Chemotherapy-Related Cognitive Dysfunction in Breast Cancer Survivors: A Systematic Review

Objectives: The major aims of this integrative review were to identify: 1) specific cognitive domains affected by chemotherapy; 2) predictors of cognitive dysfunction related to chemotherapy; 3) reported underlying mechanisms of chemotherapy-related cognitive dysfunction, and 4) clinical and research implications of chemotherapy-related cognitive dysfunction (CRCD) among breast cancer survivors. Methods: A computerized search of published research articles through the health journal databases of PubMed, CINAHL, EMBASE, and Web of Science was performed by using the keywords "chemotherapy," "cognitive dysfunction," "cognitive impairment," "cognitive decline," "breast cancer," and "breast carcinoma." References were screened according to inclusion and exclusion criteria. Results: After screening the titles and abstracts of 639 articles, 20 research studies were identified that focused on chemotherapy-related cognitive dysfunction in breast cancer for the final analysis. The 20 studies included: one longitudinal study, eleven prospective studies, two casecontrol studies, two retrospective studies, and four cross-sectional studies. The analysis of these 20 research studies contributed new knowledge about cognitive domains being affected by chemotherapy, risk factors for CRCD and underlying mechanisms of CRCD. Conclusion: This systematic review indicates significant clinical implications of early assessment and early interventions for CRCD to assist breast cancer survivors.


Introduction
Breast cancer is one of the leading cancer among women in the United States, with an estimated 276,480 cases of invasive breast cancer (BC) and 48,530 cases of non-invasive BC diagnosed in 2020 alone [1]. Chemotherapy is used to destroy and eliminate cancer cells for early-stage invasive and latestage BC [2]. Early screening and treatment for BC have improved the prognosis for breast cancer survivors (BCSs) compared to other cancers, resulting in an increased 5-year survival rate of 91%, a 10-year survival rate of 84%, and a 15 years survival rate of 80% [3]. Although chemotherapy treatment increases survival rates, chemotherapy often results in "chemotherapy-related cognitive dysfunction" (CRCD) or cognitive impairment that significantly affects breast cancer survivors' quality of life (QOL) [4].
According to the International Cognition and Cancer Task Force (ICCTF), 13%-70% of cancer patients are affected by CRCD [5]. Cognitive impairment, often described by BCSs' as "chemo-brain," varies from 20% to 90%, beginning when chemotherapy is initiated and persisting up to 10 years after treatment [6][7][8][9]. Current evidence and data indicate that changes in cognitive functions, such as 1) memory; 2) executive function; 3) processing speed; 4) visual, spatial, and constructional ability; 5) attention and concentration; 6) reaction time; and 7) motor speed and dexterity, as measured by standardized neuropsychological tests, are associated with adjuvant chemotherapy treatment [7,8,[10][11][12]. Breast cancer survivors may suffer from CRCD or chemo-brain during or after chemotherapy [13,14]. Although evidence shows an association between cognitive dysfunction and chemotherapy among BCSs, research gaps remain in this area. Specifically, there is a gap in evidence related to the relationship between (1) CRCD and the cognitive domains that have been affected [15]; (2) CRCD and predictors such as patient age, stage of breast cancer, and chemotherapy agents [16][17][18], pre-existing depression and anxiety [19]; and (3) CRCD and underlying mechanisms [20].
The overall goal of this systematic review is to identify evidence related to the impact of chemotherapy on cognitive dysfunction among BCSs through a comprehensive review of the recent ten years of published clinical research studies. This review also addresses research gaps identified above and discusses clinical and research implications of chemotherapy-related cognitive dysfunction for BCSs.

Search Strategy
The search was limited to current research studies published within the past ten years from January 2009 to January 2020. The systematic search was conducted in the health journal databases of PubMed/MEDLINE, CINAHL, EMBASE, and Web of Science. The search included specified Medical Subject Headings (MeSH) terms and keywords related to chemotherapy-related cognitive dysfunction in breast cancer survivors. MeSH terms utilized were "chemotherapy", "drug therapy", "cognitive dysfunction", "cognitive impairment", "cognitive decline", "breast cancer", "breast carcinoma", and "breast tumors". All publications were screened to retrieve the abstracts and fulltext articles by using the selection criteria. The search strategy used for the database PubMed/MEDLINE (Table 1) was also used for the other electronic health journal databases described above. Additional related published articles were identified by reviewing the reference lists from eligible full-text articles.

Study Selection
EndNote X9 was used as the reference management software package to manage all the research study citations. Screening study titles and abstracts were followed as the next step for potential articles and then reviewing full-text articles to decide if the article met the inclusion criteria. Inclusion criteria included: 1) research focused on the relationship between chemotherapy and cognitive dysfunction in BCSs who exposed to chemotherapy with any stage of cancer; 2) original publications; 3) publications in peer-reviewed journals; 4) publications in English; and 5) publications published between January 2009 to January 2020. Exclusion criteria included: 1) non-research articles; 2) not published in English; 3) research not focused on the relationship between chemotherapy and cognitive dysfunction in BCS; and 3) research focused on CRCD in breast cancer published before January 1, 2009. Study designs qualified for inclusion were randomized controlled trials (RCTs), longitudinal studies, cohort studies (prospective observational studies), cross-sectional studies, case-control studies, and retrospective analytical studies. The entire study population was restricted to breast cancer women who initiated, were in the process, or had finished chemotherapy. Studies included research conducted in US and other countries if published in English. Studies were not eliminated if they met the inclusion criteria. Studies were eliminated if they met the exclusion criteria. Two authors reviewed the chosen articles. When there was a conflict, they would go back to the original article and double-check to make sure it meets all the inclusion criteria.
After applying the inclusion and exclusion criteria to the titles and abstracts of the initial search, 35 articles met the inclusion criteria. Full-text PDF were obtained for all the articles and were reviewed carefully by the authors. After a review of articles for inclusion, 20 articles were included. The remaining 15 articles were eliminated because they did not meet all the inclusion criteria. A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) flowchart is presented in Figure 1 in this paper to show the selection process.

Data Extraction
A literature review table was implemented to extract data identifying the first author, year published, study design, study setting, research intervention, sample characteristics, outcome measures, and findings (see Table 2).   Figure 1 illustrates the process of study identification and screening. A total of 816 articles were identified through the four health journal databases searches of PubMed, CINAHL, EMBASE, and Web of Science. After duplicate articles were removed, 638 titles and abstracts were screened. After removing 604 abstracts not meeting inclusion criteria, 35 articles resulted. After a full-text review, 15 articles were eliminated, leaving 20 articles qualified for inclusion for the synthesis of literature. Descriptions and findings from the included research articles are depicted in Table 2. Table 2 summarizes the methodologic quality evaluation used in this systematic review paper. The Effective Public Health Practice Project (EPHPP) was used to evaluate the study quality of the included research articles [21]. By using EPHPP criteria of high, moderate, and weak global quality ratings, all the studies received moderate global quality ratings [13,[15][16][17][18][19][20][22][23][24][25][26][27][28][29][30][31][32][33][34]. No study received a weak global quality rating based on the EPHPP assessment tool [35]. The overall quality rating for the 20 reviewed articles was moderate.

Study Designs
Study designs used in the 20 sources included: one longitudinal study, eleven prospective studies, two casecontrol studies, two retrospective studies, and four crosssectional studies. One longitudinal study explored the longitudinal changes in the brain white matter integrity after chemotherapy and cognitive functioning [33]. Among the eleven prospective studies, ten studies evaluated patient's cognitive function changes by comparing baseline data before chemotherapy to find associations between chemotherapy and cognitive impairment [15,16,19,22,24,25,[27][28][29][30]. One of the eleven studies compared patients' cognitive function before and after standard chemotherapy that combined fluorouracil, epirubicin, and cyclophosphamide (FEC) with or without taxanes to identify the taxanes' role in CRCD [23]. Two case-control studies investigated the functional brain network changes of patient-perceived cognitive dysfunction after standard adjuvant chemotherapy [13,26]. One retrospective study compared anthracycline-based and non-anthracycline-based chemotherapy to identify anthracycline regimens' neurotoxic effect in particular cognitive domains and brain network connections [17]. One retrospective study evaluated the longterm cognitive implications of chemotherapy among BCSs over 65 years old who received chemotherapy a decade ago [18]. Two cross-sectional studies investigated the brain's functional connectivity alteration after chemotherapy [20,31]. One cross-sectional study investigated the chemotherapyinduced inflammation caused reduced hippocampal volume, which could be the basis for cognitive impairment [34]. One cross-sectional study explored the relationship between cytokine genetic variations and fatigue and cognitive decline [32].

Study Participant Characteristics
The number of study participants in each study ranged from 28 to 418 BCSs with a total of 1601 BCSs and 285 healthy controls. All the participants were 18 years and older, with a mean age around 50 years old, with most BCSs ranging from 18 years to 70 years of age [23]. The majority patient population had early-stage breast cancer and exposure to chemotherapy. Most of the studies included BCSs before, during, and after their chemotherapy, with a chemotherapy period ranging from seven days to more than ten years after chemotherapy treatment. A total of 618 BCSs were from the US, and 983 BCSs were from other countries. BCSs with pre-existing psychotic disorders, brain injury, or any neurological disorders were excluded from the subsequent clinical studies [17,18,22,23].

Specific Cognitive Domains Affected by Chemotherapy
This review identified the specific cognitive domains affected by chemotherapy among BCSs: learning and memory, processing speed and executive function, concentration and attention, and verbal fluency [15,28,36]. Memory, attention, and executive function were particularly vulnerable to change due to chemotherapy [16]. By comparing with healthy controls, Miao et al. (2016) reported that chemotherapy could cause functional disconnection in the medial temporal lobe (MTL) of BCS, which is associated Cancer Survivors: A Systematic Review with attention function [20]. Tao et al. (2016) found that chemotherapy-induced lower brain functional connectivity may lead to executive function impairment in BCS [31]. Yamada et al. (2010) conducted a retrospective study to explore the long-term cognitive implications of BCSs exposed to chemotherapy more than ten years ago. They found BCSs had lower scores which reached a significant level in the cognitive domains of working memory, divided attention, and executive functioning by comparing with noncancer healthy controls [9]. Research results showed chemotherapy has a particular adverse effect on a patient's verbal fluency and verbal memory [30]. A significant decline in the cognitive function subdomain of attention is reported after chemotherapy [22]. Significantly decreased short-term visual attention, memory, and executive functioning after chemotherapy are reported [23]. Overall, more than one cognitive domain may be affected by chemotherapy and, memory, attention, and executive functioning were affected most frequently.

Predictors of Chemotherapy-Induced Cognitive Dysfunction
This review identified specific predictors related to chemotherapy-related cognitive dysfunction. Along with chemotherapy, many other confounders such as anxiety and depression can contribute to patient-perceived cognitive dysfunction. Long-term symptoms of depression and anxiety are prevalent among BCSs [37]. Cognitive tests may be affected by high anxiety levels due to decreased attentional control [38]. Cancer-related post-traumatic stress also may impact cognitive functioning [39]. Klemp et al. (2018) explored specific predictors (patient's age, estradiol level, symptoms of depression, fatigue, neuropathy, body mass index, and exercise) of cognitive chemotherapy changes in BCSs. Results showed that symptoms of depression and fatigue were significantly increased between baseline (T1) and within 14-21 days of completing adjuvant chemotherapy (T3) with a return to baseline at eight years after chemotherapy (T4). Symptoms of depression and fatigue were identified as potential covariates of patient-perceived cognitive dysfunction. A significant relationship between body mass index (BMI) and patient-perceived cognitive dysfunction was found to be moderated by frequency of exercise [15]. Symptoms of anxiety, fatigue, depression, and distress were associated with worse physical and social cognitive functioning after chemotherapy [22,25]. Ahles et al. (2010) found that age and pretreatment cognitive reserve are essential predictors of CRCD in the processing speed domain. The cognitive reserve decides innate and developed cognitive capacity and is defined as 3 rd edition reading scores of Wide Range Achievement Test [28]. In total, pre-existing psychosocial issues such as anxiety, depression, fatigue, and emotional distress increase the chance of CRCD among BCSs. Older age and low pretreatment cognitive reserve are also predictors of CRCD. Jung et al. (2017) found that breast cancer stage was not associated with any cognitive status changes among women with early-stage localized breast cancer [24].
There was no association between patient-perceived cognitive dysfunction and objective cognitive decline [22,40]. Biglia et al. (2012) runed a prospective study in breast cancer patients undergoing chemotherapy to explore if cognitive function changes can be recognized. They found that objective cognitive decline resulted independent of the patient's emotional status. Patient self-perceived cognitive dysfunction was found not to correlate with objective neuropsychological tests during the cognitive assessment [22].  conducted a mechanical cohort study implementing comprehensive neuropsychological tests to characterize cognitive function while also exploring potential factors that may cause patient-perceived cognitive dysfunction by using laboratory and functional magnetic resonance imaging (fMRI) studies. Patient-perceived cognitive dysfunction was assessed by the questionnaire of Functional Assessment of Cancer Therapy-Cognition version 2 (FACT-Cog) and the Patient's Assessment of Own Functioning Inventory (PAFI). Objective neuropsychological tests include the Cambridge Neuropsychological Tests Automated Battery (CANTAB), the moderated Six Elements Tests (SET), and clinical neuropsychological tests. They found no association between patient-perceived cognitive dysfunction and objective neuropsychological scores [40].
Breast cancer patients often are treated with different chemotherapy regimens, and some chemotherapy regimens have a higher risk of causing CRCD. BCSs treated with doxorubicin plus cyclophosphamide with or without docetaxel had a four times higher risk of developing cognitive impairment than patients without chemotherapy [27]. Breast cancer patients treated with a regimen of fluorouracil, epirubicin, and cyclophosphamide (FEC) are reported to have altered cognitive functioning. BCS's cognitive performance was worse at the end of the cycles when treated with FEC plus taxane [23]. Kesler et al., 2016 conducted a cross-sectional study to compare anthracyclinebased versus non-anthracycline-based chemotherapy effects on cognition changes in BCSs. Patients who received anthracycline-based chemotherapy had lower memory scores on an average two years after treatment compared to those who underwent non-anthracycline chemotherapy regimens or no chemotherapy [17]. CRCD is closely related to specific chemotherapy agents such as FEC, taxanes, and anthracyclines.

Underlying Mechanisms of Chemotherapy-Induced Cognitive Dysfunction
The underlying mechanisms of CRCD are very complicated, but chemotherapy's direct or indirect effects on brain structure and brain network functional connectivity may work as the major mechanism of CRCD. After chemotherapy, the structural and functional brain changes may lead to CRCD, especially the executive function impairment caused by the functional changes in the prefrontal cortex [31]. Chemotherapy-induced inflammation may contribute to hippocampal changes, which could be the underlying of CRCD [34]. Chemotherapy decreased gray matter in the bilateral frontal area, temporal, thalamic, cerebellar, and cingulate regions resulting in CRCD [41]. Chemotherapy may also cause alterations in white matter in the brain in the long term with reductions in the brain structural volume [33,42]. Askren et al. (2014) found that the frontoparietal executive network is particularly vulnerable in breast cancer patients affecting patient spatial learning function [43].
Research found that the functional disconnection in the medial temporal lobe (MTL) subsystem of the default mode network (DMN) may have an associated relationship with the attention function of BCSs after chemotherapy by using resting-state functional magnetic resonance imaging (rs-fMRI) [20]. The DMN connectivity change may be related to the chemotherapy caused effects of neurons or surrounding cells injury, neurotransmitter level alteration, oxidative damage, hormonal level changes, altered immune response, small blood vessel coagulation of the central nervous system, anemia, and genetic predispositions [20]. Tao et al. (2016) conducted research to choose the posterior cingulate cortex as the critical seed region to examine chemotherapy-induced alterations in the brain functional framework. The wholebrain functional connectivity was investigated by rs-fMRI, and abnormal brain functional connectivity was found mainly on the frontotemporal lobes [31]. Piccirillo et al. (2015) also found that women who had self-reported cognitive dysfunction after chemotherapy had disrupted resting-state functional connectivity after chemotherapy assessed by MRI [26]. Xuan et al. (2017) investigated the neural mechanism underlying chemotherapy-induced cognitive dysfunction in BCSs from a perspective of system-level network integrity. They found that CRCD is associated with large-scale functional brain networks abnormal organization that may contribute to memory impairment in BCSs [13].
Chemotherapy may cause neural inefficiency. Jung et al. (2017) conducted a prospective study to track the trajectory of neurocognitive function changes and patient-perceived cognitive impairment after chemotherapy and to explore possible contributory factors and overall symptom burden over twelve months in breast cancer patients. Adjuvant chemotherapy was found to be an independent predictive factor in a neurocognitive deficit of the executive network for BCSs. The use of an fMRI to measure patient-perceived cognitive dysfunction and objective neurocognitive task performance and executive network capacity showed cognitive dysfunction and neural inefficiency in executive network functioning usually persist over following months for patients who received adjuvant chemotherapy compared with those without chemotherapy and compared to healthy controls [24]. The brain-derived neurotrophic factor level changes were significant after chemotherapy. This change was related to patient self-perceived concentration deficit [16]. Some underlying reasons beyond a direct impact of chemotherapy may contribute to CRCD. Breast cancer women with high-expression variants of multiple cytokine genes are associated with greater levels of depression, fatigue, and memory complaints [32]. Besides, chemotherapy does not always predict neurological tests and patient cognitive complaints. It is possible that some distinct trajectories and differing contributory factors contributing to CRCD [44].

Discussion
The prevalence and extent of CRCD are recognized as a major risk for BCSs. It was not well understood due to the lack of ideal research design, varied definitions of cognitive dysfunction, and inadequate sensitive neuropsychological assessment tools been used in previous studies. Assessment of cognitive functioning is an important and necessary component of a comprehensive oncological care plan. More evidence of CRCD in BCSs is critical to assist health care professionals, and survivors in understanding cognitive impairments associated with cancer treatments so early interventions can be implemented to achieve optimal cognitive patient outcomes [45].
Although "cognitive decline" is reported in multiple studies focused on chemotherapy among BCS, the incidence rate and severity of cognitive dysfunction vary in different research studies [46]. More than one cognitive domain can be affected by chemotherapy, and memory, attention, and executive function were particularly vulnerable [16]. Jung et al. (2017) found changes in patients' neurocognitive executive network function were worse one year after chemotherapy than pre-adjuvant treatment and women without chemotherapy [24]. Often breast cancer patients report treatment-related cognitive deficits in several domains. However, cognitive deficits are mainly written in executive functioning, such as planning, problem-solving, and multitasking [47]. Research also reported cognitive dysfunction in disease-free BCSs related to previous cancer treatment ten years ago in the cognitive domains of working memory, divided attention, and executive functioning among BCSs [9].
Patient-perceived CRCD includes decreased memory, verbal fluency, concentration, executive function, and processing speed, but these findings are not always congruent with patient objective cognitive function tests [48]. Biglia, et al. (2012) conducted a small prospective study with 40 BCSs, and they found patient self-perceived cognitive dysfunction was not correlate with objective neuropsychological tests [22]. This result was confirmed by a more extensive study later. Vardy et al. (2017) conducted a mechanical cohort study with 154 BCSs, and they found no association between subjective patient-perceived cognitive dysfunction and objective neuropsychological scores [40]. A future longitudinal study with a large sample size needs to be done to clarify further the relationship between self-perceived cognitive impairment and object cognitive decline.
Other potential risk factors for CRCD include higher chemotherapy dose [49], cytostatic agent [50], lower cognitive reserve due to older age and lower educational level [28] and genetic factors such as high-expression variants of multiple cytokine genes have been identified as an underlying reason for CRCD [32]. Various studies focused on CRCD also assessed the symptoms of depression, anxiety, and fatigue due to being identified as confounders of CRCD [23]. Aging and changes in menopausal status are identified as confounding factors for CRCD [51]. Several studies used breast cancer patient samples aged 70 years old and younger due to the possible age-related cognitive impairment and the association between underlying pathological changes such as dementia and Alzheimer's disease [23]. Menning et al. (2016) found no relationship between objective neuropsychological test scores and patient menopausal status and estrogen exposure [25].
A chemotherapy regimen of fluorouracil, epirubicin, and cyclophosphamide appears to alter the patient's cognitive function. The patient's cognitive function may worsen when taxane is added to the FEC regimen [23]. Anthracycline agents are used to treat breast cancer very commonly. Research shows that significant cognitive dysfunction occurs in women with breast cancer being treated exclusively with anthracycline-based agents [52]. Kesler et al. (2016 conducted a retrospective cross-sectional study with a small sample of 62 BCSs. They found that both anthracyclinebased and non-anthracycline-based chemotherapy are associated with CRCD, but the degree of non-anthracycline agents is lesser [17]. Anthracyclines may disrupt metabolic resources significantly than other chemotherapy agents via increased mitochondrial dysfunction and exacerbate neurotoxic physiologic cascades [53,54]. Anthracycline agents can produce reactive oxygen species which may result in oxidative stress associated with neurodegeneration [55,56]. Anthracyclines can also cause neural progenitor cell damage and increase neuroinflammation [57]. The underlying mechanisms of CRCD are complex. They might include direct neurotoxicity, cytokine level alteration, changes of hormonal levels, and small cerebral vessel thrombosis caused by chemotherapy [58]. Several mechanisms to explain CRCD have been postulated. For example, changes in brain-derived neurotrophic factor (BDNF) levels were found to be related to patient-perceived concentration deficit in BCSs exposed to anthracycline-based and taxane-based chemotherapy [16]. There is evidence that BCSs may have pre-chemotherapy cognitive dysfunction associated with cancer-related factors [59]. Pretreatment cognitive problems may be a contributing factor for CRCD [60]. Functional connectivity disconnection has been found in patients with Alzheimer's disease, cognitive dysfunction, and schizophrenia [51]. The medial temporal lobe subsystem's lower functional connectivity can contribute to cognitive decline, especially attention deficit in BCSs after chemotherapy [20]. Inflammation caused by chemotherapy may contribute to hippocampal changes [34]. Decreased gray matter in bilateral frontal area, temporal, cerebellar, thalamic, and cingulate areas were also found after chemotherapy [41]. Chemotherapy may also cause alterations in white matter in the brain and reduce the brain structure volume [33,42]. The structure alteration may reduce the brain network's functional specialization and cause modulated cognitive domains [61]. Some BCSs may be more sensitive to the standard chemotherapy treatment, resulting in alteration of functional connectivity in the brain networks controlling attention and executive function [26]. Chemotherapy caused neurotoxicity, pretreatment cognitive problems, brain structure alterations, and patient individual genetic predispositions may contribute to the underlying mechanism of CRCD.

Study Limitations
This integrative review's limitations and research implications include consideration that some of the chosen studies had a minimal sample size, which significantly limits study power for the examination of multiple variables and increases the risk of Type 1 and Type 2 errors. For example, four studies had a small sample of fewer than 50 participants [15,20,22,26]. There were four cross-sectional studies that did not have a baseline cognitive function evaluation [20,31,32,34]. Two retrospective studies [9,17], two case-control studies [13,26] and a mechanistic cohort study [40] also had no baseline cognitive function assessment. Some research did not implement objective cognitive assessments, with few identifying treatment approaches. Future randomized controlled, longitudinal studies are essential to evaluate the patient's baseline cognitive function before chemotherapy to investigate the attention deficit and executive function deficits caused by chemotherapy [20,31]. Further research could also examine genetic modifiers of cognitive impairment. One limitation is the inconsistent definition of cognitive dysfunction that vary in measurement, ranging from a small number of cognitive domain scores to more than 20 test indices [26,29]. There is no accordant number of abnormal test or cognitive domain scores required to classify cognitive dysfunction, which is vital for future investigations [25].

Clinical Implications
The clinical implications of this review include understanding the importance for health care professionals to 1) increase knowledge of CRCD due to the large BCS population has been affected; 2) initiate the early assessment of breast cancer patients' cognitive functioning who are receiving chemotherapy to decrease the potential risk factors; 3) understand the importance of starting early treatment and action to help manage CRCD due to the significant cognitive domains could be affected; and 4) continue to evaluate CRCD years after treatment has ended to implement effective interventions because CRCD can last more than a decade. Research showed that cognitive-behavioral therapy (CBT) and cognitive training methods might help with CRCD [62]. For example, breast cancer survivors' QOL and verbal memory performance can be increased through cognitive behavioral therapy and Memory and Attention Adaptation Training (MAAT) [63]. Some potential treatments based on small clinical trials also showed that metacognitive strategies, meditation, and Mindfulness-Based Stress Reduction (MBSR) might have positive effects on the symptoms of CRCD. A single group pre/post-test study with 14 BCSs showed that metacognitive strategy training was associated positively with cognitive performance and neural connectivity in BCSs with CRCD [64]. A randomized controlled trial with 47 BCSs showed that the Tibetan Sound Meditation program might be an easy and accessible way that is associated with short-term increasing in objective and subjective cognitive function in BCSs [65]. Evidence also showed that mindfulness-based stress reduction (MBSR) has significant positive effects among BCSs on psychological and physical symptoms after chemotherapy. MBSR improves subjective cognitive performance and symptom clusters [66,67]. Cognitive therapy protocols implemented after chemotherapy resulted in significantly improved verbal memory, attention, and processing speed [68].

Conclusions
Chemotherapy can cause acute and chronic cognitive dysfunction among BCSs. The major adverse effects of chemotherapy-related cognitive dysfunction include deficits in attention and executive functioning. Predictors associated with chemotherapy-related cognitive dysfunction include stress, fatigue, anxiety, depression, BMI, age, pretreatment cognitive reserve and specific chemotherapy agents. In the future, there is a need for more extensive, randomized controlled longitudinal trials and multicenter prospective studies targeting specific parameters and outcomes described in this review.