http://informahealthcare.com/dre ISSN 0963-8288 print/ISSN 1464-5165 online Disabil Rehabil, Early Online: 1–9 ! 2015 Informa UK Ltd. DOI: 10.3109/09638288.2015.1038364
PERSPECTIVES IN REHABILITATION
Coping with cancer-related cognitive dysfunction: a scoping review of the literature Alix Sleight
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Mrs. T.H. Chan Division of Occupational Science and Occupational Therapy, University of Southern California, Los Angeles, CA, USA
Abstract
Keywords
Purpose: Cancer-related cognitive dysfunction (CRCD) impacts memory, attention, concentration, language, multi-tasking, and organizational skills and decreases participation and quality of life for cancer survivors. The objectives of this article are: (1) to outline the neuroscience of CRCD, its risk factors, and its effect on participation; and (2) to identify and summarize the literature on rehabilitation interventions and coping techniques for CRCD in cancer survivors. Methods: A scoping review of articles cited in PubMed, MEDLINE, PsychINFO, and CINAHL was performed. To be included, articles must have been published in a peer-reviewed scientific journal between 1996 and 2014, written in English, and included a quantitative or qualitative non-pharmacological study of interventions and/or coping strategies for adult cancer survivors experiencing CRCD. Results: Ten articles met the inclusion criteria for final review. Six studies tested the efficacy of rehabilitation treatments on CRCD. Three involved cognitive–behavioral therapy (CBT), while three tested neuropsychological and/or cognitive training interventions. Four qualitative studies investigated coping strategies used by survivors with CRCD. Conclusions: CBT-based treatments and neuropsychological/cognitive training methods may ameliorate symptoms of CRCD. The most commonly-reported coping strategy is utilization of assistive technology and memory aids. Further research is needed about efficacious rehabilitation techniques for this population.
Cancer, chemotherapy, cognitive dysfunction History Received 31 May 2014 Revised 31 March 2015 Accepted 2 April 2015 Published online 17 April 2015
ä Implications for Rehabilitation
Cancer-related cognitive dysfunction (CRCD) may impact up to 50% of cancer survivors. CRCD can significantly decrease participation and quality of life during survivorship. Cognitive–behavioral therapy (CBT) and neuropsychological/cognitive training methods may ameliorate symptoms of CRCD. The most common coping strategy reported by cancer survivors with CRCD is the use of assistive technology and memory aids.
Introduction Adjuvant chemotherapy treatment is delivered in conjunction with primary cancer treatments such as surgery or radiation. It involves the use of drugs to kill rapidly dividing cells throughout the entire body and is designed to increase the chance of long-term survival [1]. Cancer-related cognitive dysfunction (CRCD) following adjuvant chemotherapy treatment is reported to affect cancer survivors across a variety of ages and cancer diagnoses, and the deficits can last up to years after the completion of chemotherapy [2]. Many studies cite the incidence of CRCD to be between 15% and 25% in cancer survivors [3]. Furthermore, some sources
Address for correspondence: Alix Sleight, OTD, OTR/L, Phd Student, Mrs. T.H. Chan Division of Occupational Science and Occupational Therapy, University of Southern California, 1540 Alcazar Street, CHP133, Los Angeles, CA 90033, USA. Tel: +1 (323) 442-2850. E-mail: [email protected]
estimate CRCD occurs in as many as 50% of women undergoing chemotherapy for breast cancer [4]. CRCD has been referred to by several terms, including posttreatment cognitive dysfunction, chemotherapy-induced cognitive changes, mild cognitive impairment, chemo fog, and central neurotoxicity. The most frequently used colloquial term to describe the phenomenon is chemo brain [4]. However, this term has been criticized as trivializing and not accurately portraying the processes involved in the condition [5]. For this reason, the term CRCD will be used throughout this article. Patient reported or observed mild cognitive impairment following chemotherapy was largely unacknowledged by the medical community until recently [6]. Although references to cognitive change associated with chemotherapy originated in the 1980s, serious studies on the topic did not begin until the mid-1990s [3]. Presently, breast cancer survivors are the most studied population in CRCD research. This may be due to the prevalence of breast cancer as compared to other cancers [7], the fact that breast cancer research is particularly well-funded [8], or the fact that adjuvant
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therapy drugs used for breast cancer (e.g. tamoxifen) may specifically exacerbate CRCD symptoms [9]. Regardless, it is clear that research regarding CRCD in the general cancer population has been limited [10]. CRCD is typically reported as impacting verbal and visual memory, attention, concentration, language, motor skills, multitasking, and the ability to organize information [11]. CRCD deserves closer attention and understanding from rehabilitation professionals, as it can have substantial effects on participation and quality of life for cancer survivors. In addition, clinicians should be aware of the evidence-based interventions and coping strategies available to maximize participation for individuals with CRCD. The purpose of this article is (1) to outline the neuroscience of CRCD, its risk factors, and its effect on participation for cancer survivors; and (2) to identify and summarize the literature on rehabilitation interventions and coping strategies for CRCD in cancer survivors.
Background Structural and functional explanations for CRCD Electrophysiological and imaging studies completed over the past several years confirm that there are specific structural and functional changes in the brain that may account for the appearance of CRCD [11]. In a study by Inagaki et al., magnetic resonance imaging (MRI) results indicated that the brains of breast cancer survivors who had been exposed to adjuvant chemotherapy demonstrated decreased brain volume in the gray and white matter, including in the superior and middle frontal gyri, parahippocampal gyrus, cingulated gyrus, and precuneus. The volumes of the parahippocampal gyrus, prefrontal, and precuneus were significantly correlated with behavioral measures of attention/concentration and/or visual memory [12]. Indeed, broadly speaking, the parahippocampus is involved in memory processes, while the prefrontal cortex has been linked to attention and, together with the precuneus, is involved in aspects of selfprocessing [13]. Thus, changes in these brain regions, especially as they are correlated with measures of attention and memory, suggest a possible neural basis for symptoms of CRCD. Interestingly, the brain volume changes detected by Inagaki et al. were present at 1 year post-cancer treatment, but not at 3 years post-treatment, indicating that neural structural changes causing CRCD may stabilize or disappear with time [12]. Another study by Silverman et al., however, showed that chemotherapy may cause lasting—or at least lingering—changes in brain function. Researchers used positron emission tomography (PET) scans to analyze cerebral blood flow changes and resting brain metabolism of breast cancer survivors who had received chemotherapy 5–10 years prior to the study. Results indicated significant differences between the group who had received chemotherapy and the group that had not in the inferior frontal gyrus and the posterior cerebellum near the midline. Greater recruitment of frontal cortical tissue was involved, as indicated by metabolism in this region, when chemotherapy-treated patients performed memory tasks, suggesting that even up to a decade post-treatment, patients may experience symptoms of CRCD when performing cognitive tasks [14]. Neurochemical and physiological explanations for CRCD When searching for an explanation for CRCD on a physiological and/or neurochemical level, the first natural suspect would be the chemotherapy drugs themselves. There is a known correlation between exposure to chemotherapy drugs and CRCD, particularly in the domains of episodic and working memory [15]. In order to affect the brain directly, chemotherapy drugs must be lipid soluble
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or otherwise be able to cross the blood–brain barrier. Many chemotherapy drugs, however, have been found in only minimal concentrations in the brain. Evidence from animal studies has shown that certain chemotherapy agents can cross the blood–brain barrier [16], but researchers continue to debate whether current chemotherapeutic drugs are able to cross the blood–brain barrier in humans [2]. Another possibility is that chemotherapy may damage the physical structure or functional properties of the blood–brain barrier itself, allowing an influx of inflammatory cells [4]. In short, the exact mechanism through which chemotherapy drugs produce CRCD remains unclear. Other frequent cancer side effects may also be implicated in CRCD. These mechanisms include hormonal imbalances, cytokine level imbalances, anemia, and thrombosis. For example, hormones can affect cognition processes. Estrogen, in particular, is thought to improve cognition by supporting cholinergic activity in the brain [2], but adjuvant therapy drugs such as tamoxifen, which is commonly prescribed in cases of breast cancer, decrease estrogen levels, thereby causing memory problems that can contribute to CRCD [9]. Indeed, current recommendations for survivors of estrogen receptor-positive breast cancer include a 10-year regimen of tamoxifen [17], which may in turn cause ongoing cognitive issues well into the survivorship period. Stress and anxiety, two additional confounding factors, often occur in patients with CRCD [4] and can also exacerbate cognitive dysfunction [18]. Finally, fatigue, a common complaint for many cancer survivors, can also amplify the symptoms of CRCD [19]. Cytokines, immune-mediated inflammatory agents that naturally increase in the body as a response to cancer and cancer treatment, have also been suspected of producing cognition problems [20]. Unlike chemotherapeutic drugs themselves, cytokines are absolutely able to cross the blood–brain barrier, so they remain a strong candidate as a cause for CRCD. However, the issue is complicated by the fact that cytokine mechanisms may be a result of the cancer itself or of the drugs used to treat the cancer [2]. Kipnis et al. have also suggested the possibility that the generalized immune decline caused by chemotherapy leads to CRCD [21], while another possible explanation for CRCD could be that chemical substances released by intact or damaged cancer cells, or chemical mediators of the patient’s immune response mechanisms, gain access to the brain and cause cognitive deterioration [2]. Schagen et al. have suggested that priming and pre-existing knowledge of CRCD can influence the reporting of the phenomenon itself [22]. This idea may be substantiated by findings that subjective complaints of CRCD do not always correlate with objective measures of cognitive function [23]. However, it should be noted that the lack of correlation between subjective complaints and objective measures may stem from the nuances of measuring outcomes via self-report and the dearth of functionally valid neuropsychological measures for assessing CRCD [24]. Finally, emotional factors such as depression, which often occur as a result of cancer diagnosis and treatment, may contribute to deficits in memory and cognition [10]. There is still no definitive evidence to establish a causal relationship between any one individual factor and the symptoms of CRCD. Ultimately, there is likely a complex interplay of causes involved in the generation of the cognitive disruptions seen in cancer patients. Risk factors for CRCD Regardless of its etiology, CRCD is more likely to affect people who demonstrate certain risk factors. One of the main risk factors for CRCD is age. Hormone levels decrease as human beings get
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older, and deficiencies in estrogen and progesterone are associated with reduced attention, learning, and memory [4], some of the common symptoms of CRCD. Thus, older adults— particularly post-menopausal women—may be at higher risk. In addition, despite the lack of understanding regarding the exact contribution of chemotherapy drugs to CRCD, research has shown that certain chemotherapy drugs may carry higher associations with CRCD. Cyclophosphamide, methotrexate, and fluoracil have the strongest associations, and high-dose regimens of chemotherapy also increase the risk of developing symptoms of CRCD. Other variables, such as concurrent medications, individual differences in coping abilities, and the nature of the individual disease process, may be risk factors for CRCD, but the strength of their associations are yet unknown [4].
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Effects of CRCD on participation CRCD is the most frequently documented—and most troublesome—chronic post-cancer symptom [6], and it has been shown to have emotional, interpersonal, and even economic effects on cancer survivors. Many of the ramifications from CRCD result in decreased independence. For example, many individuals report being less able to manage everyday responsibilities such as paying bills or running errands [5,6,25]. The ability to drive was also affected for some research participants as focus and memory diminished [5,6,26]. Memory is often affected by CRCD, which can negatively impact participation in everyday life. In a qualitative study of breast cancer survivors, Von Ah et al. [26] found that 100% of participants indicated that their short-term memory was affected by CRCD, causing them to forget simple everyday tasks and appointments. A total of 91% of participants in this study also indicated that long-term memory was affected, which negatively impacted day-to-day function. The participants in the Von Ah et al. study also identified information processing, attention, concentration, word-finding, and executive functioning as being impacted by CRCD. Participants indicated that everyday tasks such as balancing a checkbook and staying oriented in the community became more difficult as a result of CRCD [26]. In a meta-analysis of CRCD literature, Falleti et al. found that memory, concentration, language, and attention were the most frequently impacted areas of cognition [27], and these limitations can in turn affect a number of participation domains. For example, in more extreme circumstances, social role fulfillment can be affected when individuals are no longer able to manage the challenges of child rearing, marriage, and other significant relationships [4]. Many individuals report that CRCD causes alienation from family and friends as others fail to understand, respect, or take seriously the cognitive changes associated with chemo treatment [6,25]. Furthermore, individuals in qualitative studies of breast cancer survivors by Munir et al. [28], Fitch et al. [29], Player et al. [5], and Boykoff et al. [6] reported that CRCD affected their ability to work effectively. As focus, speed, efficiency, and memory diminished, so did the participants’ ability to perform their job duties. Cognitive impairments affecting the ability of these individuals to perform at work included short-term memory problems, issues with verbal ability, decreased speed of information processing, and executive functioning problems such as difficulty multi-tasking, making decisions, and dividing attention [29]. Some participants opted to take leaves of absence or even early retirement as a result of their CRCD [6]. Moreover, recent scholarship indicates that individuals with a high level of allostatic load at diagnosis may be particularly vulnerable to the neurocognitive effects of cancer, creating a vicious cycle for those with CRCD returning to stressful jobs after treatment [30].
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Methods In order to identify the rehabilitation interventions and coping strategies available to help cancer survivors with CRCD, a scoping review of the literature was conducted using the methodology described by Arksey and O’Malley [31] and updated by Levac et al. [32]. Scoping reviews aim to broadly summarize key concepts within a topic and identify gaps in the literature [31]. This methodology is particularly beneficial for use when a topic is complex or has not previously been comprehensively reviewed [30], when a variety of study designs are utilized [31], or when a dearth of randomized controlled trials hinders the process of systematic review [32]. Very little rigorous research has taken place to examine rehabilitation interventions for CRCD, and the topic of CRCD is particularly complex since both self-generated coping strategies and professionally-led interventions are commonly used. Thus, a scoping review was undertaken for this study using the following steps, as recommended by Arksey and O’Malley [31]: (1) Systematic search: The author searched articles cited in PubMed, MEDLINE, PsychINFO, and CINAHL between 1996 and 2014. Search terms were used to capture major rehabilitation disciplines as well as common terminology used to describe the population. Key search terms included ‘‘chemotherapy,’’ ‘‘rehabilitation’’, ‘‘cognitive’’, ‘‘cancer’’, ‘‘oncology’’, ‘‘physical therapy’’, ‘‘occupational therapy’’, ‘‘social work’’, ‘‘post-chemotherapy cognitive deficit’’, ‘‘CRCD’’, ‘‘chemotherapy-related cognitive dysfunction’’, and ‘‘cancer-related cognitive dysfunction’’. Reference lists of the included articles were hand-searched for additional relevant titles. (2) Selection of studies: To be included, articles must have met the following inclusion criteria: published in a peer-reviewed scientific journal between 1996 and 2014, written in English, and involving a quantitative or qualitative non-pharmacological study of interventions and/or coping strategies used for adult cancer survivors experiencing CRCD. Studies were excluded if they were considered ‘‘grey-literature’’ (abstracts, conference proceedings, editorials, etc.). (3) Charting the data: Data were extracted from the included studies and entered into a table (Table 1). The following fields were included: author(s), year, country, study design, population, and findings. (4) Summarizing the results: The charted data were compared and analyzed for themes, trends, breadth, and gaps. Studies were grouped according to study design and sorted according to year of publication.
Results An overview of the search and selection flow process is found in Figure 1. After removal of duplicates, a total of 234 records identified through database search were screened for inclusion. Two hundred and two abstracts were excluded, and an additional 22 full-text articles were excluded for not meeting selection criteria. Ten articles were included in the final synthesis and detailed in Table 1. Six of these studies tested the efficacy of rehabilitation interventions. Five were randomized controlled trials, and one was a single-arm pilot study. Three of these quantitative studies involved cognitive–behavioral therapy (CBT)-based interventions, while three tested neuropsychological and/or cognitive training interventions. Four qualitative studies investigated coping strategies used by survivors with CRCD. Of the 10 studies selected for inclusion, two comprised secondary analyses of pre-existing data. The average n across all studies was 42.8. The years the studies were conducted ranged from 2005 to 2014, and they took place in six different countries: United States (5), Germany (1),
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Table 1. Articles included in the scoping review.
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Author [ref.]
Country
Study design
n
Population
Findings
Quantitative studies Ferguson et al. [34]
United States
Single-arm pilot study of a cognitive–behavioral therapy (CBT) intervention, memory and attention adaptation training (MAAT)
29
Breast cancer survivors, stage I and II, average of 8 years postchemotherapy,
Poppelreuter et al. [40]
Germany
Randomized controlled trial examining efficacy of two neuropsychological training programs
96
Adult female inpatient cancer survivors undergoing oncological rehabilitation
McDougal et al. [39]a
United States
Randomized controlled trial testing the efficacy of a cognitive training intervention
22
Older adult cancer survivors, mean age 74
Ferguson et al. [35]
United States
Randomized controlled trial evaluating the efficacy of a CBT intervention, MAAT
40
Breast cancer survivors, stage I and II
Kesler et al. [38]
United States
Randomized controlled trial to examine feasibility and efficacy of an online executive function (EF) training program
41
Breast cancer survivors, stages I-III
Goedendorp et al. [36]a
Netherlands
Randomized controlled trial of effectiveness of CBT for post-cancer fatigue on decreasing cognitive disability
98
Cancer survivors, male and female, completed cancer treatment at least one year previously
MAAT intervention resulted in improvements in self-report of cognitive function, quality of life, and standard neuropsychological test performance at post-treatment, 2-month, and 6-month follow up. Participants rated MAAT as helpful in improving ability to compensate for memory problems. No significant intervention effect found for either the inperson or computer-based neuropsychological training programs. On performance measures, moderate effects were noted in the treatment group with increases in the Rivermead and HVLT memory performance scores. Moderate effects were also noted for group-by-time interactions on the Brief Visual Memory Test memory performance measure. Decreases in depression and trait anxiety were also observed in the treatment group. Significant increases in memory selfefficacy and self-reported cognitive abilities were reported. MAAT participants made significant improvements relative to controls on the spiritual well-being subscale of the quality of life measure and on verbal memory. Cognitive training led to significant improvements in cognitive flexibility, verbal fluency, and processing speed. Self-rating of EF skills, including planning, organizing, and task monitoring, were also improved in the intervention group. Participants who received CBT for post-cancer fatigue reported significantly less cognitive disability as measured by concentration subscale of the checklist individual strength and the alertness behavior subscale of the sickness impact profile.
Qualitative studies Fitch et al. [29]
Canada
Qualitative study using indepth interviews
32
Adult cancer survivors experiencing CRCD
Primary coping strategy identified wad ‘‘writing everything down’’. Participants also stressed the importance of receiving information about the potential side effects of chemo brain at the onset of treatment. (continued )
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Table 1. Continued
Author [ref.]
Country
Study design
n
Population
Findings
Breast cancer patients, stages I–IV, currently receiving chemotherapy or with a history of receiving chemotherapy Breast cancer survivors, completed chemotherapy within 6-12 months
8 coping strategies identified (e.g. keeping a journal/diary, playing mahjong, physical activity).
Cheung et al. [25]
Singapore
Qualitative study using focus groups
43
Myers [41]
United States
Qualitative study using semistructured interviews and a focus group
18
Player et al. [5]
Australia
Qualitative study using semistructured in-depth telephone and face-to-face interviews
9
Breast cancer survivors, stage II and III, completed or currently undergoing chemotherapy
7 primary coping strategies identified (e.g. writing things down, physical activity). 8 coping strategies identified by survivors (e.g. recognizing daily limits, participating in artistic pursuits).
a
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Secondary analysis of data.
Records idenfied through database search (CINAHL, MEDLINE, and PSYCINFO) (n = 242)
Addional records idenfied through hand-searching (n = 10)
Records aer duplicates removed (n = 234)
Abstracts excluded (n =202)
Full-text arcles assessed for eligibility (n =32) Full-text arcles excluded (n = 22)
Arcles included in synthesis (n =10)
Figure 1. Search results and progress through scoping review.
Netherlands (1), Canada (1), Singapore (1) and Australia (1). The studies were conducted by researchers across a wide variety of fields including psychology, oncology, nursing, kinesiology, psychiatry, rehabilitation science, and radiology. Six of the studies involved breast cancer survivors, while the other four included individuals with a range of different types of cancer. Two of the studies involved online or computer-based programs. The results of all studies included in the scoping review are detailed in the next section. Cognitive–behavioral therapy-based interventions for CRCD Three studies included CBT-based interventions for CRCD. CBT is intended to improve function and psychosocial well-being by identifying beliefs, feelings, and behaviors associated with a psychological problem and revising them through exploration and critical analysis. Through participation in CBT, individuals shape new ways of thinking, behaving, and feeling that may reduce or eliminate psychological or emotional disturbances [33].
The first study, a single-arm pilot study, investigated the feasibility and efficacy of a CBT intervention called Memory and Attention Adaptation Training (MAAT) that was aimed at helping breast cancer survivors manage CRCD. The MAAT intervention involved four individual monthly visits and three phone calls from a licensed clinical psychologist, as well as a participant workbook outlining four cognitive–behavioral components: (1) education on memory and attention; (2) self-awareness training; (3) selfregulation, emphasizing relaxation training, activity scheduling, and pacing; and (4) cognitive compensatory strategies training including schedule-making, external cueing, and covert verbal self-guidance during task performance. Significant improvements in self-report of cognitive function, quality of life, and standard neuropsychological test performance were observed post-treatment, as well as at 2-month and 6-month follow-ups [34]. The second study, led by the same principal investigator, continued to examine the efficacy of MAAT through a randomized controlled trial with a waitlist control group. The study was completed over the course of 8 weeks, and MAAT participants made significant improvements relative to the control group on verbal memory and the spiritual well-being subscale of the Quality of Life-Cancer Survivors (QOL-CS) scale. Taken together, the results of these two studies suggest that MAAT is a feasible and practical program for cancer survivors with CRCD that may improve quality of life and cognitive performance [35]. The third study examined the effect of CBT for cancer-related fatigue on CRCD using a secondary analysis of data from a randomized control trial. Cancer patients with severe fatigue received a 6-month CBT intervention focusing on the importance of identifying precipitating and perpetuating factors in the experience of fatigue. Modules addressed (1) coping with the cancer experience; (2) fear of disease recurrence; (3) dysfunctional beliefs regarding fatigue; (4) sleep dysregulation; (5) activity dysregulation; and (6) low social support/negative social interaction. The secondary analysis of this data indicated that patients who received the CBT intervention reported significantly less cognitive disability as well as a clinically relevant reduction in concentration problems as measured by the Concentration subscale of the Checklist Individual Strength and the Alertness Behavior subscale of the Sickness Impact Profile [36]. Neuropsychological/cognitive training interventions for CRCD Three studies addressed the effect of neuropsychological and/or cognitive training interventions for CRCD. Neuropsychological/ cognitive training programs often have similar attributes to CBT
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but focus more on abilities such as memory, reasoning, and speedof-processing rather than on beliefs, feelings, and behaviors [37]. The first study was a randomized controlled trial to investigate the feasibility and preliminary effectiveness of an online cognitive training program for breast cancer survivors with CRCD. The computerized training program took place over 48 sessions, each 20–30 min long, and was administered using participants’ home computers. The intervention involved various combinations of 13 different exercises designed to improve executive function (EF) skills including cognitive flexibility, working memory, processing speed, and verbal fluency. The exercises all featured visual stimuli that required a motor response and included mental rotation games (e.g. navigating a rotating maze), spatial sequencing memory games (e.g. recalling the location of coins and them finding them in the order of their value), and word stem completion games (e.g. use a word stem such as ‘‘cog’’ to produce as many different words as possible), among others. Exercises were adapted to individual ability and increased in difficulty as participants progressed. Outcome measures included a battery of psychometrically validated and standardized cognitive tests. Cognitive training led to significant improvements in cognitive flexibility, verbal fluency, and processing speed, with marginally significant improvements in verbal memory. Selfratings of EF skills, including task monitoring, organizing, and planning, also improved in the intervention group [38]. The second study was a secondary analysis of data from a randomized controlled trial investigating the efficacy of a ‘‘memory and health training intervention’’ on cognitive performance in older adults. Data from participants who were also cancer survivors (10% of the original sample) were later analyzed. Individuals in the intervention group received a 26-month training in stress management, including guided relaxation; memory selfefficacy; and memory strategy training. Participants learned skill building through developing awareness, handling of controlled challenges, and becoming confident and realistic in everyday situations. The intervention also addressed anxiety, depression, and general health, which were hypothesized to influence memory performance. Outcome measures included a battery of standardized tests to measure verbal memory, visual memory, memory performance, functional status, anxiety, depression, and memory self-efficacy. Moderate effects were noted by increased scores on the Rivermead Everyday Behavioral Memory Test and Hopkins Verbal Learning Test. Moderate effects were also found on the Brief Visual Memory Test memory performance measure. Individuals in the intervention group also demonstrated decreases in depression and trait anxiety, as well as significant improvements on the memory self-report scales. The authors suggest that in order to adapt the content of the intervention for cancer survivors, training should focus on stress and relaxation, identifying false beliefs and factors affecting memory, and training on memory remediation techniques [39]. The third study was a randomized controlled trial testing the efficacy of two different neuropsychological interventions as compared to a control group receiving no specific training. Female breast cancer patients were randomized into an in-person neuropsychological training group (NPT), an individualized computerbased training group (PC), or a no training control group. The individuals in the NPT group participated in a broad spectrum of activities involving attention and memory in an everyday context (e.g. practicing recall of information after listening to the news) as well as training in compensatory strategies for improving cognitive performance (e.g. day planners, notes). This group was led by an occupational therapist. The individuals in the PC group were individually coached using training software designed to address attention and memory. Both intervention groups received four 1-h
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training sessions per week during their inpatient stay. The measures used were a battery of standardized and validated neuropsychological tests for attention and memory, in addition to three questionnaire scales used to capture self-appraisal of cognitive performance. The majority of participants in all three groups (NPT, PC, and control) demonstrated significant improvements across measures post-intervention. Therefore, no significant intervention effect was found [40]. Self-generated coping strategies for CRCD Four qualitative studies investigated the coping strategies employed by cancer survivors with CRCD. The first was a phenomenological study conducted with nine female breast cancer survivors with self-reported CRCD symptoms from New South Wales, Australia. Data were collected through semistructured, in-depth telephone and face-to-face interviews. The investigators found that participants used a combination of selfgenerated organizational and preventative strategies to manage CRCD symptoms, in addition to seeking help when necessary. The most common strategies employed to maintain function included taking notes by using diaries, smartphones, or calendars; structuring the day in order to schedule important daily tasks and self-care; and seeking emotional and practical support from others. Other strategies identified by the participants included exercise and relaxation, relying on a partner to coordinate tasks and appointments, recognizing daily limits and avoiding stressful situations, doing Sudoku puzzles, and participating in artistic pursuits [5]. The second study investigated the experiences of 32 cancer survivors with CRCD through in-depth interviews. Participants identified a variety of strategies used to cope with CRCD, and the most frequently reported strategy was ‘‘writing everything down’’. In addition, individuals indicated that in order to help them cope most effectively with CRCD, it was important that their health care providers provide information about the potential for cognitive change at the beginning of their treatment [29]. In the third qualitative study, 43 chemotherapy-receiving breast cancer patients in Singapore participated in structured focus group discussions conducted by trained psychosocial oncologists and medical social workers. Psychosocial strategies were the most commonly reported for managing CRCD. These strategies included controlling mood and expectations, seeking family support, and engaging in social activities. Other coping strategies identified included sleeping well, eating a balanced diet, participating in exercise, participating in mental activities (e.g. reading, playing mahjong), using written reminders (e.g. keeping a journal, using sticky notes), and using technology (e.g. smartphone reminders, mind-stimulating computer games) [25]. The fourth study used semi-structured interviews and focus groups to investigate the experiences of 18 cancer survivors who reported CRCD symptoms. The most common coping strategy identified was writing things down. Other coping strategies included seeking support and validation, helping others, depending on others, focusing on one task at a time, not rushing, and giving oneself permission to make mistakes. Participants also identified exercise, getting enough rest, and mind stimulation as important coping techniques [41].
Discussion This scoping review of the literature identified a number of evidence-based rehabilitation interventions for cancer survivors with CRCD. These interventions fell into one of two categories: (1) CBT or (2) neuropsychological/cognitive training. While the review revealed some overlap between the two categories, several unique intervention areas emerged from both. Distinct CBT
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DOI: 10.3109/09638288.2015.1038364
interventions relevant to rehabilitation included education on memory and attention; self-awareness training regarding precipitating/perpetuating factors of CRCD symptoms; activity scheduling and pacing; and increasing social support. Unique neuropsychological/cognitive training interventions relevant to rehabilitation included the use of computer games designed to improve EF skills (i.e. those targeting cognitive flexibility, working memory, processing speed, and verbal fluency); memory strategy training; and practicing activities involving attention and memory in an everyday context (e.g. practicing recall of information after listening to the news). Interventions common to both CBT and neuropsychological/cognitive training included stress management, guided relaxation, and training in cognitive compensatory strategies such as schedule-making, notetaking, external cueing, and covert verbal self-guidance during task performance. The scoping review also identified a number of self-generated coping mechanisms used by cancer survivors for CRCD symptoms. Many of these coping mechanisms can be taught and developed during the process of rehabilitation. The most commonly reported coping mechanism for self-management of CRCD was the use of assistive memory devices such notebooks, smartphones, calendars, and sticky notes to aid with planning and recording everyday events and tasks. Other common compensatory strategies included seeking support from friends, family, and social circles; increasing quality of sleep; eating a more healthful diet; participating in physical activity; and participating in mentally-stimulating activities (e.g. Sudoku puzzles, mahjong). Notably, adaptive cognitive strategies were identified as efficacious in 7 of the 10 studies, and rehabilitation professionals may be particularly qualified to teach these techniques [42]. In addition to the strategies outlined in this scoping review, Raffa et al. recommend that cancer survivors utilize environmental modifications, memorization exercises, mnemonic devices, and avoidance of distractions [2] in order to manage CRCD. Accordingly, a rehabilitation professional might guide a patient to establish a daily calendar, to-do-list, or reminder system to compensate for problems with memory or focus; or he or she might assist a patient in reorganizing a desk space or closet in order to promote order and minimize distractions during daily tasks, or place important items in easy-to-see places in the home in order to prompt memory. Another noteworthy theme was the use of relaxation training or stress management in order to manage CRCD. Stress and anxiety often occur in patients with CRCD [4] and can exacerbate cognitive dysfunction [18]. Many rehabilitation professionals are well-equipped to address stress and anxiety in order to promote better outcomes in patient care [43]. Occupational and physical therapists may, for example, help patients to learn and implement progressive relaxation techniques in order to combat anxiety or manage workload and schedule in order to decrease stress. The results of this scoping review also indicated that physical activity is used to address CRCD symptoms, both as a rehabilitation intervention and as a self-generated coping technique. This finding is consistent with the results of recent animal studies that demonstrated an amelioration of chemotherapy-induced cognitive impairments following a physical activity regimen [16]. Rehabilitation professionals can encourage patients to develop and maintain exercise routines in a number of ways. Physical therapists may be instrumental in creating appropriate routines for physical activity, while occupational therapists, social workers, and other practitioners might assist patients with creating a sustainable schedule for making healthy habit change to incorporate exercise into everyday life. Finally, the scoping review results demonstrated that personally meaningful activity engagement (e.g. social activity, artistic
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pursuits) can be used to ameliorate symptoms of CRCD. Cancer survivors suffering from CRCD may lose the ability to participate in daily life as they abandon their most valued activities due to cognitive deficits. Therefore, clinicians may wish to establish new or pre-existing activity interests and ensure that patients are working towards goals that will enhance fulfillment and a sense of life purpose. By doing so, they can help patients compensate for some of the decrease in participation that can result from CRCD by introducing new, more appropriate activities and keeping cancer survivors fully engaged in their lives. Given that symptoms of CRCD may begin soon after the onset of cancer treatment and last up to a decade [2,14], rehabilitation professionals working throughout the full spectrum of patient care—from inpatient to outpatient and beyond—should be prepared to address symptoms of CRCD in clients. Of course, ongoing rehabilitation services can become costly. For this reason, clinicians should ask clients at the onset of treatment and frequently thereafter about the development of any cognitive deficits in order to identify and treat symptoms as early as possible.
Limitations, gaps, and future directions One of the major limitations of this scoping review is that the majority of the studies included focused on breast cancer survivors only. Since CRCD affects individuals across a wide range of types of cancer, this narrow focus limits the generalizability of the results of these studies to a broader population of survivors. The small average n size across all studies also reflects a lower generalizability. The review was limited by the fact that the search did not address grey material, which may have resulted in missing relevant information. No assessment of the quality of the studies in the review was completed, which may be considered an additional limitation of this paper. However, this decision was justified as quality evaluation is typically not conducted in established scoping review methodology. Finally, the review did not include several large-scale studies of interventions for CRCD that are currently recruiting or completed but not yet published [44]. These studies, when published, may yield important additions to the literature on rehabilitation interventions for CRCD in cancer survivors. Based on the results of this scoping review, the following gaps in the literature should be prioritized in future research: (1) coping strategies and interventions used with a population of a greater variety cancers, including but not limited to breast cancer; (2) the efficacy of rehabilitation techniques outside of cognitive/neuropsychological or cognitive–behavioral training (e.g. meditation, yoga); (3) investigation of the contributions of specific rehabilitation fields (e.g. occupational therapy, physical therapy, social work) in CRCD interventions; and (4) development of assessments to accurately measure various presentations of CRCD. In a best evidence synthesis, Egan et al. found a dearth of evidence supporting the general role of rehabilitation professionals in cancer care [45]. Therefore, future research should also serve to elucidate the broader role of rehabilitation in cancer survivorship, both with CRCD and with other related issues.
Conclusions CRCD is a complex and relatively unstudied phenomenon in the field of rehabilitation. While we understand the neuroscience behind many of its structural and functional manifestations, many questions remain as to its etiology and treatment. This scoping review revealed a small cache of evidence regarding nonpharmacological rehabilitation interventions for CRCD. Current research provides preliminary evidence that CBT and neuropsychological and cognitive training interventions—both in-person and computer-based—may be efficacious in improving symptoms
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of CRCD. Qualitative studies also offer insight into effective coping strategies for self-management of CRCD, most notably the use of assistive memory devices, stress management, and physical activity. Further research is needed about the lived experience of cancer survivors with CRCD and about appropriate rehabilitation techniques for this population. Ultimately, with an awareness of the neuroscience of CRCD, its risk factors, and the evidencebased interventions and coping strategies available for its treatment, rehabilitation professionals can contribute to ameliorating—or even eliminating entirely—the negative mental, physical, and participation-related consequences of CRCD.
Acknowledgements
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The author would like to extend sincere thanks to Dr. Florence Clark, Dr. Lisa Aziz-Zadeh and Alison Cogan, and the anonymous reviewers for their insightful comments on earlier drafts of this article.
Declaration of interest The author reports no conflicts of interest.
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16. Fardell JE, Vardy J, Shah J, Johnston IN. Cognitive impairments caused by oxaliplatin and 5-fluorouracil chemotherapy are ameliorated by physical activity. Psychopharmacology 2012;220: 183–93. 17. Davies C, Pan H, Godwin J, Gray R, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013;381:805–16. 18. Mulrooney T. Cognitive impairment after breast cancer treatment. Clin J Oncol Nurs 2008;12:678–80. 19. American Cancer Society. Chemo brain. Available from: http:// www.cancer.org/treatment/treatmentsandsideeffects/physicalsideeffects/chemotherapyeffects/chemo-brain [last accessed 14 Dec 2013]. 20. Wilson C, Finch C, Cohen H. Cytokines and cognition—the case for a head-to-toe inflammatory paradigm. J Am Geriatr Soc 2002;50: 2041–56. 21. Kipnis J, Derecki N, Yang C, Scrable H. Immunity and cognition: what do age-related dementia, HIV-dementia, and ‘chemo-brain’ have in common? Trends Immunol 2008;29:455–63. 22. Schagen S, Das D, Fris S. The influence of priming and pre-existing knowledge of chemotherapy-associated cognitive complaints on the reporting of such complaints in breast cancer patients. PsychoOncology 2008;18:674–8. 23. Schagen S, van Dam F, Muller M, et al. Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer 1999;85:640–50. 24. Ferguson RJ, Martinson A. An overview of cognitive-behavioral management of memory dysfunction associated with chemotherapy. Psicooncologia 2011;8:385–404. 25. Cheung YT, Shwe M, Tan YP, et al. Cognitive changes in multiethnic Asian breast cancer patients: a focus group study. Ann Oncol 2012;23:2547–52. 26. Von Ah D, Habermann B, Carpenter JS, Schneider BL. Impact of perceived cognitive impairment in breast cancer survivors. Eur J Oncol Nurs 2012;17:236–41. 27. Falleti M, Maruff P, Weih L, Phillips K. The nature and severity of cognitive impairment associated with adjurvant chemotherapy in women with breast cancer: a meta-analysis of the current literature. Brain Cognit 2005;59:60–70. 28. Munir F, Burrows J, Yarker J, et al. Women’s perceptions of chemotherapy-induced cognitive side effects on work ability: a focus group study. J Clin Nurs 2010;19:1362–70. 29. Fitch MI, Armstrong J, Tsang S. Patients’ experiences with cognitive changes after chemotherapy. Can Oncol Nurs J 2007;18: 180–92. 30. Andreotti C, Root JC, Ahles TA, et al. Cancer, coping, and cognition: a model for the role of stress reactivity in cancerrelated cognitive decline. Psycho-Oncology 2014; doi:10.1002/ pon.3683. 31. Arksey H, O’Malley L. Scoping studies: towards a methodological framework. Int J Soc Res Methodol 2005;8:19–32. 32. Levac D, Colquhoun H, O’Brien KK. Scoping studies: advancing the methodology. Implement Sci 2010;5:1–9. 33. Courtois A, Ford J, eds. Treating complex traumatic stress disorders: scientific foundations and therapeutic models. New York (NY): Guilford Press; 2009:243. 34. Ferguson RJ, Ahles TA, Saykin AJ, et al. Cognitive-behavioral management of chemotherapy-related cognitive change. PsychoOncology 2007;16:772–7. 35. Ferguson RJ, McDonald BC, Rocque MA, et al. Development of CBT for chemotherapy-related cognitive change: results of a waitlist control trial. Psycho-Oncology 2012;21:176–86. 36. Goedendorp MM, Knoop H, Gielissen MF, et al. The Effects of cognitive behavioral therapy for postcancer fatigue on perceived cognitive disabilities and neuropsychological test performance. J Pain Sympt Manage 2012;47:35–44. 37. Rebok GW, Ball K, Guey LT, et al. Ten-year effects of the advanced cognitive training for independent and vital elderly cognitive training trial on cognition and everyday functioning in older adults. J Am Geriatr Soc 2014;62:16–24. 38. Kesler S, Hosseini SM, Heckler C, et al. Cognitive training for improving executive function in chemotherapy-treated breast cancer survivors. Clin Breast Canc 2013;13:299–306. 39. McDougall GJ, Becker H, Acee TW, et al. Symptom management of affective and cognitive disturbance with a group of cancer survivors. Arch Psychiatr Nurs 2011;25:24–35.
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43. American Occupational Therapy Association. The role of occupational therapy in oncology; 2011. Available from: http://www. aota.org/Consumers/Professionals/WhatIsOT/MH/Facts/OT-RoleOncology.aspx [last accessed 22 Nov 2012]. 44. Gehring K, Roukema JA, Sitskoorn M. Review of recent studies on interventions for cognitive deficits in patients with cancer. Expert Rev Anticancer Therap 2012; 12:255–69. 45. Egan M, McEwen S, Sikora L, et al. Rehabilitation following cancer treatment. Disabil Rehabil 2013;35:2245–58.
PERSPECTIVES IN REHABILITATION
Coping with cancer-related cognitive dysfunction: a scoping review of the literature Alix Sleight
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Mrs. T.H. Chan Division of Occupational Science and Occupational Therapy, University of Southern California, Los Angeles, CA, USA
Abstract
Keywords
Purpose: Cancer-related cognitive dysfunction (CRCD) impacts memory, attention, concentration, language, multi-tasking, and organizational skills and decreases participation and quality of life for cancer survivors. The objectives of this article are: (1) to outline the neuroscience of CRCD, its risk factors, and its effect on participation; and (2) to identify and summarize the literature on rehabilitation interventions and coping techniques for CRCD in cancer survivors. Methods: A scoping review of articles cited in PubMed, MEDLINE, PsychINFO, and CINAHL was performed. To be included, articles must have been published in a peer-reviewed scientific journal between 1996 and 2014, written in English, and included a quantitative or qualitative non-pharmacological study of interventions and/or coping strategies for adult cancer survivors experiencing CRCD. Results: Ten articles met the inclusion criteria for final review. Six studies tested the efficacy of rehabilitation treatments on CRCD. Three involved cognitive–behavioral therapy (CBT), while three tested neuropsychological and/or cognitive training interventions. Four qualitative studies investigated coping strategies used by survivors with CRCD. Conclusions: CBT-based treatments and neuropsychological/cognitive training methods may ameliorate symptoms of CRCD. The most commonly-reported coping strategy is utilization of assistive technology and memory aids. Further research is needed about efficacious rehabilitation techniques for this population.
Cancer, chemotherapy, cognitive dysfunction History Received 31 May 2014 Revised 31 March 2015 Accepted 2 April 2015 Published online 17 April 2015
ä Implications for Rehabilitation
Cancer-related cognitive dysfunction (CRCD) may impact up to 50% of cancer survivors. CRCD can significantly decrease participation and quality of life during survivorship. Cognitive–behavioral therapy (CBT) and neuropsychological/cognitive training methods may ameliorate symptoms of CRCD. The most common coping strategy reported by cancer survivors with CRCD is the use of assistive technology and memory aids.
Introduction Adjuvant chemotherapy treatment is delivered in conjunction with primary cancer treatments such as surgery or radiation. It involves the use of drugs to kill rapidly dividing cells throughout the entire body and is designed to increase the chance of long-term survival [1]. Cancer-related cognitive dysfunction (CRCD) following adjuvant chemotherapy treatment is reported to affect cancer survivors across a variety of ages and cancer diagnoses, and the deficits can last up to years after the completion of chemotherapy [2]. Many studies cite the incidence of CRCD to be between 15% and 25% in cancer survivors [3]. Furthermore, some sources
Address for correspondence: Alix Sleight, OTD, OTR/L, Phd Student, Mrs. T.H. Chan Division of Occupational Science and Occupational Therapy, University of Southern California, 1540 Alcazar Street, CHP133, Los Angeles, CA 90033, USA. Tel: +1 (323) 442-2850. E-mail: [email protected]
estimate CRCD occurs in as many as 50% of women undergoing chemotherapy for breast cancer [4]. CRCD has been referred to by several terms, including posttreatment cognitive dysfunction, chemotherapy-induced cognitive changes, mild cognitive impairment, chemo fog, and central neurotoxicity. The most frequently used colloquial term to describe the phenomenon is chemo brain [4]. However, this term has been criticized as trivializing and not accurately portraying the processes involved in the condition [5]. For this reason, the term CRCD will be used throughout this article. Patient reported or observed mild cognitive impairment following chemotherapy was largely unacknowledged by the medical community until recently [6]. Although references to cognitive change associated with chemotherapy originated in the 1980s, serious studies on the topic did not begin until the mid-1990s [3]. Presently, breast cancer survivors are the most studied population in CRCD research. This may be due to the prevalence of breast cancer as compared to other cancers [7], the fact that breast cancer research is particularly well-funded [8], or the fact that adjuvant
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therapy drugs used for breast cancer (e.g. tamoxifen) may specifically exacerbate CRCD symptoms [9]. Regardless, it is clear that research regarding CRCD in the general cancer population has been limited [10]. CRCD is typically reported as impacting verbal and visual memory, attention, concentration, language, motor skills, multitasking, and the ability to organize information [11]. CRCD deserves closer attention and understanding from rehabilitation professionals, as it can have substantial effects on participation and quality of life for cancer survivors. In addition, clinicians should be aware of the evidence-based interventions and coping strategies available to maximize participation for individuals with CRCD. The purpose of this article is (1) to outline the neuroscience of CRCD, its risk factors, and its effect on participation for cancer survivors; and (2) to identify and summarize the literature on rehabilitation interventions and coping strategies for CRCD in cancer survivors.
Background Structural and functional explanations for CRCD Electrophysiological and imaging studies completed over the past several years confirm that there are specific structural and functional changes in the brain that may account for the appearance of CRCD [11]. In a study by Inagaki et al., magnetic resonance imaging (MRI) results indicated that the brains of breast cancer survivors who had been exposed to adjuvant chemotherapy demonstrated decreased brain volume in the gray and white matter, including in the superior and middle frontal gyri, parahippocampal gyrus, cingulated gyrus, and precuneus. The volumes of the parahippocampal gyrus, prefrontal, and precuneus were significantly correlated with behavioral measures of attention/concentration and/or visual memory [12]. Indeed, broadly speaking, the parahippocampus is involved in memory processes, while the prefrontal cortex has been linked to attention and, together with the precuneus, is involved in aspects of selfprocessing [13]. Thus, changes in these brain regions, especially as they are correlated with measures of attention and memory, suggest a possible neural basis for symptoms of CRCD. Interestingly, the brain volume changes detected by Inagaki et al. were present at 1 year post-cancer treatment, but not at 3 years post-treatment, indicating that neural structural changes causing CRCD may stabilize or disappear with time [12]. Another study by Silverman et al., however, showed that chemotherapy may cause lasting—or at least lingering—changes in brain function. Researchers used positron emission tomography (PET) scans to analyze cerebral blood flow changes and resting brain metabolism of breast cancer survivors who had received chemotherapy 5–10 years prior to the study. Results indicated significant differences between the group who had received chemotherapy and the group that had not in the inferior frontal gyrus and the posterior cerebellum near the midline. Greater recruitment of frontal cortical tissue was involved, as indicated by metabolism in this region, when chemotherapy-treated patients performed memory tasks, suggesting that even up to a decade post-treatment, patients may experience symptoms of CRCD when performing cognitive tasks [14]. Neurochemical and physiological explanations for CRCD When searching for an explanation for CRCD on a physiological and/or neurochemical level, the first natural suspect would be the chemotherapy drugs themselves. There is a known correlation between exposure to chemotherapy drugs and CRCD, particularly in the domains of episodic and working memory [15]. In order to affect the brain directly, chemotherapy drugs must be lipid soluble
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or otherwise be able to cross the blood–brain barrier. Many chemotherapy drugs, however, have been found in only minimal concentrations in the brain. Evidence from animal studies has shown that certain chemotherapy agents can cross the blood–brain barrier [16], but researchers continue to debate whether current chemotherapeutic drugs are able to cross the blood–brain barrier in humans [2]. Another possibility is that chemotherapy may damage the physical structure or functional properties of the blood–brain barrier itself, allowing an influx of inflammatory cells [4]. In short, the exact mechanism through which chemotherapy drugs produce CRCD remains unclear. Other frequent cancer side effects may also be implicated in CRCD. These mechanisms include hormonal imbalances, cytokine level imbalances, anemia, and thrombosis. For example, hormones can affect cognition processes. Estrogen, in particular, is thought to improve cognition by supporting cholinergic activity in the brain [2], but adjuvant therapy drugs such as tamoxifen, which is commonly prescribed in cases of breast cancer, decrease estrogen levels, thereby causing memory problems that can contribute to CRCD [9]. Indeed, current recommendations for survivors of estrogen receptor-positive breast cancer include a 10-year regimen of tamoxifen [17], which may in turn cause ongoing cognitive issues well into the survivorship period. Stress and anxiety, two additional confounding factors, often occur in patients with CRCD [4] and can also exacerbate cognitive dysfunction [18]. Finally, fatigue, a common complaint for many cancer survivors, can also amplify the symptoms of CRCD [19]. Cytokines, immune-mediated inflammatory agents that naturally increase in the body as a response to cancer and cancer treatment, have also been suspected of producing cognition problems [20]. Unlike chemotherapeutic drugs themselves, cytokines are absolutely able to cross the blood–brain barrier, so they remain a strong candidate as a cause for CRCD. However, the issue is complicated by the fact that cytokine mechanisms may be a result of the cancer itself or of the drugs used to treat the cancer [2]. Kipnis et al. have also suggested the possibility that the generalized immune decline caused by chemotherapy leads to CRCD [21], while another possible explanation for CRCD could be that chemical substances released by intact or damaged cancer cells, or chemical mediators of the patient’s immune response mechanisms, gain access to the brain and cause cognitive deterioration [2]. Schagen et al. have suggested that priming and pre-existing knowledge of CRCD can influence the reporting of the phenomenon itself [22]. This idea may be substantiated by findings that subjective complaints of CRCD do not always correlate with objective measures of cognitive function [23]. However, it should be noted that the lack of correlation between subjective complaints and objective measures may stem from the nuances of measuring outcomes via self-report and the dearth of functionally valid neuropsychological measures for assessing CRCD [24]. Finally, emotional factors such as depression, which often occur as a result of cancer diagnosis and treatment, may contribute to deficits in memory and cognition [10]. There is still no definitive evidence to establish a causal relationship between any one individual factor and the symptoms of CRCD. Ultimately, there is likely a complex interplay of causes involved in the generation of the cognitive disruptions seen in cancer patients. Risk factors for CRCD Regardless of its etiology, CRCD is more likely to affect people who demonstrate certain risk factors. One of the main risk factors for CRCD is age. Hormone levels decrease as human beings get
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older, and deficiencies in estrogen and progesterone are associated with reduced attention, learning, and memory [4], some of the common symptoms of CRCD. Thus, older adults— particularly post-menopausal women—may be at higher risk. In addition, despite the lack of understanding regarding the exact contribution of chemotherapy drugs to CRCD, research has shown that certain chemotherapy drugs may carry higher associations with CRCD. Cyclophosphamide, methotrexate, and fluoracil have the strongest associations, and high-dose regimens of chemotherapy also increase the risk of developing symptoms of CRCD. Other variables, such as concurrent medications, individual differences in coping abilities, and the nature of the individual disease process, may be risk factors for CRCD, but the strength of their associations are yet unknown [4].
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Effects of CRCD on participation CRCD is the most frequently documented—and most troublesome—chronic post-cancer symptom [6], and it has been shown to have emotional, interpersonal, and even economic effects on cancer survivors. Many of the ramifications from CRCD result in decreased independence. For example, many individuals report being less able to manage everyday responsibilities such as paying bills or running errands [5,6,25]. The ability to drive was also affected for some research participants as focus and memory diminished [5,6,26]. Memory is often affected by CRCD, which can negatively impact participation in everyday life. In a qualitative study of breast cancer survivors, Von Ah et al. [26] found that 100% of participants indicated that their short-term memory was affected by CRCD, causing them to forget simple everyday tasks and appointments. A total of 91% of participants in this study also indicated that long-term memory was affected, which negatively impacted day-to-day function. The participants in the Von Ah et al. study also identified information processing, attention, concentration, word-finding, and executive functioning as being impacted by CRCD. Participants indicated that everyday tasks such as balancing a checkbook and staying oriented in the community became more difficult as a result of CRCD [26]. In a meta-analysis of CRCD literature, Falleti et al. found that memory, concentration, language, and attention were the most frequently impacted areas of cognition [27], and these limitations can in turn affect a number of participation domains. For example, in more extreme circumstances, social role fulfillment can be affected when individuals are no longer able to manage the challenges of child rearing, marriage, and other significant relationships [4]. Many individuals report that CRCD causes alienation from family and friends as others fail to understand, respect, or take seriously the cognitive changes associated with chemo treatment [6,25]. Furthermore, individuals in qualitative studies of breast cancer survivors by Munir et al. [28], Fitch et al. [29], Player et al. [5], and Boykoff et al. [6] reported that CRCD affected their ability to work effectively. As focus, speed, efficiency, and memory diminished, so did the participants’ ability to perform their job duties. Cognitive impairments affecting the ability of these individuals to perform at work included short-term memory problems, issues with verbal ability, decreased speed of information processing, and executive functioning problems such as difficulty multi-tasking, making decisions, and dividing attention [29]. Some participants opted to take leaves of absence or even early retirement as a result of their CRCD [6]. Moreover, recent scholarship indicates that individuals with a high level of allostatic load at diagnosis may be particularly vulnerable to the neurocognitive effects of cancer, creating a vicious cycle for those with CRCD returning to stressful jobs after treatment [30].
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Methods In order to identify the rehabilitation interventions and coping strategies available to help cancer survivors with CRCD, a scoping review of the literature was conducted using the methodology described by Arksey and O’Malley [31] and updated by Levac et al. [32]. Scoping reviews aim to broadly summarize key concepts within a topic and identify gaps in the literature [31]. This methodology is particularly beneficial for use when a topic is complex or has not previously been comprehensively reviewed [30], when a variety of study designs are utilized [31], or when a dearth of randomized controlled trials hinders the process of systematic review [32]. Very little rigorous research has taken place to examine rehabilitation interventions for CRCD, and the topic of CRCD is particularly complex since both self-generated coping strategies and professionally-led interventions are commonly used. Thus, a scoping review was undertaken for this study using the following steps, as recommended by Arksey and O’Malley [31]: (1) Systematic search: The author searched articles cited in PubMed, MEDLINE, PsychINFO, and CINAHL between 1996 and 2014. Search terms were used to capture major rehabilitation disciplines as well as common terminology used to describe the population. Key search terms included ‘‘chemotherapy,’’ ‘‘rehabilitation’’, ‘‘cognitive’’, ‘‘cancer’’, ‘‘oncology’’, ‘‘physical therapy’’, ‘‘occupational therapy’’, ‘‘social work’’, ‘‘post-chemotherapy cognitive deficit’’, ‘‘CRCD’’, ‘‘chemotherapy-related cognitive dysfunction’’, and ‘‘cancer-related cognitive dysfunction’’. Reference lists of the included articles were hand-searched for additional relevant titles. (2) Selection of studies: To be included, articles must have met the following inclusion criteria: published in a peer-reviewed scientific journal between 1996 and 2014, written in English, and involving a quantitative or qualitative non-pharmacological study of interventions and/or coping strategies used for adult cancer survivors experiencing CRCD. Studies were excluded if they were considered ‘‘grey-literature’’ (abstracts, conference proceedings, editorials, etc.). (3) Charting the data: Data were extracted from the included studies and entered into a table (Table 1). The following fields were included: author(s), year, country, study design, population, and findings. (4) Summarizing the results: The charted data were compared and analyzed for themes, trends, breadth, and gaps. Studies were grouped according to study design and sorted according to year of publication.
Results An overview of the search and selection flow process is found in Figure 1. After removal of duplicates, a total of 234 records identified through database search were screened for inclusion. Two hundred and two abstracts were excluded, and an additional 22 full-text articles were excluded for not meeting selection criteria. Ten articles were included in the final synthesis and detailed in Table 1. Six of these studies tested the efficacy of rehabilitation interventions. Five were randomized controlled trials, and one was a single-arm pilot study. Three of these quantitative studies involved cognitive–behavioral therapy (CBT)-based interventions, while three tested neuropsychological and/or cognitive training interventions. Four qualitative studies investigated coping strategies used by survivors with CRCD. Of the 10 studies selected for inclusion, two comprised secondary analyses of pre-existing data. The average n across all studies was 42.8. The years the studies were conducted ranged from 2005 to 2014, and they took place in six different countries: United States (5), Germany (1),
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Table 1. Articles included in the scoping review.
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Author [ref.]
Country
Study design
n
Population
Findings
Quantitative studies Ferguson et al. [34]
United States
Single-arm pilot study of a cognitive–behavioral therapy (CBT) intervention, memory and attention adaptation training (MAAT)
29
Breast cancer survivors, stage I and II, average of 8 years postchemotherapy,
Poppelreuter et al. [40]
Germany
Randomized controlled trial examining efficacy of two neuropsychological training programs
96
Adult female inpatient cancer survivors undergoing oncological rehabilitation
McDougal et al. [39]a
United States
Randomized controlled trial testing the efficacy of a cognitive training intervention
22
Older adult cancer survivors, mean age 74
Ferguson et al. [35]
United States
Randomized controlled trial evaluating the efficacy of a CBT intervention, MAAT
40
Breast cancer survivors, stage I and II
Kesler et al. [38]
United States
Randomized controlled trial to examine feasibility and efficacy of an online executive function (EF) training program
41
Breast cancer survivors, stages I-III
Goedendorp et al. [36]a
Netherlands
Randomized controlled trial of effectiveness of CBT for post-cancer fatigue on decreasing cognitive disability
98
Cancer survivors, male and female, completed cancer treatment at least one year previously
MAAT intervention resulted in improvements in self-report of cognitive function, quality of life, and standard neuropsychological test performance at post-treatment, 2-month, and 6-month follow up. Participants rated MAAT as helpful in improving ability to compensate for memory problems. No significant intervention effect found for either the inperson or computer-based neuropsychological training programs. On performance measures, moderate effects were noted in the treatment group with increases in the Rivermead and HVLT memory performance scores. Moderate effects were also noted for group-by-time interactions on the Brief Visual Memory Test memory performance measure. Decreases in depression and trait anxiety were also observed in the treatment group. Significant increases in memory selfefficacy and self-reported cognitive abilities were reported. MAAT participants made significant improvements relative to controls on the spiritual well-being subscale of the quality of life measure and on verbal memory. Cognitive training led to significant improvements in cognitive flexibility, verbal fluency, and processing speed. Self-rating of EF skills, including planning, organizing, and task monitoring, were also improved in the intervention group. Participants who received CBT for post-cancer fatigue reported significantly less cognitive disability as measured by concentration subscale of the checklist individual strength and the alertness behavior subscale of the sickness impact profile.
Qualitative studies Fitch et al. [29]
Canada
Qualitative study using indepth interviews
32
Adult cancer survivors experiencing CRCD
Primary coping strategy identified wad ‘‘writing everything down’’. Participants also stressed the importance of receiving information about the potential side effects of chemo brain at the onset of treatment. (continued )
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5
Table 1. Continued
Author [ref.]
Country
Study design
n
Population
Findings
Breast cancer patients, stages I–IV, currently receiving chemotherapy or with a history of receiving chemotherapy Breast cancer survivors, completed chemotherapy within 6-12 months
8 coping strategies identified (e.g. keeping a journal/diary, playing mahjong, physical activity).
Cheung et al. [25]
Singapore
Qualitative study using focus groups
43
Myers [41]
United States
Qualitative study using semistructured interviews and a focus group
18
Player et al. [5]
Australia
Qualitative study using semistructured in-depth telephone and face-to-face interviews
9
Breast cancer survivors, stage II and III, completed or currently undergoing chemotherapy
7 primary coping strategies identified (e.g. writing things down, physical activity). 8 coping strategies identified by survivors (e.g. recognizing daily limits, participating in artistic pursuits).
a
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Secondary analysis of data.
Records idenfied through database search (CINAHL, MEDLINE, and PSYCINFO) (n = 242)
Addional records idenfied through hand-searching (n = 10)
Records aer duplicates removed (n = 234)
Abstracts excluded (n =202)
Full-text arcles assessed for eligibility (n =32) Full-text arcles excluded (n = 22)
Arcles included in synthesis (n =10)
Figure 1. Search results and progress through scoping review.
Netherlands (1), Canada (1), Singapore (1) and Australia (1). The studies were conducted by researchers across a wide variety of fields including psychology, oncology, nursing, kinesiology, psychiatry, rehabilitation science, and radiology. Six of the studies involved breast cancer survivors, while the other four included individuals with a range of different types of cancer. Two of the studies involved online or computer-based programs. The results of all studies included in the scoping review are detailed in the next section. Cognitive–behavioral therapy-based interventions for CRCD Three studies included CBT-based interventions for CRCD. CBT is intended to improve function and psychosocial well-being by identifying beliefs, feelings, and behaviors associated with a psychological problem and revising them through exploration and critical analysis. Through participation in CBT, individuals shape new ways of thinking, behaving, and feeling that may reduce or eliminate psychological or emotional disturbances [33].
The first study, a single-arm pilot study, investigated the feasibility and efficacy of a CBT intervention called Memory and Attention Adaptation Training (MAAT) that was aimed at helping breast cancer survivors manage CRCD. The MAAT intervention involved four individual monthly visits and three phone calls from a licensed clinical psychologist, as well as a participant workbook outlining four cognitive–behavioral components: (1) education on memory and attention; (2) self-awareness training; (3) selfregulation, emphasizing relaxation training, activity scheduling, and pacing; and (4) cognitive compensatory strategies training including schedule-making, external cueing, and covert verbal self-guidance during task performance. Significant improvements in self-report of cognitive function, quality of life, and standard neuropsychological test performance were observed post-treatment, as well as at 2-month and 6-month follow-ups [34]. The second study, led by the same principal investigator, continued to examine the efficacy of MAAT through a randomized controlled trial with a waitlist control group. The study was completed over the course of 8 weeks, and MAAT participants made significant improvements relative to the control group on verbal memory and the spiritual well-being subscale of the Quality of Life-Cancer Survivors (QOL-CS) scale. Taken together, the results of these two studies suggest that MAAT is a feasible and practical program for cancer survivors with CRCD that may improve quality of life and cognitive performance [35]. The third study examined the effect of CBT for cancer-related fatigue on CRCD using a secondary analysis of data from a randomized control trial. Cancer patients with severe fatigue received a 6-month CBT intervention focusing on the importance of identifying precipitating and perpetuating factors in the experience of fatigue. Modules addressed (1) coping with the cancer experience; (2) fear of disease recurrence; (3) dysfunctional beliefs regarding fatigue; (4) sleep dysregulation; (5) activity dysregulation; and (6) low social support/negative social interaction. The secondary analysis of this data indicated that patients who received the CBT intervention reported significantly less cognitive disability as well as a clinically relevant reduction in concentration problems as measured by the Concentration subscale of the Checklist Individual Strength and the Alertness Behavior subscale of the Sickness Impact Profile [36]. Neuropsychological/cognitive training interventions for CRCD Three studies addressed the effect of neuropsychological and/or cognitive training interventions for CRCD. Neuropsychological/ cognitive training programs often have similar attributes to CBT
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A. Sleight
but focus more on abilities such as memory, reasoning, and speedof-processing rather than on beliefs, feelings, and behaviors [37]. The first study was a randomized controlled trial to investigate the feasibility and preliminary effectiveness of an online cognitive training program for breast cancer survivors with CRCD. The computerized training program took place over 48 sessions, each 20–30 min long, and was administered using participants’ home computers. The intervention involved various combinations of 13 different exercises designed to improve executive function (EF) skills including cognitive flexibility, working memory, processing speed, and verbal fluency. The exercises all featured visual stimuli that required a motor response and included mental rotation games (e.g. navigating a rotating maze), spatial sequencing memory games (e.g. recalling the location of coins and them finding them in the order of their value), and word stem completion games (e.g. use a word stem such as ‘‘cog’’ to produce as many different words as possible), among others. Exercises were adapted to individual ability and increased in difficulty as participants progressed. Outcome measures included a battery of psychometrically validated and standardized cognitive tests. Cognitive training led to significant improvements in cognitive flexibility, verbal fluency, and processing speed, with marginally significant improvements in verbal memory. Selfratings of EF skills, including task monitoring, organizing, and planning, also improved in the intervention group [38]. The second study was a secondary analysis of data from a randomized controlled trial investigating the efficacy of a ‘‘memory and health training intervention’’ on cognitive performance in older adults. Data from participants who were also cancer survivors (10% of the original sample) were later analyzed. Individuals in the intervention group received a 26-month training in stress management, including guided relaxation; memory selfefficacy; and memory strategy training. Participants learned skill building through developing awareness, handling of controlled challenges, and becoming confident and realistic in everyday situations. The intervention also addressed anxiety, depression, and general health, which were hypothesized to influence memory performance. Outcome measures included a battery of standardized tests to measure verbal memory, visual memory, memory performance, functional status, anxiety, depression, and memory self-efficacy. Moderate effects were noted by increased scores on the Rivermead Everyday Behavioral Memory Test and Hopkins Verbal Learning Test. Moderate effects were also found on the Brief Visual Memory Test memory performance measure. Individuals in the intervention group also demonstrated decreases in depression and trait anxiety, as well as significant improvements on the memory self-report scales. The authors suggest that in order to adapt the content of the intervention for cancer survivors, training should focus on stress and relaxation, identifying false beliefs and factors affecting memory, and training on memory remediation techniques [39]. The third study was a randomized controlled trial testing the efficacy of two different neuropsychological interventions as compared to a control group receiving no specific training. Female breast cancer patients were randomized into an in-person neuropsychological training group (NPT), an individualized computerbased training group (PC), or a no training control group. The individuals in the NPT group participated in a broad spectrum of activities involving attention and memory in an everyday context (e.g. practicing recall of information after listening to the news) as well as training in compensatory strategies for improving cognitive performance (e.g. day planners, notes). This group was led by an occupational therapist. The individuals in the PC group were individually coached using training software designed to address attention and memory. Both intervention groups received four 1-h
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training sessions per week during their inpatient stay. The measures used were a battery of standardized and validated neuropsychological tests for attention and memory, in addition to three questionnaire scales used to capture self-appraisal of cognitive performance. The majority of participants in all three groups (NPT, PC, and control) demonstrated significant improvements across measures post-intervention. Therefore, no significant intervention effect was found [40]. Self-generated coping strategies for CRCD Four qualitative studies investigated the coping strategies employed by cancer survivors with CRCD. The first was a phenomenological study conducted with nine female breast cancer survivors with self-reported CRCD symptoms from New South Wales, Australia. Data were collected through semistructured, in-depth telephone and face-to-face interviews. The investigators found that participants used a combination of selfgenerated organizational and preventative strategies to manage CRCD symptoms, in addition to seeking help when necessary. The most common strategies employed to maintain function included taking notes by using diaries, smartphones, or calendars; structuring the day in order to schedule important daily tasks and self-care; and seeking emotional and practical support from others. Other strategies identified by the participants included exercise and relaxation, relying on a partner to coordinate tasks and appointments, recognizing daily limits and avoiding stressful situations, doing Sudoku puzzles, and participating in artistic pursuits [5]. The second study investigated the experiences of 32 cancer survivors with CRCD through in-depth interviews. Participants identified a variety of strategies used to cope with CRCD, and the most frequently reported strategy was ‘‘writing everything down’’. In addition, individuals indicated that in order to help them cope most effectively with CRCD, it was important that their health care providers provide information about the potential for cognitive change at the beginning of their treatment [29]. In the third qualitative study, 43 chemotherapy-receiving breast cancer patients in Singapore participated in structured focus group discussions conducted by trained psychosocial oncologists and medical social workers. Psychosocial strategies were the most commonly reported for managing CRCD. These strategies included controlling mood and expectations, seeking family support, and engaging in social activities. Other coping strategies identified included sleeping well, eating a balanced diet, participating in exercise, participating in mental activities (e.g. reading, playing mahjong), using written reminders (e.g. keeping a journal, using sticky notes), and using technology (e.g. smartphone reminders, mind-stimulating computer games) [25]. The fourth study used semi-structured interviews and focus groups to investigate the experiences of 18 cancer survivors who reported CRCD symptoms. The most common coping strategy identified was writing things down. Other coping strategies included seeking support and validation, helping others, depending on others, focusing on one task at a time, not rushing, and giving oneself permission to make mistakes. Participants also identified exercise, getting enough rest, and mind stimulation as important coping techniques [41].
Discussion This scoping review of the literature identified a number of evidence-based rehabilitation interventions for cancer survivors with CRCD. These interventions fell into one of two categories: (1) CBT or (2) neuropsychological/cognitive training. While the review revealed some overlap between the two categories, several unique intervention areas emerged from both. Distinct CBT
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DOI: 10.3109/09638288.2015.1038364
interventions relevant to rehabilitation included education on memory and attention; self-awareness training regarding precipitating/perpetuating factors of CRCD symptoms; activity scheduling and pacing; and increasing social support. Unique neuropsychological/cognitive training interventions relevant to rehabilitation included the use of computer games designed to improve EF skills (i.e. those targeting cognitive flexibility, working memory, processing speed, and verbal fluency); memory strategy training; and practicing activities involving attention and memory in an everyday context (e.g. practicing recall of information after listening to the news). Interventions common to both CBT and neuropsychological/cognitive training included stress management, guided relaxation, and training in cognitive compensatory strategies such as schedule-making, notetaking, external cueing, and covert verbal self-guidance during task performance. The scoping review also identified a number of self-generated coping mechanisms used by cancer survivors for CRCD symptoms. Many of these coping mechanisms can be taught and developed during the process of rehabilitation. The most commonly reported coping mechanism for self-management of CRCD was the use of assistive memory devices such notebooks, smartphones, calendars, and sticky notes to aid with planning and recording everyday events and tasks. Other common compensatory strategies included seeking support from friends, family, and social circles; increasing quality of sleep; eating a more healthful diet; participating in physical activity; and participating in mentally-stimulating activities (e.g. Sudoku puzzles, mahjong). Notably, adaptive cognitive strategies were identified as efficacious in 7 of the 10 studies, and rehabilitation professionals may be particularly qualified to teach these techniques [42]. In addition to the strategies outlined in this scoping review, Raffa et al. recommend that cancer survivors utilize environmental modifications, memorization exercises, mnemonic devices, and avoidance of distractions [2] in order to manage CRCD. Accordingly, a rehabilitation professional might guide a patient to establish a daily calendar, to-do-list, or reminder system to compensate for problems with memory or focus; or he or she might assist a patient in reorganizing a desk space or closet in order to promote order and minimize distractions during daily tasks, or place important items in easy-to-see places in the home in order to prompt memory. Another noteworthy theme was the use of relaxation training or stress management in order to manage CRCD. Stress and anxiety often occur in patients with CRCD [4] and can exacerbate cognitive dysfunction [18]. Many rehabilitation professionals are well-equipped to address stress and anxiety in order to promote better outcomes in patient care [43]. Occupational and physical therapists may, for example, help patients to learn and implement progressive relaxation techniques in order to combat anxiety or manage workload and schedule in order to decrease stress. The results of this scoping review also indicated that physical activity is used to address CRCD symptoms, both as a rehabilitation intervention and as a self-generated coping technique. This finding is consistent with the results of recent animal studies that demonstrated an amelioration of chemotherapy-induced cognitive impairments following a physical activity regimen [16]. Rehabilitation professionals can encourage patients to develop and maintain exercise routines in a number of ways. Physical therapists may be instrumental in creating appropriate routines for physical activity, while occupational therapists, social workers, and other practitioners might assist patients with creating a sustainable schedule for making healthy habit change to incorporate exercise into everyday life. Finally, the scoping review results demonstrated that personally meaningful activity engagement (e.g. social activity, artistic
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pursuits) can be used to ameliorate symptoms of CRCD. Cancer survivors suffering from CRCD may lose the ability to participate in daily life as they abandon their most valued activities due to cognitive deficits. Therefore, clinicians may wish to establish new or pre-existing activity interests and ensure that patients are working towards goals that will enhance fulfillment and a sense of life purpose. By doing so, they can help patients compensate for some of the decrease in participation that can result from CRCD by introducing new, more appropriate activities and keeping cancer survivors fully engaged in their lives. Given that symptoms of CRCD may begin soon after the onset of cancer treatment and last up to a decade [2,14], rehabilitation professionals working throughout the full spectrum of patient care—from inpatient to outpatient and beyond—should be prepared to address symptoms of CRCD in clients. Of course, ongoing rehabilitation services can become costly. For this reason, clinicians should ask clients at the onset of treatment and frequently thereafter about the development of any cognitive deficits in order to identify and treat symptoms as early as possible.
Limitations, gaps, and future directions One of the major limitations of this scoping review is that the majority of the studies included focused on breast cancer survivors only. Since CRCD affects individuals across a wide range of types of cancer, this narrow focus limits the generalizability of the results of these studies to a broader population of survivors. The small average n size across all studies also reflects a lower generalizability. The review was limited by the fact that the search did not address grey material, which may have resulted in missing relevant information. No assessment of the quality of the studies in the review was completed, which may be considered an additional limitation of this paper. However, this decision was justified as quality evaluation is typically not conducted in established scoping review methodology. Finally, the review did not include several large-scale studies of interventions for CRCD that are currently recruiting or completed but not yet published [44]. These studies, when published, may yield important additions to the literature on rehabilitation interventions for CRCD in cancer survivors. Based on the results of this scoping review, the following gaps in the literature should be prioritized in future research: (1) coping strategies and interventions used with a population of a greater variety cancers, including but not limited to breast cancer; (2) the efficacy of rehabilitation techniques outside of cognitive/neuropsychological or cognitive–behavioral training (e.g. meditation, yoga); (3) investigation of the contributions of specific rehabilitation fields (e.g. occupational therapy, physical therapy, social work) in CRCD interventions; and (4) development of assessments to accurately measure various presentations of CRCD. In a best evidence synthesis, Egan et al. found a dearth of evidence supporting the general role of rehabilitation professionals in cancer care [45]. Therefore, future research should also serve to elucidate the broader role of rehabilitation in cancer survivorship, both with CRCD and with other related issues.
Conclusions CRCD is a complex and relatively unstudied phenomenon in the field of rehabilitation. While we understand the neuroscience behind many of its structural and functional manifestations, many questions remain as to its etiology and treatment. This scoping review revealed a small cache of evidence regarding nonpharmacological rehabilitation interventions for CRCD. Current research provides preliminary evidence that CBT and neuropsychological and cognitive training interventions—both in-person and computer-based—may be efficacious in improving symptoms
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of CRCD. Qualitative studies also offer insight into effective coping strategies for self-management of CRCD, most notably the use of assistive memory devices, stress management, and physical activity. Further research is needed about the lived experience of cancer survivors with CRCD and about appropriate rehabilitation techniques for this population. Ultimately, with an awareness of the neuroscience of CRCD, its risk factors, and the evidencebased interventions and coping strategies available for its treatment, rehabilitation professionals can contribute to ameliorating—or even eliminating entirely—the negative mental, physical, and participation-related consequences of CRCD.
Acknowledgements
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The author would like to extend sincere thanks to Dr. Florence Clark, Dr. Lisa Aziz-Zadeh and Alison Cogan, and the anonymous reviewers for their insightful comments on earlier drafts of this article.
Declaration of interest The author reports no conflicts of interest.
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