Chemotherapy‐induced cognitive impairment in breast cancer survivors: A systematic review of studies from 2000 to 2021

Abstract Background Studies have indicated that apart from enhancing patient survival, chemotherapy has adverse side effects on the psychological, social, and cognitive functions of breast cancer survivors. Aims This study was conducted to understand chemotherapy's impact on breast cancer survivors' cognitive functions. Methods and Results Our study is a systematic review based on the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement. We searched English databases, including PubMed/MEDLINE, PsycINFO, and Web of Science, and Persian databases, such as Irandoc and Elmnet, using Persian keywords of cancer, breast cancer, chemotherapy, cognitive functions, executive functions, and neuropsychological functions. Two reviewers independently evaluated the full text of the articles according to predefined criteria. Among the 937 available studies, 26 were selected based on the inclusion and exclusion criteria, of which 17 (65%) were longitudinal and 9 (35%) were cross‐sectional. The findings indicated a significant relationship between the use of chemotherapy and cognitive impairments, most notably attention, working and short‐term memory, and executive functions. However, the studies differed in their findings regarding the long‐term persistence of cancer‐related cognitive impairment (CRCI), which could be due to the wide range of tools used, different methods to measure cognitive functions, and the difference in the sample size of the studies. Conclusion Chemotherapy, affecting cortical and subcortical brain structures, causes a set of cognitive impairments that can lead to impairments in social responsibility acceptance, daily functioning, and quality of life of women. Therefore, rigorous and extensive research design is required to understand the causes and consequences of CRCI using standardized and sensitive measures of cognitive functions. Specifically, studies comparing the effects of different chemotherapy regimens on cognition and potential mechanisms and/or moderators of CRCI would be instrumental in designing more effective therapy regimens and evaluating the efficacy and cost‐effectiveness of cognitive rehabilitation and supportive care programs.

potential mechanisms and/or moderators of CRCI would be instrumental in designing more effective therapy regimens and evaluating the efficacy and cost-effectiveness of cognitive rehabilitation and supportive care programs.

K E Y W O R D S
breast cancer, chemotherapy, cognitive function, systematic review, women

| INTRODUCTION
Breast cancer is a major health concern for women, as it is the most prevalent type of cancer and the second leading cause of death among them. 1,2In Iran, the age-standardized incidence rate of breast cancer escalated from 18.8 per 100 000 in 1990 to 34.0 per 100 000 in 2019 among females and from 0.2 to 0.3 per 100 000 among males. 3Advancements in oncology, surgery, and treatments such as radiotherapy, chemotherapy, and hormone therapy have significantly improved the survival rate of breast cancer patients, with over 90% surviving for 5 years. 4,5Nonetheless, these treatments, especially chemotherapy, have adverse effects on various aspects of the well-being of breast cancer survivors. 6e of the most common and debilitating effects is cancerrelated cognitive impairment (CRCI), [7][8][9] which affects attention, memory, concentration, learning ability, processing speed, language, and executive functions. 10CRCI is a term that encompasses the cognitive changes that may occur during or after cancer diagnosis and treatment.In the past, this phenomenon was sometimes referred to as chemo brain or chemo fog, 11 as it was first observed among women with breast cancer undergoing chemotherapy in the 1980s. 12Currently, using these terms is not recommended as they may create an expectation of negative outcomes, potentially influencing patients' treatment decisions. 13Moreover, these terms are inaccurate, as they imply that only chemotherapy affects cognitive functions, while evidence suggests that other factors may also contribute to CRCI. 14,15though CRCI is a vast field that encompasses a wide range of cognitive impairment experienced by cancer survivors, regardless of treatment, 16 the present review will specifically concentrate on the cognitive impairments that occur as a result of chemotherapy.
The prevalence, duration, and severity of CRCI vary widely across studies.Some studies report that 15% to 50% of breast cancer survivors experience CRCI, 17 while others estimate that more than 75% of them suffer from it. 18Moreover, some studies suggest that CRCI is transient and resolves within a year after completing chemotherapy, 19 but others indicate that it persists for years after diagnosis, 20 impairing the quality of life of women. 218][29][30] Moreover, the exact causes and mechanisms of CRCI are still unclear, 31 but several factors have been proposed to explain how cancer and specifically chemotherapy affect cognitive functions.These include increased gray matter atrophy, metabolic disorders, vascular injuries, 32,33 and accelerated aging processes. 34ven the importance of cognitive functions for daily functioning in breast cancer survivors and the contradictions in the literature about their cognitive impairments, a systematic review is needed to provide reliable information for clinical decision-making.Several systematic reviews and meta-analyses have been conducted to summarize the existing evidence on the effects of chemotherapy on the cognitive functions of breast cancer survivors.However, these reviews have some limitations that warrant an updated and comprehensive review.For example, some reviews are outdated and do not include recent studies that have used more advanced methods and tools to assess cognitive functions. 35,36Some meta-analyses have shown conflicting results regarding the impact of chemotherapy for breast cancer on cognitive function.While some studies have reported significant and widespread cognitive deficits across multiple domains, one meta-analysis found minor deficits. 36[37][38] Therefore, this systematic review aims to provide a comprehensive and up-to-date synthesis of the evidence on the specific effects of chemotherapy on the cognitive functions of breast cancer survivors.It will address the following research questions 1 : which domains or aspects of cognitive functions are most affected by chemotherapy? 2 how long does CRCI last after completing chemotherapy?and 3 what is the longterm effect of using chemotherapy on cognitive functions?Furthermore, our systematic review will serve as a pivotal point of reference, prompting increased attention and concerted efforts from researchers and healthcare professionals to develop and implement interventions, thereby alleviating the challenges associated with CRCI.This encompasses refining clinical practice, fostering multidisciplinary collaboration, enhancing patient support, and encouraging further research to optimize patient care.

| Inclusion/exclusion criteria
We used the Population, Intervention, Comparison, Outcome, Study design (PICOS) framework 39 to define the inclusion criteria for our systematic review.We included studies that met the following criteria:

| Search strategy and data sources
Our study, conducted between December 2021 and January 2022, focused on studies published in English and Persian on the cognitive functions of women treated for breast cancer.We carried out a literature search of the English studies available in the PubMed/MEDLINE, PsycINFO, and Web of Science databases during 2000-2021 with the keywords of "breast cancer", "breast malignancy", and "chemotherapy" in combination with "cognitive" or "cognition"; "executive function"; "neuropsychological"; along with "dysfunction"; "complaints" using search operators and/or.We also searched for papers published in Persian journals with the Persian keywords of "cancer", "breast cancer", "chemotherapy", "cognitive functions", "executive functions", and "neuropsychological functions" using search operators or/and without any time constraints up to 2021.The supplementary file provides more details about the search strategies we used (Appendix S2).

| Selection and data collection process
We utilized a two-stage screening process to ensure a rigorous and unbiased selection of studies.At first, two researchers independently assessed the titles and abstracts of the articles.This step was crucial for quickly identifying studies that potentially met our inclusion criteria while excluding irrelevant ones.Afterward, the same researchers conducted a detailed examination of the full texts of the articles that passed the initial screening.This comprehensive review was based on our predefined inclusion and exclusion criteria.Disagreements between researchers at this stage were resolved through discussion or, if necessary, consultation with a third researcher.

| Quality assessment
We employed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement's 22-item checklist to evaluate the quality of the studies.Previous research has suggested that observational studies published in high-quality journals have an average of 69% of the STROBE items.Therefore, we set a cut-off score of 15 (69%) for inclusion and exclusion criteria. 41,42This rigorous assessment ensured that only studies with a high methodological standard were included in our review.

| Data extraction and synthesis
Data extraction was conducted systematically, with information on author, year of publication, sample characteristics, study design, number of participants, control group characteristics, measurement tools, and types of cognitive impairment being collated.The PICOS tool was utilized for this purpose.For the synthesis of results, we applied a narrative synthesis method.This approach allowed us to comprehensively analyze and compare the findings across the included studies, providing a nuanced understanding of the impact of chemotherapy on cognitive functions in breast cancer survivors.

| Classification of cognitive domains
In order to systematically assess and present the cognitive functions affected by chemotherapy in breast cancer survivors, we adopted a comprehensive classification system for cognitive domains.This classification was based on widely recognized cognitive frameworks and was tailored to the specific context of CRCI.The cognitive domains we focused on included: (i) overall cognitive functions; (ii) executive functions; (iii) attention; (iv) memory; and (v) language functions.Each study included in our review was analyzed based on these cognitive domains.The classification allowed for a structured and comprehensive synthesis of the effects of chemotherapy on cognitive functions, facilitating a clearer understanding of the specific cognitive areas impacted.

| Identification and selection of articles
Our comprehensive search across electronic databases yielded 937 articles (934 in English and 3 in Persian), initially meeting the PRISMA checklist criteria.We then screened all the articles and excluded 732 studies that did not match the topic of this systematic review, and 96 duplicate studies.In conclusion, 109 studies entered the second screening.Then, we screened all selected papers by the exclusion criteria in terms of the relevance of the abstract to the topic of our study, research design, participants, the treatment used, and the quality of the article.At this stage, we discarded 72 articles due to participant and treatment type issues, and 11 studies for not meeting the minimum criteria related to the PRISMA checklist.Finally, we included 26 studies published from 2004 to 2019 in this systematic review.Figure 1 illustrates the study selection process.

| Characteristics of the included studies
Of the 26 selected studies, 17 (65%) were longitudinal, and 9 (35%) were cross-sectional.Among the longitudinal studies, 10 (38%) evaluated the impact of chemotherapy on cognitive functions at three distinct time points: before treatment, after treatment initiation, and during follow-up (ranging from one to 6 months).The combined sample size of the included studies was 1629 female breast cancer survivors.The sample sizes ranged from 17 43 to 196 20 participants, with participant ages spanning from 44.07 44 to 72.00 22 years.The average age was 52.98 years (SD = 7.27).Post-chemotherapy treatment duration varied from 1 month 45 to 21 years, 20 with an average duration of 3.90 years.The studies comprised 19 (73%) with control groups and 7 (27%) without.The control group in 16 studies (61%) included healthy women, in 6 studies (23%) included women with breast cancer treated by other methods, and in 4 studies (16%) included women with breast cancer undergoing other treatment methods.Table 1 details the characteristics and results of each study.

| Cognitive function domains
The effects of chemotherapy on various cognitive dimensions were explored across the selected studies.These studies employed various outcome measures to evaluate specific cognitive domains.Table 2 F I G U R E 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart to illustrate the study search and inclusion process.
T A B L E 1 Description of the studies included in this systematic review on chemotherapy's impact on breast cancer survivors' cognitive functions.summarizes these outcome measures, categorizing them according to the cognitive dimensions they assess.

| Chemotherapy and overall cognitive functions
A total of eight studies investigated the index of cognitive functions using the Mini-Mental State Examination (MMSE), the Cognitive Fusion Questionnaire (CFQ), the self-report measures of cognitive functioning, and the self-report cognitive difficulties scale (see Table 1).The results indicated that chemotherapy is associated with a reduction in overall cognitive function scores in breast cancer survivors post-treatment. 22,46-52

| Chemotherapy and executive functions
Executive functions refer to higher-order cognitive processes that underlie flexible goal-directed behavior, such as planning and problem-solving. 44,53The evaluation of executive functions was conducted across 17 studies 21,22,24,28,43,44,[46][47][48][49][54][55][56][57][58][59][60] 1). In a sudy, the executive functions of 60 women who have survived breast cancer were measured at 1, 6, and 18 months after the end of the treatment period.The results showed that the executive function problems started in parallel at the end of the treatment period and persisted at the subsequent follow-ups.24

| Chemotherapy and attention
The ability to select and examine a particular aspect of the environment and ignore other aspects is defined as attention, which is considered a crucial factor in memory. 61In the studies, we reviewed, attention was mainly measured using the color-interference Stroop task and Cognitive Symptoms Checklist (CSC).Deficits in attention and simultaneously memory problems have been patients' most prevalent cognitive problems during chemotherapy, and 12 studies confirmed this finding 20,22,[50][51][52][54][55][56][57][58]62,63 (see Table 1).

| Chemotherapy and memory
The cognitive ability to store and utilize information, known as memory, is a multifaceted phenomenon that manifests in various forms, such as working memory, short-term memory, and verbal memory. 61showed that chemotherapy use is related to the memory problems of people who have experienced cancer.In this way, working memory dysfunction [20][21][22]24,28,50,51,56,58,60,[62][63][64]66 is the most reported problem, followed by short-term memory 20,43,55,62 and verbal memory, 24,48,50,54 in four studies, visuospatial memory 24,45,59 in three studies, and past and prospective memory, 57 respectively, included the most studies (see Table 1).
(2017), 44 Menning et al. (2017), 47 Mihuta et al. (2016), 57 Nguyen et al. (2013), 22  In the first section of our results, the reviewed studies indicated a potential connection between chemotherapy and cognitive impairments.The observed impairments span various cognitive domains, such as overall cognitive function, executive functions, retrospective and prospective memory, language functions (including verbal learning and fluency), visual-spatial perception, and processing speeds.Thus, chemotherapy appears to be a potential predictor of these cognitive impairments.The basis for these cognitive deficits may lie in structural changes in the brains of those undergoing chemotherapy. 9,27,59Chemotherapy can potentially affect brain regions like the left anterior cingulate, middle frontal gyrus, precuneus, bilateral insula, and left middle frontal gyrus. 30wever, assessing long-term cognitive impairment necessitates long-term follow-up, a challenge evident in the reviewed longitudinal studies.While certain studies 20,22,50,57,67 suggest persistent cognitive deficits years after treatment, others 46,51,54,63 indicate these might be transient.For example, one study of 166 breast cancer survivors who had completed chemotherapy an average of 20 years ago found that most performed poorly on memory and attention tests. 50However, another study reported that cognitive impairments were more severe after treatment but showed a decrease in severity during follow-up assessments. 51Similarly, another study found that more than 80% of the survivors reported attention deficits shortly after starting chemotherapy, but these problems reduced in severity after 1 year. 63 exploring the factors contributing to cognitive impairments in breast cancer survivors, our review highlights the complexity of attributing these impairments solely to chemotherapy.Some early studies attributed the cognitive changes to aging and noted that older subjects were more affected by chemotherapy.However, later studies controlled for age and found persistent cognitive impairments even 10 years after the treatment. 22Some studies also suggested that different types of chemotherapy and drugs had different effects on cognitive functions, but others did not find a significant correlation between the type of chemotherapy agent (such as taxane, anthracycline, 5-fluorouracil, cyclophosphamide, and methotrexate) and the risk of dementia. 68Also, initial explanations considered the cause of the disease and type of cancer as the reason for cognitive impairments, but subsequent studies observed no significant correlation between them. 12One study compared verbal fluency among three groups: those treated with high-dose chemotherapy, those treated with medium-dose chemotherapy, and healthy peers.After controlling intervening variables such as age, education, intelligence scores, use of tamoxifen, and the last time of treatment (peer-to-peer method), the results suggested that verbal fluency could be affected by chemotherapy and that the high-dose group performed worse than the other two groups. 56Another study controlled for education, ethnicity, and menstrual factors and found that breast cancer survivors who underwent chemotherapy reported more verbal impairments than healthy women and breast cancer survivors who did not receive chemotherapy.
In light of these findings, it appears that chemotherapy may be linked to cognitive impairments, but there is no definitive evidence that it is the exclusive or primary cause.Our review of three studies with adequate methodology, sample size, and control of confounding variables found that 94%, 86%, and 61% of their participants, respectively, had cognitive impairments after chemotherapy. 49,58,66These impairments affected more than half of the survivors and had a significant impact on their daily functioning.Many of them reported difficulties in performing simple tasks such as cooking, keeping track, paying bills, and finishing them on time.They also experienced deficits in their cognitive abilities, such as memory, multitasking, calculation, and language, which could lead to anxiety, depression, fatigue, and poor quality of life.
The variability in study methodologies, including the range of cognitive function measurement tools and differences in sample sizes, contributes to the challenge of drawing definitive conclusions.The sample sizes in the reviewed studies varied from 16 to 196 participants, and control groups ranged from women with no history of breast cancer to those treated with alternative methods.
Thus, the current evidence suggests a complex interplay of factors influencing cognitive function post-chemotherapy without providing definitive conclusions about the long-term effects of chemotherapy alone.
Our study's limitations include the limited number of languages, the absence of a meta-analysis, and the lack of protocol registration.
The decision to forego a meta-analysis was based on several key considerations.First, the included studies exhibit a wide range of designs, methodologies, and statistical analyses, introducing significant heterogeneity and potentially undermining the validity of any pooled estimates.Second, the cognitive assessment tools used in the studies varied, each with its psychometric properties and scales, making it challenging to generate comparable effect sizes.Third, the studies have widely varying sample sizes and age demographics, contributing to heterogeneity and potential bias.Fourth, the comparison groups across studies varied, some comparing against healthy peers and others against breast cancer survivors who did not receive chemotherapy, leading to potential confounding.Fifth, the timing of cognitive assessments relative to chemotherapy treatment varied greatly among studies, affecting the understanding of cognitive trajectory post-treatment.Given these challenges, we opted for a narrative synthesis to provide a more nuanced understanding of the evidence regarding chemotherapy's impact on cognitive functions in breast cancer survivors.
Despite these limitations, our study's strength lies in its comprehensive examination of cognitive impairments.We recommend future research to investigate the psychological and psychosocial impacts of these impairments.Clinicians and healthcare professionals must pay more attention to CRCI and develop cognitive rehabilitation programs to address these challenges.and pursue more research on its causes, evaluation, treatment, and prevention. 15By doing so, we can improve the diagnosis and management of CRCI and provide better support and care for this population.

| CONCLUSION
(i) population: women treated for breast cancer; (ii) intervention: studies focusing on the effects of chemotherapy on cognitive functions; (iii) comparator: not restricted; (iv) outcome: cognitive function assessments in breast cancer survivors; and (v) study design: descriptive research, case reports, and cohort studies.The additional inclusion criteria were (i) studies published in both Persian and English languages; (ii) fulltext article accessibility; and (iii) studies published from 2000 to 2021.This time range was chosen considering the significant advances in chemotherapy and cognitive assessment methods over the past two decades, which might have influenced the results of the studies.Consequently, older studies that might not reflect current knowledge and practice were excluded.The exclusion criteria are as follows: (i) studies on non-human subjects; (ii) studies based on experimental and interventional methods; (iii) review and meta-analysis studies; (iv) articles published in conferences and conventions; (v) articles with no accessible full text; and (vi) studies with serious methodological weaknesses or not meeting minimum qualitative criteria based on the PRISMA checklist.