvements reported were in executive function following speed feedback therapy via bicycle ergometry.39 Although gains in executive function were reported, the dosage for the intervention was low compared with previous studies measuring the effects of physical activity on cognition in younger adults (<65 years) with a history of breast cancer. In both the older adult population and in younger survivors of cancer, the lowest dose duration of a physical exercise intervention resulting in improved cognition was at least 30 minutes of physical activity per session, which is 6 times higher than the dosage used in the study employing speed feedback therapy via bicycle ergometry. In addition, the outcomes of an aerobic exercise program on CRCD in the young cancer population translated into improved executive function,31 which was not congruent with the extent of improved executive functions as a result of bicycle ergometry. However, the measures employed differed, which makes it difficult to compare the extent of improvement between studies. Future studies should include a measure of executive function when assessing the effect of aerobic exercise on CRCD in older adults.

The 2 studies that included a cognitive training intervention also varied in dosage and frequency.37,38 The intervention duration spanned from 8 weeks to 12 months, while the frequency of training sessions varied from 1 time per week of memory training to 5 times per week of computerized cognitive training. Although these 2 studies that included older adults with a history of cancer had different dosages of cognitive training, this is not unlike the variability in cognitive training interventions used in older adult noncancer populations.

Five cognitive domains were assessed across the 2 studies: global cognition, memory, complex attention, perceptual-motor, and executive function.37,38 The significant between-group improvements observed were in complex attention (reaction time) as a result of completing a computerized cognitive training program37 and memory (memory self-efficacy and internal memory strategy use) following a memory training program.38 Memory self-efficacy and internal memory strategy use were both measured via self-report following a group memory training intervention. Therefore, the risk for potential bias in both the results and intervention exists.

Various cognitive domains were assessed across the 4 studies, with memory being the cognitive domain most frequently assessed; however, wide variations existed between outcome measures employed. Wu et al37 used CNSVS, an objective outcome measure, while McDougall et al38 assessed memory via a combination of 5 outcome measures, including objective and subjective methods. Executive function was the next most frequently measured domain and was assessed via multiple outcomes, though in contrast to memory, each outcome was objective. Two out of 4 studies included a measure of global cognition.36,37 Neither of the 2 studies measuring global cognition broke impairments down by specific cognitive domain but rather reported results generally as cognitive impairment or cognitive function. The variability of the tools used to assess CRCD in the included studies highlights the need to identify and then use a valid standardized measure of CRCD in older adults.


The limitations of this systematic review include the possibility for publication bias resulting in the exclusion of other relevant studies. Despite 4 databases being searched, gray literature was not included, nor were any studies published in languages other than English, which increased the possibility of missing qualified studies. The memory training study38 was not originally designed for survivors of cancer and was performed as a secondary analysis. Although none of the included studies used it as an intervention, meditation has shown promising effects on cognitive function in younger survivors of cancer, particularly in memory and processing speed.19 Future studies may wish to consider employing meditation as a possible intervention for CRCD in older adults.


Notwithstanding the paucity of studies, this review described the effectiveness of nonpharmacologic interventions on CRCD in older adults with a history of cancer. We suggest that studies of aerobic exercise and cognitive training interventions be considered for older adults with CRCD, as promising evidence has been shown in both young survivors of cancer and older adults without cancer.17,20,22–24,29–34 Future studies are needed to implement a larger sample size, use standardized neuropsychological assessments to ensure methodological homogeneity, and include follow-up data to identify if cognitive improvements are retained long-term. Lastly, given the prevalence of CRCD in adults with a history of cancer, greater attention should be made to assessing and employing interventions that improve both cognitive function and physical health to aid in wellness and recovery post-cancer.


The authors would like to acknowledge Kateri Rybicki for her contributions to the review of the literature and data extraction and the University of Michigan-Flint for financial support.


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cognitive dysfunction; neoplasms; older adults

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