Interventions for Cognitive Deficits in Breast Cancer Survivors Treated With Chemotherapy

Vance, David E. PhD, MGS; Frank, Jennifer Sandson PhD; Bail, Jennifer RN; Triebel, Kristen L. PsyD; Niccolai, Lindsay M. MA; Gerstenecker, Adam PhD; Meneses, Karen PhD, RN, FAAN

doi: 10.1097/NCC.0000000000000349
Articles: Online Only

Background: Cognitive deficits are distressing adverse effects of chemotherapy that have a negative effect on quality of life in breast cancer survivors (BCSs). Cognitive deficits in cancer survivors are a top research and clinical practice priority.

Objective: The aims of this study were to describe cognitive deficits that occur after chemotherapy, describe deficits in BCSs treated with chemotherapy within a framework of cognitive reserve and neuroplasticity, and discuss cognitive interventions (ie, cognitive training interventions, compensatory strategies with cognitive training interventions, pharmacological interventions, and complementary and integrative medicine interventions).

Methods: PubMed search yielded 21 intervention studies of cognitive deficits in BCSs.

Results: Cognitive training interventions and compensatory strategies with cognitive training resulted in improvement of cognitive deficits. Methylphenidate did not result in cognitive improvement. Modafinil showed improvement in attention. Some complementary and integrative medicine interventions are promising.

Conclusions: Cognitive training has been most beneficial. Effectiveness of pharmacologic and complementary and integrative medicine interventions has not yet been established.

Implications for Practice: While limited evidence is available to guide clinical management of cognitive deficits in BCSs, validating patients’ symptom experience and evaluating co-occurring symptom clusters such as fatigue, sleep, and depression, are suggested.

Author Affiliations: School of Nursing (Drs Vance, Frank, and Meneses and Ms Bail) and Department of Neurology (Drs Trievel and Gerstenecker and Ms Niccolai), University of Alabama at Birmingham.

The authors have no funding or conflicts of interest to disclose.

Correspondence: Jennifer Bail, RN, School of Nursing, University of Alabama at Birmingham, 1720 University Blvd, Birmingham, AL 35294 (jbail@uab.edu).

Accepted for publication December 17, 2015.

Article Outline

Breast cancer is a highly survivable disease with 5-year survival rates of approximately 90%.1 Chemotherapy and hormonal therapy are associated with self-reported and objective cognitive deficits and in multiple domains including attention, memory, speed of processing, and executive functioning.2 Cognitive deficits have a negative impact on quality of life3 and are associated with psychological distress, sleep disturbance, fatigue,4 and lower overall health status.5 In recognition of such distressing adverse effects, the Oncology Nursing Society (ONS)6 identified cognitive deficits after chemotherapy as a top research priority. The National Comprehensive Cancer Network (NCCN) Guidelines7 also identified cognitive deficits associated with cancer treatment as a significant problem for cancer survivors. It also noted there is limited evidence to guide management but has provided several recommendations for practice, with one of the first recommendations being to validate the patient’s symptom experience of cognitive deficits (see Implications for Clinical Practice).

The purposes of this integrative review are to (1) describe the potential mechanisms by which cognitive deficits in BCSs occur after chemotherapy; (2) describe cognitive deficits in BCSs within a framework of cognitive reserve and neuroplasticity; (3) discuss cognitive interventions for BCSs including (a) cognitive training interventions, (b) compensatory strategies with cognitive training interventions, (c) pharmacological interventions, and (d) complementary and integrative medicine interventions; and (4) explore implications for practice and research. A conceptual overview is provided to serve as a guide and visual synopsis. Potential cognitive deficits associated with biological/targeted therapy or specific chemotherapeutic agents are beyond the scope of this article.

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Conceptual Overview

Cognitive Deficits in BCSs Treated With Chemotherapy

Cognitive deficits associated with chemotherapy, sometimes referred to as “chemobrain,” are frequently reported by BCSs, with prevalence rates ranging from 21% to 90%.5,8 Despite the high prevalence of self-reported cognitive deficits, BCS performance on cognitive tests is variable, as described in a previous review,9 ranging from no deficits on cognitive testing to subtle deficits in 1 or more cognitive domains (eg, memory, executive functioning, speed of processing, attention) to significant deficits in multiple domains.9 This variability is most likely related to methodological differences (eg, cross-sectional vs longitudinal design, control group composition, time since treatment, type of cognitive tests administered, type of treatment regimen, and definition of cognitive deficit) across studies.2

Although some chemotherapy regimens are associated with neurotoxicity, the specific mechanisms underlying chemotherapy-induced cognitive deficits are multifactorial and largely unknown. Possible mechanisms may be psychological (eg, styles of coping with stress, fatigue, and depression) and physiological (eg, direct injury to brain tissue, oxidative stress and inflammation, cytokine dysregulation, DNA damage and telomere shortening, genetic polymorphisms, and microvascular injury).10 Decreased estrogen levels may mediate some underlying mechanisms, which can be particularly problematic for those who experience acute menopause after chemotherapy.11 Although potential mechanisms have been identified, the structural and functional brain changes underlying the cognitive impairments associated with chemotherapy are not well understood. Regardless, brain changes have been observed via magnetic resonance imaging (MRI) and functional MRI in BCSs following chemotherapy.12

Although most chemotherapy drugs do not cross the blood-brain barrier, higher than expected levels of these agents have been found in the brain and cerebral spinal fluid of cancer survivors.13 The presence of chemotherapeutic agents in the central nervous system has a number of likely ramifications. First, while many cancer drugs damage DNA as a means to achieve tumor cell apoptosis, the DNA of normal cells is also affected. Second, chemotherapy is associated with increased levels of cytokines in the central nervous system, and increased cytokine activity has been associated with cognitive deficits, fatigue, depression, and residual chronic inflammation and DNA damage.14 In addition to the effects of chemotherapy on cognition, other troubling adverse effects include fatigue, sleep disturbance, and depression, which likely have a bidirectional relationship with brain health and cognition.8 Other factors that influence cognitive deficits following chemotherapy include age, education, anxiety, genetic factors, menopausal status, and hormonal therapy.10

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Cognitive Reserve and Neuroplasticity

Cognitive reserve refers to the brain’s ability to efficiently process information using existing and alternative neural networks in the presence of damage or disease-related insults (eg, chemotherapy-induced brain changes).15 It reflects the intricacy, complexity, strength, and efficiency of the brain’s neural connections.16 Cognition emerges from these connections by means of neurons processing information and communicating with one another. As a rule, the more efficient such connections are in processing information, the better one’s cognitive performance. Also, additional cognitive reserve has a protective benefit in the presence of brain damage, allowing the flow of information to be rerouted through alternative neural pathways, a concept referred to as the neural compensation mechanism.17 Thus, an individual who has greater cognitive reserve may suffer from fewer cognitive deficits following a neurological insult,17 such as that associated with chemotherapy.

Furthermore, the underlying mechanism behind cognitive reserve is neuroplasticity, which can be viewed as being either positive or negative. Positive neuroplasticity refers to the brain’s ability to increase the number and strength of neural connections when provided with novel, enriching stimuli and adequate physiological support (ie, nutrition, sleep). Negative neuroplasticity refers to a decrease in the number and strength of neural connections associated with an absence of stimulation and/or inadequate physiological support (ie, neurotransmitter imbalance, insulin resistance, fatigue). Therefore, the absence of novel stimuli as may typically be provided by employment, social interaction, and other complex activities may produce negative changes in cognitive reserve in BCSs.15,16

A basic conceptual overview in which chemotherapy negatively impacts cognitive reserve, resulting in “chemobrain” and poorer cognitive functioning, is depicted in the Figure. Cognitive interventions may improve or protect cognitive reserve, which may improve cognitive functioning. Interventions for cognitive deficits following chemotherapy fall within this framework of cognitive reserve and neuroplasticity. The underlying principle is that BCSs may be able to improve their functioning following exposure to stimulating or enriching interventions. Interacting with challenging or novel stimuli (ie, positive neuroplasticity) can then induce neurological changes, thus increasing BCSs’ cognitive reserve. Exposure to pharmacological or physiological interventions may either (1) increase neuroplasticity through an as yet unknown mechanism or (2) allow the brain to become more receptive to the positive neuroplastic benefits of external stimulation by decreasing other factors such as fatigue, which would hinder such interaction.18–20

It is important to note that the effects of neuroplasticity on cognitive reserve are indirectly observed in changes in cognitive performance. Measuring cognitive performance is easier and relatively inexpensive to measure. However, it is still subject to testing error and the state of the participant (ie, slept poorly the night before cognitive testing). In many studies of cognitive functioning following an intervention, more objective measures of neuroplasticity such as MRIs, positron emission tomography scans, and increases/decreases in neurotropic factors are used to detect morphological and biochemical changes in the brain.21,22 These technologies require extensive financial and technical resources unavailable to most of the studies examining cognitive deficits in BCSs.

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Methods

A PubMed search was conducted on June 9, 2015, for articles using the combination of keywords “breast cancer survivors” and “cognitive training” yielding 77 articles, “breast cancer survivors” and “cognitive rehabilitation” yielding 72 articles, “breast cancer survivors” and “cognitive intervention” yielding 103 articles, and “breast cancer survivors” and “cognitive treatment” yielding 302 articles. Of the 554 articles resulting from the initial search, 234 were duplicates, resulting in 320 unique abstracts for review. Inclusion criteria included BCSs comprising the majority of participants in an intervention for cognitive deficits and published in the English language. All types of cognitive interventions, including both pharmacological and nonpharmacological, were acceptable as long as they were not case study designs. Eleven studies were found to meet such criteria, and an additional 10 studies were located through manual review of their reference lists for a total of 21 studies on interventions for cognitive deficits in BCSs.

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Cognitive Interventions for BCSs

Interventions for cognitive deficits in chemotherapy-treated BCSs can be broadly classified into 4 categories: (1) cognitive training interventions, (2) compensatory strategies with cognitive training interventions, (3) pharmacological interventions, and (4) complementary and integrative medicine interventions. Each intervention approach and its relative effectiveness are discussed below with details described in the Table. Effectiveness is measured in change in cognitive performance (a proxy of cognitive reserve), which is prone to the normal problems associated with neuropsychological testing. These interventions may directly (through learning via positive neuroplasticity) or indirectly (through stress reduction, so people can learn) contribute to treatment effectiveness.

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Cognitive Training Interventions

Two of the 21 reviewed studies addressed cognitive training interventions, defined here as methods for restoring cognitive function through repeated practice with cognitive exercises tapping domains such as attention, memory, speed of processing, or executive functioning.23 Within the framework of neuroplasticity, cognitive training produces actual neurological change either by strengthening connections in the brain typically involved in performing a task or by creating new neural connections that result in improved cognitive performance. Cognitive exercises involved in cognitive training interventions are usually adaptive; the difficulty level of the training exercises increases as performance improves, while accuracy remains constant, and the task remains engaging.

To examine the effects of cognitive training, Von Ah and colleagues24 randomized BCSs with self-reported cognitive deficits to either a memory or a speed of processing training. Speed of processing is a neuropsychological ability reflecting the ease or difficulty of quickly analyzing information from the external environment, which has been shown to influence many tasks of everyday functioning, particularly driving.25 Speed of processing can be influenced by underlying difficulties with cognitive processes such as attention and spatial abilities or by other factors such as fatigue.

Both the memory and speed of processing training programs were implemented in small groups and included 10 sessions conducted over 6 to 8 weeks. In the memory training intervention, participants learned mnemonic strategies for remembering word lists and sequences and completed memory exercises. In the speed of processing training intervention, the participants completed increasingly difficult computerized tasks in which they were required to quickly process visual information to solve problems. Outcome measures of memory and visual attention/speed of processing were assessed at 3 time points: baseline, immediately postintervention, and at 2-month follow-up. Both intervention groups demonstrated significant improvement in memory and visual attention/speed of processing compared with wait-list control subjects. However, improvement varied by intervention type. The memory training group demonstrated significant improvement as compared with control subjects on tests of memory, but only at the 2-month postintervention testing. Compared with control subjects, the speed of processing training group was significantly faster at both postintervention intervals. Interestingly, only the speed of processing training group showed generalization of the training intervention with significant improvement also noted on tests of memory at both the immediate and the longer testing interval. Both interventions were associated with improvements in perceived cognitive functioning, symptom distress, and quality of life. In addition, satisfaction was high for both interventions.

In a second study of cognitive training, Kesler and colleagues26 investigated the efficacy of a commercially available, home-based computerized cognitive training program focusing on executive function, the higher-order processes necessary for organization and planning (http://www.Lumosity.com/). Participants in the experimental treatment completed 12 weeks of online training for a total of 48 sessions. The online sessions focused on training working memory, speed of processing, cognitive flexibility (the ability to change tasks, mental set, or generate alternative solutions to a problem) and verbal fluency and included cognitive exercises such as switching spatial location of a stimulus, mental rotation, spatial sequencing, word stem completion, route planning, and rule-based puzzle solving. Outcome measures consisted of a battery of neuropsychological tests including the Wisconsin Card Sorting Test, a well-validated measure of cognitive flexibility, and a letter fluency test, which reflects executive function. Compared with the wait-list control group, BCSs receiving cognitive training showed significant improvements in strategy formation and set shifting, verbal fluency, timed visual search and matching, and self-reported executive function. Improvements in memory were not significant, although some transfer to verbal memory was evident.

In both of these studies, cognitive performance was improved as a result of training and learning. Future studies of BCSs may also include measures of neuroplasticity such as MRI to determine where in the brain cognitive reserve is being increased or which neural pathways are being strengthened. It is notable that cognitive training studies with other populations (eg, healthy older adults) have been shown to result in both anatomical and functional brain changes.21,22

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Compensatory Strategies With Cognitive Training Interventions

Five of the reviewed studies used a combination of compensatory strategies and either combined these strategies with cognitive training or examined the cognitive benefits of such strategies.27–31 Consistent with principles of positive neuroplasticity, extensive practice with mnemonics and other strategies can improve cognitive functioning. Dolbeault and colleagues27 conducted a randomized wait-list control trial of a psychoeducational intervention consisting of thematic group discussions, stress management information, and training in stress management techniques. However, self-reported measures of cognitive functioning were not statistically improved following the intervention.

Using a single-arm design, Ercoli and colleagues29 evaluated the effectiveness of a 5-week manualized cognitive training intervention to improve attention, executive function, and memory administered in a group setting to BCSs.28 Participants were educated about cognitive training and compensatory strategies, given opportunities to practice during the session, and assigned homework exercises. Significant and sustained improvements over time were found on cognitive measures of speed of processing and executive functioning and on self-reported measures of executive functioning deficits. Ercoli and colleagues subsequently completed a randomized controlled trial of a similar 5-week cognitive training and rehabilitation intervention in BCSs with self-reported cognitive deficits. The module-guided program again focused on the areas of attention, executive function, and memory. When compared with a wait-list control group, BCSs who received the intervention showed significant improvement over time in ratings of their own cognitive functioning as well as significantly greater improvement on tests of immediate and delayed memory.

In a single-arm pilot study, Ferguson and colleagues30 explored the usefulness of a Memory and Attention Adaptation Training (MAAT), based on cognitive-behavioral principles. The program involved 4 individual monthly visits with monthly phone contacts between visits for support and review. Visits addressed current knowledge of chemotherapy-associated memory problems, learning how to identify situations where memory failures may arise, and learning and rehearsing compensatory strategies relevant to the individual’s unique cognitive deficits. The MAAT program also included education about aspects of memory and attention, relaxation training, and a variety of other compensatory strategies (ie, self-instructional training, verbal rehearsal of auditory information, schedule making, external cueing, and outlining written material). Participants received a MAAT workbook with guides on applying compensatory strategies, and homework was used as a means of practicing skills learned during sessions. Outcome measures consisted of self-rating questionnaires and a cognitive test battery administered at baseline, immediately postintervention, and at 2- and 6-month follow-up. Improvement from baseline was observed on cognitive tests across a range of cognitive domains. In addition, participants reported a decrease in cognitive deficits and increased quality of life at the follow-up assessments.

In a follow-up study, Ferguson and colleagues31 randomized BCSs to either the MAAT program or a wait-list control group. In this trial, BCSs in the intervention condition improved on tests of verbal memory, but not in other cognitive domains. Consistent with results of the previous pilot study, BCSs in the intervention group self-reported increases in some aspects of quality of life, specifically those related to spiritual well-being. Overall, the MAAT studies demonstrate that psychoeducational strategies to compensate for cognitive deficits result in improvement on some cognitive measures, as well as gains in quality of life.

In this section, neuroplasticity, as exhibited by improved cognitive functioning, is facilitated by 2 processes. First, as before, standard learning through repetitive practice exercises is used. But second, compensatory strategies are used to support function in areas of cognitive deficits. The use of compensatory strategies provides “mental scaffolding” that allows one to rely on other techniques, which can over time gradually transition from external support (eg, mnemonics, external cues) to internal cognitive processes.32 In summary, cognitive training and compensatory strategies with cognitive training demonstrated promising outcomes in reducing cognitive deficits among BCSs.

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Pharmacological Interventions

Six of the reviewed articles evaluated pharmacological interventions for cognitive deficits in chemotherapy-treated BCSs. Based largely on its ability to improve cognitive function in other populations (eg, children and adults with attention-deficit/hyperactivity disorder),33 pharmacological therapy may be a potential intervention for cognitive deficits in BCSs both during and following chemotherapy. Medications tested with BCSs include methylphenidate, modafinil, and epoetin alfa.33–38 Donepezil and memantine, currently approved for the treatment of Alzheimer disease, have been tested in survivors with types of cancer other than breast cancer, such as brain metastases and lung cancer with modest or negligible effects.39 The pharmacological agents discussed below have 2 potential mechanisms of action, potentially improving cognition either as a secondary effect of reducing fatigue or increasing wakefulness or by an unknown primary mechanism of increasing positive neuroplasticity.

Methylphenidate, a psychostimulant dopamine agonist, is commonly used for the treatment of attention-deficit/hyperactivity disorder.33 Methylphenidate was used in 3 studies with BCSs, with the primary end point being fatigue. Lower and colleagues33 conducted a multicenter randomized placebo-controlled parallel-group study with cancer survivors (78% were BCSs) at least 2 months after chemotherapy. Eight weeks of treatment resulted in significantly reduced fatigue in comparison to control subjects; however, there was no significant change in cognitive function in either treatment group. Mar Fan and colleagues36 conducted a similar randomized study of methylphenidate with BCSs who were receiving chemotherapy. Participants were administered the High-Sensitivity Cognitive Screen (HSCS) and the Revised Hopkins Verbal Learning Test 3 times: before starting methylphenidate, at chemotherapy completion (when methylphenidate treatment ended), and at a 4- to 6-month follow-up. Analysis revealed no difference between BCSs receiving methylphenidate and those receiving placebo on any measure at any time point, again failing to support the use of methylphenidate for cognitive deficits. In a third study of methylphenidate in BCSs receiving chemotherapy, Escalante and colleagues37 conducted a randomized placebo-controlled crossover trial of sustained-release methylphenidate for the treatment of fatigue. Breast cancer survivors received either (1) methylphenidate for 14 days and then a placebo for 14 days or (2) a placebo for 14 days and then methylphenidate for 14 days. The 2 groups did not significantly differ for fatigue. Yet, BCSs receiving chemotherapy performed significantly better on tests of verbal learning, memory, visual perception, and scanning speed in the methylphenidate condition.

Modafinil, also a psychostimulant dopamine agonist, promotes wakefulness and is known to improve cognitive performance in healthy adults.34 Kohli and colleagues34 randomized a sample of BCSs postchemotherapy to receive either modafinil or placebo for treatment of fatigue. The modafinil group showed significant improvement in speed and quality of memory and attention after 8 weeks of treatment compared with the placebo group.

The effects of psychostimulant dopamine agonists (ie, methylphenidate and modafinil) on cognition are indeed mixed. One possible reason for these variable results is that these medications do not directly contribute to neuroplasticity; instead, they facilitate alertness/arousal and minimize fatigue. Therefore, the cognitive performance benefit is a result of this, not from actual structural changes in the brain. Yet unto itself, increased alertness/arousal may be of moderate benefit to some patients. The use of these medications has been shown to reduce total cholesterol, low-density lipoprotein, and triglyceride levels,40 which could improve cerebrovascular functioning, indirectly fostering brain health. As such, a healthier brain is generally more neuroplastic, which facilitates cognitive reserve.

Lastly, 2 trials investigated the use of recombinant human erythropoietin (epoetin alfa), a synthetic drug that stimulates red blood cell production, on cognitive deficits in BCSs.35,38 The hypothesis was that epoetin alfa ameliorates cognitive deficits on the basis of reduced fatigue due to increased hemoglobin levels. An independent neuroprotective mechanism of the drug was also theorized. O’Shaughnessy and colleagues conducted a randomized double-blind placebo controlled pilot trial to examine the effect of epoetin alfa on cognitive deficits in BCSs undergoing chemotherapy.35 Breast cancer survivors treated with either epoetin alfa or placebo received a questionnaire measuring executive function prior to chemotherapy, during chemotherapy, and 6 months after chemotherapy completion. Epoetin alfa–treated BCSs scored significantly better than did control subjects on the questionnaire during treatment but not at the 6-month follow-up. Breast cancer survivors treated with epoetin alfa also reported less fatigue and higher quality of life than did the control group at 6 months. Mar Fan and colleagues38 compared the performance of BCSs treated with epoetin alfa in conjunction with chemotherapy with a control group treated with standard chemotherapy on a commonly used neuropsychological screening test, the HSCS. They found that the treatment group reported a better overall quality of life at follow-up, but no difference in cognitive performance on the HSCS between the 2 groups.

The use of epoetin alfa for producing positive neuroplastic changes to improve cognitive performance is also mixed. In O’Shaughnessy and colleagues’35 study, cognitive improvement only occurred in the short term. Perhaps as epoetin alfa increases red blood cell counts, oxygenation is systemically improved through the body, including the brain. As a result, the brain may perceive a decrease in fatigue, providing a short-lived boost in cognitive functioning. Whether this produces a sustained increase in neuroplasticity cannot be determined at this time. Unfortunately, epoetin alfa increases the risk of cardiovascular and thrombovascular events, which prompted the US Food and Drug Administration to issue a black box warning of these agents, which are no longer recommended for use in any cancer survivor.41

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Complementary and Integrative Medicine Interventions

Another class of interventions for cognitive deficits in BCSs, comprising 8 of the 21 articles in this review, involves complementary and integrative medicine. This approach consists of a group of varied treatments and practices that are complementary to standard care for symptom relief.42 Unlike the previous classifications of cognitive interventions that share similar delivery characteristics (ie, cognitive training, pharmaceuticals), complementary and integrative medicine interventions consist of several unique approaches that must be considered individually as there is sometimes no unifying theme to compare them to each other. Yet, cancer survivors have used these interventions for relief of pain, depression, and/or insomnia.42 Specific interventions in which cognitive deficits were evaluated in BCSs include meditation, tai chi, medical qigong, yoga, exercise, and biofeedback.43–50

Meditation and other forms of mindfulness that use focused attention to control breathing are frequently used to achieve relaxation and control stress.51 To examine the feasibility and efficacy of a Tibetan Sound Meditation program, Milbury and colleagues43 conducted a randomized controlled trial with BCSs receiving hormonal therapy. Breast cancer survivors in the intervention group participated in 2 weekly meditation sessions for 6 weeks and were encouraged to practice meditation at home. Self-report and cognitive performance outcome measures were completed at baseline, postintervention, and 1-month follow-up. The intervention group reported fewer cognitive deficits, although not significant, immediately postintervention, and showed a trend toward improved performance at 1-month follow-up on tests of verbal memory, short-term memory, and processing speed.

Another meditation-type approach includes tai chi. Tai chi is a Chinese martial art involving mindfulness, active relaxation, and slow breathing, combining safe exercise with meditation.46 In a randomized study, Reid-Arndt and colleagues46 administered preintervention and postintervention cognitive testing to cancer survivors (67% were BCSs) at least 12 months after chemotherapy. The intervention consisted of a 10-week program of biweekly classes providing instruction in a simplified form of tai chi fundamentals. Statistically significant improvement was found in the domains of immediate and delayed memory, verbal fluency, and executive function. Self-reported memory scores were significantly improved, as was balance; self-reported stress levels were also significantly reduced.

Qigong is an ancient Chinese art similar to tai chi, which combines gentle movements with meditation.44 Medical qigong incorporates safe physical movement, meditation, and breathing exercises to improve health. Oh and colleagues44 compared self-reported cognitive function in cancer survivors (32.4% were BCSs) assigned to either a medical qigong intervention group or a usual care group. The intervention consisted of attendance in at least 1 medical qigong class each week for 10 weeks. Classes consisted of group discussion, body movement and poses, and meditation. Participants were also encouraged to practice at home. After the intervention, participants in the medical qigong group scored significantly better on self-reported measures of cognitive function and quality of life than did the control subjects, suggesting that such controlled breathing and movement exercises may stimulate the brain.

Yoga is another meditation-type approach that has been used to improve cognition. Yoga, an ancient Eastern mind-body practice that focuses on breathing, flexibility, balance, strength, and relaxation, is increasingly being practiced by the general population.48 Galantino and colleagues48 attempted to explore the effect of a 12-week Iyengar yoga intervention on cognition and quality of life during chemotherapy and at postchemotherapy follow-up; unfortunately, only 4 BCSs s were enrolled. Although the small sample size precludes definitive conclusions, the intervention resulted in some improvement on a computerized measure of cognition in 2 BCSs; however, there was no control for either attention or exercise.

Culos-Reed and colleagues49 delivered a 7-week yoga program to cancer survivors (85% were BCSs) incorporating breathing exercises, yoga postures, and relaxation. A modest reduction in confusion was observed immediately postintervention in the yoga group but not in control participants. In a third yoga intervention study, Derry and colleagues45 conducted a randomized controlled trial with BCSs who self-reported cognitive deficits. Breast cancer survivors in the 12-week yoga intervention were given a detailed instructional yoga pamphlet and a professional yoga video and were encouraged to practice yoga at home. Participants completed a self-assessment of cognitive deficits at baseline, immediately postintervention, and 3-month follow-up. Participants in the yoga intervention group did not differ from wait-list control participants at baseline or immediately following the intervention. At the 3-month follow-up, however, BCSs in the yoga condition reported significantly fewer cognitive complaints than did the control participants. There was a significant correlation between practice frequency and improvement.

In these last 6 studies incorporating meditation-type approaches (eg, tai chi, yoga), small improvements were observed in cognition, but such improvements were notably observed on self-reported cognition (ie, confusion, cognitive complaints), not objective neuropsychological measures of cognitive performance. It is unclear whether there were actual neuroplastic changes as exhibited by objective changes in cognitive performance. It is also likely that stress reduction from these interventions may have either (1) reduced the cognitive load on existing cognitive reserve, resulting in a more optimistic appraisal of one’s cognition, and/or (2) reduced the stress response, which in turn may have produced a decrease in cortisol, reducing neurotoxicity and allowing more positive neuroplastic processes to occur.52 However, as cognition was a secondary outcome for most of this class of studies, scientific rigor in measuring cognitive performance was lacking.

In a different complementary and integrative medicine approach, speed-feedback therapy is an exercise intervention consisting of a bicycle ergometer connected to a computer.50 Participants pedal the bicycle at the speed displayed on the screen. The number of rotations required per minute to achieve the target speed is also displayed, requiring the use of sustained attention. Miki and colleagues50 examined the feasibility and efficacy of speed-feedback therapy on cognitive function in elderly cancer survivors (55% were BCSs) participating in a 4-week intervention. Assessments were conducted at baseline and at the end of the therapy. Compared with a control group, cancer survivors in the speed-feedback therapy group showed significant improvement on a brief neuropsychological battery testing executive and motor functioning; this study suggests some positive neuroplastic change as a result of this therapy.

Lastly, biofeedback, a unique complementary and integrative medicine approach, resulted in improvement on 4 measures of self-rated cognitive functioning administered 3 times over a 10-week intervention.47 Participants receiving the intervention listened to relaxing music interrupted periodically by auditory feedback regarding whole-brain activity; no response was required. Perceived cognitive functioning continued to improve throughout the intervention and was maintained when reassessed at a 4-week follow-up. But as mentioned in prior studies, no objective measure of cognitive performance was provided. As with the meditation-type studies above, it remains unclear if actual neuroplastic changes occurred as a result of training.

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Discussion

The 21 intervention studies showed variable outcomes among BCSs. Two studies of cognitive training are promising,24,26 with both interventions resulting in improvement on tests of cognitive performance and evidence of generalization of benefits across cognitive domains (eg, speed of processing training resulted in improved memory). Similarly, 4 of the 5 studies27–31 of compensatory strategy interventions demonstrated significantly improved cognitive performance.

The results of the 6 pharmacological interventions require further study to establish effectiveness. Two of 3 studies33,36,37 using methylphenidate failed to result in cognitive improvement, although the one study34 using modafinil found significantly improved memory 4 weeks following treatment, supporting the idea that pharmacological interventions can improve directed attention, and increased attendance and focus may potentially mitigate other cognitive deficits. The 2 studies35,38 of erythropoietin found only minimal cognitive improvement. Moreover, a black box warning from the USDA removed this agent from clinical use.41

The results of complementary and integrative medicine studies are preliminary requiring effectiveness data, and some are promising. Seven studies43,45–47,49,50 reported some aspect of subjective cognitive improvement. These interventions are generally accessible and acceptable. Future study consisting of an individualized program using multiple complementary and integrative medicine approaches may yield additional benefit. Some of those benefits may be on improvements in mood themselves; because these studies relied heavily on subjective measures of cognitive functioning, boosts in mood from such complementary and integrative medicine may have improved only the perception of one’s cognitive ability instead of one’s actual cognitive functioning.

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Implications for Clinical Practice

At present, 2 evidence-based guidelines are available to assist practitioners in addressing cognitive deficits among BCSs. The NCCN guidelines7 outline several principles for general survivorship care related to cognitive function. First, there is growing evidence that validates patient-reported cognitive deficits associated with cancer treatment and supports a modest correlation between patient reports and objective confirmation of deficits. Second, the NCCN acknowledged limited evidence to guide clinical management of cognitive deficits, with the most evidence found in breast cancer. Third, there are, as yet, no effective brief screening tools for mild cognitive dysfunction experienced by BCSs. More importantly, patients who have received chemotherapy are most likely to experience cognitive deficits.

The NCCN has several recommendations for practice. First, validating the patient’s symptom experience of cognitive deficits; evaluating concerns with other symptoms such as fatigue, sleep, and depression; and providing education are the most clinically beneficial implication as these may directly or indirectly support neuroplasticity. Here, the findings from this literature review may be helpful. For example, cognitive training, such as speed of processing, and/or compensatory strategies, such as reminders that can be incorporated into one’s routine, may be useful. Variable effectiveness of the different medications and complementary and integrative medicine, to date, can be conveyed to BCSs. Breast cancer survivors often wish to ascribe the “cause” of their cognitive changes to aspects of treatment. However, clinicians can refocus the clinical encounter to help BCSs place cognitive deficits in the broader symptom experience. For example, factors that can reduce neuroplasticity in patients such as medications, emotional distress, symptom burden, comorbidity, and alcohol use that may contribute to cognitive deficits can be discussed and addressed.19 In fact, some studies have shown that social stimulation itself may be an important contributor to neuroplasticity.53

The NCCN also noted that a cognitive assessment can target specific cognitive deficits such as difficulty with attention and memory. Breast cancer survivors who fall below a cutoff on an assessment may benefit from referral for formal neuropsychological evaluation. Breast cancer survivors with persistent cognitive deficits can be screened for potentially treatable contributing conditions such as depression.7 And finally, although not addressed in the NCCN guidelines, despite time limitations in typical clinical encounters, assessment of cognitive deficits should be routine in standard follow-up care.

Most recently, the ONS issued its excellent review of evidence-based interventions for cancer and treatment-related cognitive impairment.23 The guidelines examined the evidence from 24 studies of interventions among mixed cancer survivors, including BCSs. The recommendation deemed likely to be effective was cognitive training. Interventions in which effectiveness has not been established include biofeedback, meditation, mindfulness-based stress reduction, and qigong. Some pharmacologic approaches such as methylphenidate and modafinil need further study to establish effectiveness. Because of a high risk of adverse effects, erythropoietin is not recommended.

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Directions for Future Research

With the growing number of BCSs living longer, future study of cognitive interventions would benefit from longitudinal approaches examining whether the cognitive gains remain a year or more after the intervention. From the larger cognitive intervention literature in older adults without breast cancer, it is known that some interventions, such as speed of processing training, produce cognitive gains that are present up to 2 years after completing the intervention.54 Such cognitive interventions may produce similar gains in BCSs that are resistant to decay over time. Alternatively, BCSs may benefit from periodic or regularly scheduled repeated intervention throughout recovery as this may facilitate positive neuroplasticity and promote optimal cognitive reserve.

Second, because cognitive training and compensatory strategies are likely to be effective, additional studies are warranted before determining how best to incorporate such strategies into clinical guidelines. Among the issues that must be addressed are the appropriate length and spacing of training, the necessity of “booster” training sessions, and tailoring of training to an individual’s specific cognitive deficits.

Third, research on the cognitive mechanisms underlying improvement deserves further investigation. For example, to improve verbal memory, various components of training may be incorporated. One component could focus on practicing quickly hearing vowels, consonants, and syllables; this will help correctly hearing the words first so they can be encoded. Another component would be to practice mnemonic strategies for recall words over longer periods. In fact, some commercially available online cognitive training programs incorporate such individual cognitive mechanisms to improve an overall cognitive ability such as verbal memory.55

Fourth, pharmacological interventions with other agents, including selective serotonin reuptake inhibitors, lithium, angiotensin receptor blockers, and antioxidants, such as resveratrol, have been suggested for future investigation.56 Several of these agents have been shown to have neuroprotective effects from free radicals, which support neuronal function.19 Thus, if neuronal health is promoted, this encourages positive neuroplasticity.

Lastly, MRI and functional MRI studies allow for direct examination of changes in brain structure and function associated with cognitive interventions. These instruments have been used to examine neurological changes in BCSs performing cognitive tasks, but have not yet been used to evaluate the effectiveness of whether interventions directly support positive neuroplasticity and increase cognitive reserve.57,58

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Conclusion

Breast cancer survivors treated with chemotherapy can experience cognitive deficits that can impair their health behaviors and overall quality of life. The NCCN guidelines and ONS recommendations address the problem of cognitive deficits, as well as the constellation of symptoms surrounding cognitive deficits. A growing number of clinical investigations across a broad group of strategies are emerging as potential therapies to mitigate the effects of cognitive deficits in BCSs. Implementing these strategies into day-to-day clinical practice with large numbers of BCSs and other cancer survivors represents a significant challenge to health care providers and may eventually require changes in NCCN, ONS, and other practice guidelines. This challenge is a unique opportunity for oncology nurses to make a significant difference in cancer survivorship.

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Keywords:

Breast cancer survivors; Chemotherapy; Cognition; Cognitive intervention; Cognitive remediation therapy

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