Vol. 49 No. 4 April 2015
Journal of Pain and Symptom Management 697
Original Article
Perceived Cognitive Function in Breast Cancer Survivors: Evaluating Relationships With Objective Cognitive Performance and Other Symptoms Using the Functional Assessment of Cancer TherapydCognitive Function Instrument Diane Von Ah, PhD, RN, and Eileen F. Tallman, BS, BA Department of Adult Health (D.V.A.), Indiana University School of Nursing; and Department of Radiology and Imaging Sciences (E.F.T.), Indiana University School of Medicine, Indianapolis, Indiana, USA
Abstract Context. Perceived cognitive impairment (PCI) has been shown to be one of the most common symptoms after breast cancer treatment. However, this symptom does not always correlate with objective cognitive performance and is often highly associated with other patient-reported symptoms. Objectives. Using a sample of breast cancer survivors (BCS), this study examined relationships among the Functional Assessment of Cancer Therapy-Cognitive (FACT-Cog) scale, a self-report questionnaire that measures PCI; impact on quality of life (QoL); comments from others (other); perceived cognitive ability (PCA); objective cognitive performance on tests of verbal memory, speed of processing, and executive functioning; and other symptoms (fatigue, depression, anxiety, and sleep disturbance). Methods. The BCS who were aged 40 years or older and at least one year post-chemotherapy treatment were enrolled. Participants completed questionnaires and a brief neuropsychological assessment. Results. A total of 88 BCS who were on average 56.7 (SD 8.5) years old and 5.3 (SD 4.1) years post-treatment participated; 94% reported clinically significant PCI. The PCI was significantly correlated with some objective measures of immediate and delayed verbal memory and executive function, whereas PCA was associated with all these measures. The PCI and PCA were both significantly associated with depressive symptoms, fatigue, and anxiety, but only PCI was related to poor global sleep quality. Conclusion. The PCA was highly correlated with objective neuropsychological performance and may be clinically useful in identifying problems with verbal memory and executive functioning in BCS. J Pain Symptom Manage 2015;49:697e706. Ó 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. Key Words Cognitive impairment, breast cancer survivor, symptoms, neuropsychological assessment
Introduction Breast cancer survivors (BCS) often report changes in cognitive function after cancer and cancer treatment.1e4 In fact, researchers have shown that perceived cognitive impairment (PCI) is one of their most prevalent symptoms over three phases of the
Address correspondence to: Diane Von Ah, PhD, RN, Department of Community and Health Systems, Indiana University School of Nursing, Indianapolis, IN 46202, USA. E-mail: [email protected] Ó 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.
disease.5 The PCI after cancer and cancer treatment, often referred to as ‘‘chemo brain’’ by BCS,1,3,6,7 has been associated with difficulties in everyday functioning and reported by survivors as problems with memory, attention, speed of processing, and decision making.4,8 PCI has been shown to have a significant
Accepted for publication: August 14, 2014.
0885-3924/$ - see front matter http://dx.doi.org/10.1016/j.jpainsymman.2014.08.012
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impact on BCS’ self-perceptions, social network, work ability, and overall quality of life (QoL).1,2,4,6,9 Cognitive impairment also has been documented among BCS using objective neuropsychological tests. Researchers have shown that cancer survivors perform more poorly on objective neuropsychological tests relative to healthy age- and education-matched women and to published norms.10e13 Although neuropsychological tests are considered the gold standard in assessing cognitive impairment, such tests are not always feasible or affordable.14 Administration of neuropsychological test batteries requires a trained and qualified professional and is often time intensive, which limits their use in practice.15 In addition, administration of large and lengthy neuropsychological test batteries may lead to conflicting test results because of fatigue, loss of attention, and decreased motivation.15,16 Concerns also have been raised in some studies that neuropsychological assessments are not always sensitive to the subtle cognitive impairment incurred by BCS.15 Accurate subjective reports of cognitive impairment, however, would be clinically useful in identifying survivors with subtle deficits.14 Although studies have not always supported a relationship between PCI and objective neuropsychological tests,17e22 subjective measures of impairment have been shown to correlate significantly with changes on magnetic resonance imaging that demonstrate impairment.23e25 In fact, Ferguson et al23 found that one BCS with substantial cognitive complaints had both structural changes (increased white matter hyperintensities) and functional changes (expanded spatial activation during a working memory task) compared with her nonaffected twin. Therefore, finding efficient screening tools capable of identifying patients with clinically significant cognitive impairment is needed for both research and practice. The Functional Assessment of Cancer Therapy Cognitive Scale (FACT-Cog, Version 3)14,25e28 is one of the most well-known and widely used self-assessment measures of cognitive concerns and has even been translated into other languages.29 This instrument was originally developed using cancer patient focus groups and oncology clinical experts. The FACT-Cog is unique in that it measures both cognitive concerns (impairment or deficiency) and cognitive abilities--two concepts that are distinct and independent of one another.14,30 Notably, the Patient Reported Outcomes Measurement and Information System (PROMIS, www.nihpromis. org), an initiative by the National Institutes of Health (NIH) to develop reliable and valid patient-reported symptoms measures, has identified both perceived cognitive concerns and cognitive abilities as concepts of interest in assessing cognition. The FACT-Cog, both the total score and more recently the subscale scores of
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PCI and perceived cognitive ability (PCA), has been widely used; however, little information is available regarding the relationship of this instrument and subscale scores with objective cognitive performance.14 More research is needed to understand these relationships, as well as relationships between the FACT-Cog and its subscale scores with other symptoms (anxiety, depression, fatigue, and sleep). In fact, although the FACT-Cog has been shown to be significantly correlated with other symptoms,26 researchers recently have identified that PCI may relate more to other clinical features such as depression and anxiety than PCA. These findings suggest that these subscales are tapping into distinct and separate constructs, supporting the need for further research examining the use of both subscales and their relationship to other clinical symptoms.30 Therefore, the purpose of this study was to explore the perceived cognitive functioning of BCS using the FACT-Cog and its subscale scores and their relationships to objective cognitive performance (verbal memory, speed of processing, and executive function) and to other symptoms (depression, fatigue, anxiety, and sleep).
Methods This study was part of a longitudinal, randomized controlled trial to test advanced cognitive training programs in BCS.31 All data used in this study were collected at one time at baseline assessment.
Procedure The BCS were recruited from a Midwestern cancer center and affiliated clinics. Women included in this study were aged at least 40 years or older, postmenopausal, and underwent at least 12 months postcancer treatment that had included chemotherapy. In addition, based on self-report and medical record review, participants were free of any psychiatric (including major depression) or neurological (encephalitis, traumatic brain injury, brain surgery, dementia, or Alzheimer’s disease) disorders. Women included in the study reported having cognitive problems since their diagnosis and treatment for breast cancer and were seeking treatment for them.
Measures Eligible and interested women were consented and completed subjective questionnaires that assessed demographic and medical information; perceived cognitive functioning; and symptoms of depression, fatigue, anxiety, and global sleep quality. They also completed a brief objective battery of neuropsychological tests; the battery was brief to minimize fatigue. The neuropsychological tests were administered by the same trained psychology graduate student at the academic health
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center in a quiet, private, and designated space for the assessments. The assessments took approximately 50 minutes to complete. Subjective and objective cognitive measures were administrated at the same appointment. All tests were administered in the same fixed order to reduce variability resulting from test presentation. Demographic and Medical Information. An investigatordeveloped questionnaire was used to collect demographic information including age, education, employment status, marital status, income, and medical information (stage of disease, time posttreatment, type of adjuvant therapy, use of antihormonal medications including tamoxifen and aromatase inhibitors). Medical information was validated by a medical record review. Perceived Cognitive Function. Perceived cognitive function was measured by the FACT-Cog,25,26 a 37-item measure designed to assess cognitive complaints in cancer patients. The FACT-Cog Version 3 includes negatively worded (e.g., I have had trouble concentrating) and positively worded (e.g., My mind is as sharp as it has always been) items. The FACT-Cog yields a total score and four subscale scores including: 1) PCI, 2) perceived impairments in QoL, 3) perception and comments from others, and 4) PCA. When rating PCI and comments from others (other), participants must rate on a five-point Likert scale (0 ¼ never to 4 ¼ several times a day) the frequency with which each phenomenon had occurred in the past seven days. The QoL and PCA are rated on five-point scales (from 0 ¼ not at all to 4 ¼ very much). Negatively worded items are reverse scored to create subscale scores, with higher scores reflecting fewer cognitive problems and better QoL. The FACT-Cog was developed through interviews with cancer patients and also validated with cancer patients including BCS.25 This instrument has demonstrated acceptable reliability in BCS14,25 and in this study, the Cronbach alpha was 0.86 for the total score, with subscale scores ranging from 0.77 to 0.86. Cognitive Performance. Cognitive performance was determined through the use of a brief battery of neuropsychological tests to measure immediate and delayed verbal memory, speed of processing, and executive function. The neuropsychological tests chosen for this study have been used in large clinical trials in both the well elderly32 and BCSs.17 Objective verbal memory (immediate and delayed) was assessed by two separate measures including the Rey Auditory Verbal Learning Test (AVLT) and the Rivermead Behavioral Memory Test (RBMT). The AVLT33 is a word list reading task commonly used to
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test verbal memory. Individuals are presented with a 15-item word list. Five learning trials are conducted and immediate recall is taken after each. An interference list precedes the short-term delayed recall of the initial list and after 30 minutes, a long-term delayed recall is taken. The score is the number of words recalled at each trial, with higher scores indicating better performance. The AVLT has evidence of construct validity when compared with other measures of verbal memory, such as the California Verbal Learning test34 and divergent validity with other neuropsychological tests such as the Trail Making Test, a measure of executive function.35 This instrument also has demonstrated sensitivity in identifying significant cognitive impairment in studies with BCS.18,36 The AVLT has strong reliability, with test-retest correlation coefficients for immediate memory ranging from r ¼ 0.79 to 0.84 and delayed memory r ¼ 0.74 to 0.77.37,38 The AVLT was selected over other tools (e.g., Wechsler Memory Scale-IV) for inclusion in NIH epilepsy neuropsychological common data elements39 and has been identified as an NIH Toolbox instrument.40 The RBMT Story Subtest41 is a story recall test used to assess verbal memory. Participants listen to a short passage that is read aloud and then asked to write down as much as they can remember immediately afterward and again after a 30 minute delay, producing immediate and delayed recall scores.42 Two stories were presented at each assessment and the average score was used, with higher scores indicating better performance. The RBMT has been validated with other verbal learning and memory tests, as well as by consistently demonstrating poorer scores for patients identified by therapists as experiencing memory deficits.43 The RBMT has demonstrated adequate test-retest reliability (r ¼ 0.60) in cognitively impaired populations.44 However, the main advantage for using this test is that it has been shown to reliably assess memory performance in BCS.17,45 Objective speed of processing was measured with the Symbol Digit Modalities Test (SDMT) oral response format.46 Participants were asked to substitute simple geometric shapes for numbers using a legend. Responses were reported orally over 90 seconds. The oral format has demonstrated moderate test-retest reliability (r ¼ 0.76)47 and adequate construct validity48 and has been used with BCS.36 Objective executive functioning was measured by the Controlled Oral Word Association (COWA).49 For this test, participants are asked to spontaneously produce words beginning with a given letter (C, F, L or P, R, W) for one minute. The participants also are instructed to refrain from using words with similar endings (i.e., love or loving), proper nouns, or numbers. High reliability for the COWA has been demonstrated (r ¼ 0.83) as well as significant test-
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retest reliability (r ¼ 0.74).50 Construct validity was demonstrated by statistically significant correlations between the COWA and two other neuropsychological assessments of executive function (Wechsler Adult Intelligence Scale-Similarities Test and Ruff Figural Fluency Test).51 This instrument has been used in cancer patients including BCS.17,36 Depressive Symptoms. The 20-item Center for Epidemiologic Studies Depression Scale (CES-D) assesses depressive symptoms over the past week (total score range 0e60, with higher scores indicating greater symptom burden).52 A score higher than 16 indicates high levels of depressive symptoms and has been used as a proxy for clinically significant depression in previous studies.52,53 The CES-D has shown strong correlation with other measures of depression and has strong internal consistency,53 and it has been widely used in cancer patients,53,54 including BCS.31,55 The Cronbach alpha in this study was 0.89. Fatigue. The Functional Assessment of Cancer Therapy-Fatigue (FACT-F)56 is a 13-item measure that asks respondents to rate symptoms of fatigue over the last seven days on a five-point scale ranging from zero (not at all) to four (very much so). Higher scores reflect lower fatigue. The FACT-F has strong internal consistency and test-retest reliability (r ¼ 0.90). Convergent validity has been demonstrated through high correlations with the Piper Fatigue Scale and Profile of Mood States-Fatigue Subscale (r ¼ 0.77 and 0.83, respectively). This instrument was designed and validated for cancer patients56 and has been used extensively with that population,57,58 including BCS.59,60 In this study, the Cronbach alpha was 0.94. State Anxiety. The 40-item Spielberger State-Trait Anxiety Inventory-State Subscale (STAI-S)61 has two subscales assessing state and trait anxiety. In this study, we assessed state anxiety because this has been correlated with cognitive functioning in other studies.62 The STAI-S comprises 20 questions that require participants to rate how they feel at the present time (‘‘at this moment’’) using a scale from one (almost never) to four (almost always). Higher scores indicate more anxiety. The STAI-S has demonstrated acceptable correlations (r ¼ 0.80) with other established anxiety measures and strong reliability (Cronbach alpha ¼ 0.93).63 This instrument has been widely used in cancer patients including BCS.64 The Cronbach alpha was 0.89 in this study. Sleep. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality and disturbances during the past week.65 The 19-item questionnaire includes items asking about usual bed time, wake time, number
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of actual hours slept, and number of minutes to fall asleep, all on Likert response scales. The tool produces a global sleep quality score based on seven component scores: sleep quality, latency, duration, efficiency, disturbance, use of sleep medications, and daytime dysfunction. Higher scores indicate poorer overall sleep quality.65 Psychometrics support reliability and validity among BCS.66,67 The Cronbach alpha was 0.72 in this study.
Statistical Analysis Characteristics of the sample were assessed with descriptive statistics including mean (M) and SD or frequency data. Pearson’s correlation coefficient was used to examine the relationships of the FACT-Cog, including the total score and all four subscale scores, to cognitive performance tests and other symptoms. To further explore relationships between the FACT-Cog subscale scores of PCI and PCA, respectively, and objective measures of cognitive functioning, we obtained partial correlations, controlling for the covariates of age, depressive symptoms, fatigue, anxiety, and sleep.
Results Sample Table 1 displays demographic and medical information about the sample. Briefly, 88 BCS who were aged 40e74 years (M ¼ 56.7, SD ¼ 8.5) participated. Most of these survivors were Caucasian (88.6%), married (59.1%), and most had some college education (M ¼ 15.7 years, SD ¼ 2.6). Most had Stage II disease; all had had chemotherapy, with only 25% having had radiation therapy; and slightly more than half (51.1%) were currently taking antihormonal medication (either tamoxifen or an aromatase inhibitor). Means and SDs for each of the neuropsychological tests and symptoms (fatigue, depression, anxiety, and sleep disturbance) have been reported in a study by Von Ah et al.31 However, to give a sense of the level of cognitive impairment incurred by these BCS, we compared their scores to published norms for the AVLT. Based on these published norms,68 we identified that 20e23% of the participants had clinically significant memory impairment in immediate and delayed memory, respectively (defined as 1.0 SD below the norm-based test). This finding is similar to our previous work, which noted a 17% impairment on the AVLT immediate and delayed memory tests.36
Relationships Among Perceived Cognitive Function, Cognitive Performance, and Symptoms Perceived Cognitive FunctiondTotal Score. The FACTCog total score was significantly related to immediate
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Table 1 Descriptive Statistics of the Sample Including Personal Characteristics and Medical and Treatment Factors (N ¼ 88) Parameters
Mean (SD)
Age, yrs 56.7 (8.54) Time post-treatment 5.3 (4.07) Ethnicity African American Caucasian Highest level education Less than high school High school diploma Some college Bachelor’s degree Some graduate school Master’s degree Doctoral degree Employment status Employed full time Employed part time Homemaker Retired Unemployed Other Marital status Single Single/living with partner Married Widowed Other Income No difficulty paying for basics Some difficulty A lot of difficulty Stage of disease 0 I IIA IIB IIIA IIIB Type of adjuvant therapy Radiation No radiation Chemotherapy Tamoxifen and aromatase inhibitor use Never used Tamoxifen current and past use Aromatase inhibitor I current and past use
n (%)
10 (11.4) 78 (88.6) 2 10 23 28 3 16 6
(2.3) (11.4) (26.1) (31.8) (3.4) (18.2) (6.8)
40 17 5 19 6 1
(45.5) (19.3) (5.7) (21.6) (6.8) (1.1)
22 1 52 5 8
(25.0) (1.1) (59.1) (5.7) (9.1)
70 (79.5) 15 (17.0) 3 (3.4) 4 22 32 19 8 3
(4.5) (25.0) (36.4) (21.6) (9.1) (3.4)
22 (25.0) 66 (75.0) 88 (100.0) 11 (12.5) 52 (59.0) 44 (50.0)
verbal memory on the AVLT (r ¼ 0.29; P < 0.01); delayed verbal memory, as assessed by the RBMT Paragraph Recall test (r ¼ 0.30; P < 0.01); and executive function using the COWA (r ¼ 0.24; P < 0.05). However, it was not related to the delayed verbal memory assessed by the AVLT (r ¼ 0.21, P < 0.08). In addition, perceived cognitive function (total score) was not significantly related to speed of processing as measured by the SDMT. The FACT-Cog total score also was significantly (P < 0.01) related to each symptom assessed, ranging from r ¼ 0.31 to 0.60 (Table 2). That is, more perceived cognitive problems were associated with more depressive symptoms, fatigue, anxiety, and poor sleep quality.
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Perceived Cognitive Impairment. Similar to the FACTCog total scores, significant relationships were found between PCI and, respectively, objective measures of immediate verbal memory (AVLT; r ¼ 0.25, P < 0.05), delayed verbal memory (RBMT; r ¼ 0.24, P < 0.05), and executive function (COWA; r ¼ 0.23, P < 0.05). However, no relationship was noted between PCI and the other tests of memory (RBMT immediate verbal memory and AVLT delayed verbal memory) or speed of processing. In addition, PCI was significantly and positively correlated with measures of depressive symptoms, fatigue, anxiety, and sleep problems (Table 2). Perceived Impairments on the QoL Subscale. There were no significant relationships noted with the subscale score of perceived impairments on QoL with any of the objective measures of cognitive performance. There were, however, significant relationships between QOL scores and depressive symptoms, fatigue, anxiety, and sleep, with coefficients ranging from r ¼ 0.33 to 0.49 (Table 2). Perception and Comments From Others Subscale. The FACT-Cog subscale of perceptions and comments of others was significantly (P < 0.01) related to one measure of immediate verbal memory (AVLT). In addition, the subscale was significantly (P < 0.05) related to both measures of delayed verbal memory, However, it was not related to speed of processing or executive function. This subscale was highly correlated with each of the symptom measures, with coefficients ranging from r ¼ 0.37 to 0.50. These relationships indicated that perceptions of cognitive concerns by others were related to depressive symptoms, fatigue, anxiety, and poorer sleep (P < 0.01; Table 2). Perception of Cognitive Abilities. As displayed in Table 2, PCA was significantly related to both measures of immediate verbal memory, with coefficients ranging from r ¼ 0.26 to 0.27. In addition, PCA was significantly (P < 0.05) related to delayed verbal memory on the RBMT. However, it was not significantly related to delayed verbal memory as measured by the AVLT. In addition, PCA was significantly related (P < 0.01) to executive function, but not to speed of processing. The PCA also was related to depressive symptoms, fatigue, and anxiety, with coefficients ranging from r ¼ 0.43 to 0.48. The PCA was not related significantly to global problems with sleep.
Relationships of PCI and PCA to Cognitive Performance, Controlling for Covariates Controlling for age, depression, fatigue, anxiety, and sleep, partial correlations were computed
0.17 0.10 0.02 0.17 0.26b 0.49a 0.29a 0.25b 0.13 0.29a 0.27a PCF total PCI QoL Other PCA Memory immediate (AVLT) Memory immediate (RBMT) Memory delayed (AVLT) Memory delayed (RBMT) Speed of processing Executive function Depression Fatigue Anxiety Sleep
AVLT ¼ Rey Auditory Verbal Learning Test; RBMT ¼ Rivermead Behavioral Memory Test; PCI ¼ perceived cognitive impairment; QoL ¼ impairment in quality of life; Other ¼ comments of others; PCA ¼ perceived cognitive ability. a P < 0.01. b P < 0.05.
0.54a 0.51a 0.47a 0.43a 0.43a 0.15 0.02 0.01 0.08 0.20 0.17 0.74a 0.55a
Anxiety Fatigue
0.60a 0.56a 0.49a 0.50a 0.48a 0.25b 0.09 0.19 0.11 0.19 0.19 0.73a 0.56a 0.53a 0.46a 0.48a 0.46a 0.14 0.04 0.09 0.02 0.22b 0.20 0.24b 0.23b 0.13 0.20 0.33a 0.36a 0.19 0.27b 0.23b 0.38a 0.10 0.11 0.04 0.08 0.15 0.51a 0.48a 0.52a 0.48a 0.30a 0.24b 0.09 0.24b 0.35a 0.51a 0.88a 0.44a
Depressive Symptoms Executive Function Speed of Processing Memory Delayed (RBMT) Memory Delayed (AVLT) Memory Immediate (RBMT) Memory Immediate (AVLT) Parameters
Table 2 Relationships Among Perceived Cognitive Function, Cognitive Performance, and Symptoms in Breast Cancer Survivors
0.21 0.17 0.04 0.22b 0.19 0.81a 0.39a
Sleep
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0.31a 0.29a 0.33a 0.37a 0.15 0.03 0.06 0.12 0.12 0.09 0.00 0.43a 0.53a 0.36a d
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between the measures of PCI and PCA, respectively, and all measures of objective cognitive function. After controlling for confounding factors, only PCI and delayed verbal memory were significantly correlated (r ¼ 0.29; P < 0.05). PCA, on the other hand, remained correlated with immediate verbal memory, delayed verbal memory, and executive functioning, with coefficients ranging from r ¼ 0.19 to 0.48.
Discussion The cognitive changes associated with cancer and cancer treatment are a complex and significant problem for cancer survivors.69 In fact, cognitive changes have been consistently identified by clinicians as one of the most persistent late effects of treatment, both distressing to patients and difficult to manage for clinicians.70 In an effort to identify and effectively treat this bothersome and lingering symptom, clinically useful assessment measures are needed. Therefore, the purpose of the present study was to examine one of the most widely used perceived cognitive function instruments and explore its relationship to objective cognitive performance as well as to other symptoms. Although there have been a number of studies examining the relationship between objective neuropsychological tests and perceived cognitive function, to our knowledge this is the first to use the current version of the FACT-Cog and its subscale scores, particularly PCI and PCA, and exploring their relationships to both objective cognitive performance and to other symptoms.17 The most interesting finding in this study was that the total FACT-Cog scores (perceived function) and, specifically, the subscale scores of PCI and PCA were correlated with objective measures of immediate verbal memory, delayed verbal memory, and executive function. This finding is important because there has long been a concern regarding the failure to find associations between subjective and objective measures of cognitive function in cancer survivors. To our knowledge, Vardy et al71 have been the only researchers to examine relationships between the FACTCog and objective cognitive assessments; in 29 patients with breast and colorectal cancer, they found no correlations. However, that study may have been limited by a lack of power, given the small sample size. In a recent review article, Hutchison et al17 examined 24 studies and found that only eight noted a correlation between perceived and objective cognitive function. These authors speculate that the disparate findings may be a result of methodological variations in both the subjective and objective assessments used. Similarly, Bender et al72 noted that the studies with contradictory results often used brief subjective measures; some having only
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one or two items, and they suggested that more comprehensive and multidimensional measures may be more sensitive to the subtle cognitive impairment incurred by cancer survivors. Other researchers, however, suggest that subjective cognitive measures are not identifying cognitive impairment, but rather are indicators of distress or depressive symptoms.8,15,21,73e75 To address this issue, we explored whether the relationships between subjective and objective cognitive function would remain after controlling for relevant demographic (age) and common correlated symptoms such as depressive symptoms, fatigue, anxiety, and sleep problems. We found that most of the relationships on the PCI (impairment) subscale were no longer significant but that the significant correlations between the PCA (ability) subscale and objective performance remained significant. These preliminary findings are significant. First, this work supports the work by Lai et al14,30 in the development of the FACT-Cog as a PROMIS measure conceptualizing PCI and PCA as two separate and distinct concepts. Second, these findings suggest that the negatively worded PCI items might be tapping into more of the negative affect (e.g., depressive symptoms, distress, and so on) than the positively focused ability items. In fact, researchers have noted that depression and negative affectivity may induce negative appraisals of cognitive function76 and thus, negatively worded or problemfocused items may be identifying negative affect vs. cognitive functioning. On the other hand, the positively framed PCA items, as hypothesized by Lai et al,30 may reduce the effects of negative emotional states, providing a valid measure of cognitive function. Finally, our results suggest that PCA may serve as an indicator of cognitive function in BCS. Similar results have been reported by Bender et al,72 who found a significant relationship between perceived cognitive functioning and measures of verbal memory using the RBMT in 31 BCSs. In the review by Hutchinson et al,17 six of the eight studies demonstrating correlations between subjective and objective cognitive function identified correlations between PCI and measures of memory.74,77e81 In addition, we identified only one other study that found a relationship between PCI and executive function. Poppelreuter et al74 noted such a relationship in 119 patients receiving cancer rehabilitation, although correlations were not significant when affective states were controlled. Although our results are preliminary, the data suggest that the FACT-Cog, and specifically the PCA (ability) subscale, may be a clinically useful tool to identify cognitive function. Future research is needed in larger, demographically and ethnically diverse samples of cancer patients.
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As anticipated, perceived cognitive function as measured by the FACT-Cog and subscale scores were significantly correlated with other symptoms including depressive symptoms, fatigue, anxiety, and sleep problems. Previous research has demonstrated that these symptoms are highly correlated in BCSs.5 Future work is needed to identify whether these affective states predict PCI or whether the recognition of cognitive impairment is accompanied by these affective symptoms. One of the major limitations of this study is that it was conducted with BCS who were reporting cognitive concerns, which may have created sampling bias and limit generalizability of the results. This study also was limited by the small homogeneous sample of mostly Caucasian women who were well educated. Further research is needed in a larger and more diverse sample of cancer survivors that includes those with and without cognitive concerns to confirm the results presented. Importantly, this work needs to include a diverse set of cancer survivors because most of this work has been conducted with BCS. In addition, to improve the clinical utility of these instruments, future research is needed to establish cutpoints on the FACT-Cog and subscales of PCI and PCA for cognitive impairment so that clinicians and researchers can identify clinically significant cognitive impairment.
Conclusion Identifying a measure that can recognize subtle cognitive impairment in cancer survivors is important to advance clinical practice and research in this area. Despite the limitations, the results of this study suggest that the FACT-Cog, and specifically the subscales of PCI (impairment) and PCA (ability), may be clinically useful in identifying BCS with cognitive impairment.
Disclosures and Acknowledgments This study was supported by the Robert Wood Johnson Foundation Nurse Faculty Scholar Program (#64194, Principal Investigaor [PI]: Von Ah); American Cancer Society Institutional Research Grant (#84-00225, PI: Von Ah); Indiana University School of Nursing Center for Enhancing Quality of Life in Chronic Illness; and the Mary Margaret Walther Program of the Walther Cancer Institute (#0097.01, PI: Von Ah). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Robert Wood Johnson Foundation, which funded this trial. The funding agency had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.
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References 1. Boykoff N, Moieni M, Subramanian SK. Confronting chemobrain: an in-depth look at survivors’ reports of impact on work, social networks, and health care response. J Cancer Surviv 2009;3:223e232. 2. Munir F, Burrows J, Yarker J, Kalawsky K, Bain M. Women’s perceptions of chemotherapy-induced cognitive side affects on work ability: a focus group. J Clin Nurs 2010;19:1362e1370. 3. Myers JS. Chemotherapy-related cognitive impairment: the breast cancer experience. Oncol Nurs Forum 2012;39: E31eE40. 4. Von Ah D, Habermann B, Carpenter J, Schneider BL. Impact of perceived cognitive impairment in breast cancer survivors. Eur J Oncol Nurs 2013;17:236e241. 5. Bender CM, Ergyn FS, Rosenzweig MQ, Cohen SM, Sereika SM. Symptom clusters in breast cancer across 3 phases of the disease. Cancer Nurs 2005;28:219e225. 6. Myers JS. Cancer- and chemotherapy-related cognitive changes: the patient experience. Semin Oncol Nurs 2013; 29:300e307. 7. Mitchell T, Turton P. ‘‘Chemobrain’’: concentration and memory effects in people receiving chemotherapy - a descriptive phenomenological study. Eur J Cancer Care 2011;20:1e10. 8. Pullens MJ, De Vries J, Roukema JA. Subjective cognitive dysfunction in breast cancer patients: a systematic review. Psychooncology 2010;19:1127e1138. 9. Mitchell T. The social and emotional toll of chemotherapy patients’ perspectives. Eur J Cancer Care 2007;16: 39e47. 10. Jim HS, Phillips KM, Chait S, et al. Meta-analysis of cognitive functioning in breast cancer survivors previously treated with standard-dose chemotherapy. J Clin Oncol 2012;30:3578e3587. 11. Stewart A, Bielajew C, Collins B, Parkinson M, Tomiak E. A meta-analysis of the neuropsychological effects of adjuvant chemotherapy treatment in women treated for breast cancer. Clin Neuropsychol 2006;20:76e89. 12. Jansen CE, Miakowski C, Dodd M, Dowling G, Kramer J. A meta analysis of studies of the effects of cancer chemotherapy on various domains of cognitive function. Cancer 2005;104:222e233. 13. Falleti MG, Sanfilippo A, Maruff P, Weih L, Phillips KA. The nature and severity of cognitive impairment associated with adjuvant chemotherapy in women with breast cancer: a meta-analysis of the current literature. Brain Cogn 2005; 59:60e70. 14. Lai J, Butt Z, Wagner L, et al. Evaluating the dimensionality of perceived cognitive function. J Pain Symptom Manage 2009;37:982e995. 15. Jansen C. Cognitive changes associated with cancer and cancer therapy: patient assessment and education. Semin Oncol Nurs 2013;4:270e279.
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impairment following chemotherapy for cancer: a systematic review. Cancer Treat Rev 2012;38:926e934. 18. Schagen SB, van Dam FS, Muller MJ, et al. Cognitive deficits after postoperative adjuvant chemotherapy for breast cancer. Cancer 1999;85:640e650. 19. Cull A, Hay C, Love SB, et al. What do cancer patients mean when they complain of concentration and memory problems? Br J Cancer 1996;74:1674e1679. 20. Jenkins V, Shilling V, Fallowfield L, Howell A, Hutton S. Does hormone therapy for the treatment of breast cancer have a detrimental effect on memory and cognition? A pilot study. Psychooncology 2004;13:61e66. 21. Jenkins V, Shilling V, Deutsch G, et al. A 3-year prospective study of the effects of adjuvant treatments on cognition in women with early stage breast cancer. Br J Cancer 2006;94: 828e834. 22. Paganini-Hill A, Clark LJ. Preliminary assessment of cognitive function in breast cancer patients treated with tamoxifen. Breast Cancer Res Treat 2000;64:165e176. 23. Ferguson RJ, McDonald BC, Saykin AJ, Ahles TA. Brain structure and function differences in monozygotic twins: possible effects of breast cancer chemotherapy. J Clin Oncol 2007;25:3866e3870. 24. Deprez S, Amant F, Yigit R, et al. Chemotherapyinduced structural changes in cerebral white matter and its correlation with impaired cognitive functioning in breast cancer patients. Hum Brain Mapp 2011;32:480e493. 25. Wagner L, Sweet J, Butt Z, et al. Measuring patient selfreported cognitive function: development of the functional assessment of cancer therapydcognitive function instrument. J Support Oncol 2009;7:W32eW39. 26. Jacobs SR, Jacobsen PB, Booth-Jones M, Wagner LI, Anasetti C. Evaluation of the functional assessment of cancer therapy cognitive scale with hematopoietic stem cell transplant patients. J Pain Symptom Manage 2007;33:13e23. 27. Wagner L, Lai JS, Cella D, Sweet J, Forrestal S. Chemotherapy-related cognitive deficits: development of the FACT-Cog instrument. Ann Behav Med 2004;27(Suppl 10). 28. Deprez S, Amant F, Smeets A, et al. Longitudinal assessment of chemotherapy induced structural changes in cerebral white matter and its correlation with impaired cognitive function. J Clin Oncol 2012;30:274e281. 29. Joly F, Lange M, Rigal O, et al. French version of the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) version 3. Support Care Cancer 2012;20: 3297e3305. 30. Lai JS, Wagner LI, Jacobsen PB, Cella D. Self-reported cognitive concerns and abilities: two sides of one coin? Psychooncology 2014; [Epub ahead of print]. 31. Von Ah D, Carpenter JS, Saykin A, et al. Advanced cognitive training for breast cancer survivors: a randomized controlled trial. Breast Cancer Res Treat 2012;135:799e809. 32. Jobe JB, Smith DM, Ball K, et al. ACTIVE: a cognitive intervention trial to promote independence in older adults. Control Clin Trials 2001;22:453e479.
16. Ouimet LA, Stewart A, Collins B, Schindler D, Bielajew C. Investigation of neuropsychological screen for chemo-fog. Oncol Rev 2011;5:205e213.
33. Rey A. L’examen psychologique dans les cas d’encephalopathie traumatique. Arch Psychol 1941;28:286e340.
17. Hutchison AD, Hosking JR, Kichenadasse G, Mattiske JK, Wilson C. Objective and subjective cognitive
34. Stallings GA, Boake C, Sherer M. Comparison of the California Verbal Learning Test and the Rey Auditory Verbal
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Learning Test in head-injured patients. J Clin Exp Neuropsychol 1995;17:706e712. 35. Magalhes S, Malloy-Diniz LF, Hamdan AC. Validity convergent and reliability test-retest of the Rey Auditory Verbal Learning Test. Clin Neuropsychiatry 2012;9:129e137. 36. Von Ah D, Harvison K, Monahan P, et al. Cognitive function in breast cancer survivors compared to healthy age- and education-matched women. Clin Neuropsychol 2009;23:661e674. 37. Knight RG, McMahon J, Skeaff M, Green TJ. Reliable change index scores for persons over the age of 65 tested on alternate forms of the Rey AVLT. Arch Clin Neuropsychol 2007;22:513e518. 38. Geffen GM, Butterworth P, Geffen LB. Test-retest reliability of a new form of the auditory verbal learning test (AVLT). Arch Clin Neuropsychol 1994;9:303e316. 39. Loring D, Bauer RM. Testing the limits: cautions and concerns regarding the new Wechsler IQ and memory scales. Neurology 2010;74:685e690.
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52. Weissman MM, Sholomskas D, Pottenger M, Prusoff BA, Locke BZ. Assessing depressive symptoms in five psychiatric populations: a validation study. Am J Epidemiol 1977;106:203e214. 53. Radloff LS. The CES-d scale. Appl Psychol Meas 1977;1: 385e401. 54. van Wilgen CP, Dijkstra PU, Stewart RW, Ranchor AW, Roodenburg JL. Measuring somatic symptoms with the CES-D to assess depression in cancer patients after treatment: comparison among patients with oral/oropharyngeal, gynecological, colorectal, and breast cancer. Psychosomatics 2006;47:465e470. 55. Ferguson RJ, McDonald BC, Rocque MA, et al. Cognitvebehavioral management of chemotherapy-related cognitive change. Psychooncology 2007;16:772e777. 56. Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E. Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J Pain Symptom Manage 1997;13:63e74.
40. National Institutes of Health. NIH toolbox auditory verbal learning test (Rey). 2013. Available at: http://www.nihtoolbox. org/WhatAndWhy/Cognition/EpisodicMemory/Pages/NIHToolbox-Auditor-Verbal-Learning-Test-(Rey).aspx. Accessed June 1, 2013.
57. Graziano F, Bisonni R, Catalano V, et al. Potential role of levocarnitine supplementation for the treatment of chemotherapy-induced fatigue in non-anaemic cancer patients. Br J Cancer 2002;86:1854e1857.
41. Wilson B, Cockburn J, Baddeley A. The rivermead behavioral memory test. England and Michigan: Thames Valley Test, Co. and National Rehabilitation Services, 1985.
58. Shafqat A, Einhorn LH, Hanna N, et al. Screening studies for fatigue and laboratory correlates in cancer patients undergoing treatment. Ann Oncol 2005;16: 1545e1550.
42. Lezak MD, Howieson DB, Loring DW. Neuropsycholgical assessment, 4th ed. New York: Oxford Unviersity Press, 2004. 43. de Wall C, Wilson BA, Baddeley AD. The extended Rivermead Behavioural Memory Test: a measure of everyday memory performance in normal adults. Memory 1994;2: 149e166. 44. Wilson BA. The assessment, evaluation and rehabilitation of everyday memory problems. New York: Psychology Press, 2014. 45. Paraska KK, Bender CM. Cognitive dysfunction following adjuvant chemotherapy for breast cancer: two case studies. Oncol Nurs Forum 2003;30:473e478. 46. Smith A. Symbol Digit Modalities Test. Los Angeles: Western Psychological Services, 1982. 47. Sbordone RJ, Saul RE, Purisch AD. Neuropsychology for psychologists, health care professionals and attorneys, 3rd ed. Boca Raton, FL: CRC Press, 2007. 48. Berrigan LI, Fisk JD, Walker LA, et al. Reliability of regression-based normative data for the oral symbol digit modalities test: an evaluation of demographic influences, construct validity, and impairment classification rates in multiple sclerosis samples. Clin Neuropsychol 2014;28:281e299.
59. Pinto BM, Rabin C, Abdow S, Papandonatos GD. A pilot study on disseminating physical activity promotion among cancer survivors: a brief report. Psychooncology 2008;17:517e521. 60. Tchen N, Juffs HG, Downie FP, et al. Cognitive function, fatigue, and menopausal symptoms in women receiving adjuvant chemotherapy for breast cancer. J Clin Oncol 2003; 21:4175e4183. 61. Spielberger CD, Gorsuch RI, Lushene RG. Manual for the state-trait anxiety inventory. Palo Alto, CA: Consulting Press, 1971. 62. McCracken LM, Iverson GL. Predicting complaints of impaired cognitive functioning in patients with chronic pain. J Pain Symptom Manage 2001;21:392e396. 63. Spielberger CD. Manual for the state-trait anxiety inventory (Form Y). Palo Alto, CA: Consulting Psychologists Press, 1983. € 64. OZalp G, Sarioglu R, Tuncel G, Aslan K, Kadiogullari N. Preoperative emotional states in patients with breast cancer and postoperative pain. Acta Anaesthesiol Scand 2003;47:26e29.
49. Benton AL, Hamsher KD. Multilingual aphasia examination. Iowa City, IA: AJA Associates, 1989.
65. Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989;28:193e213.
50. Ruff RM, Light RH, Parker SB, Levin HS. Benton controlled oral word association test: reliability and updated norms. Arch Clin Neuropsychol 1996;11:329e338.
66. Carpenter JS, Andrykowski MA. Psychometric evaluation of the Pittsburgh sleep quality Index. J Psychosom Res 1998;45:5e13.
51. Ruff RM, Light RH, Parker SB, Levin HS. The psychological construct of word fluency. Brain Lang 1997;57: 394e405.
67. Fortner BV, Stephanski EJ, Wang SC, Kasprowicz S, Durrence HH. Sleep and quality of life in breast cancer patients. J Pain Symptom Manage 2002;24:471e480.
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68. Uchiyama CL, D’Elia LF, Dellinger AM, et al. Alternate forms of the auditory-verbal learning test: issues of test comparability, longitudinal reliability and moderating demographic variables. Arch Clin Neuropsychol 1995;10:133e145. 69. Bender CM, Thelen BD. Cancer and cognitive changes: the complexity of the problem. Semin Oncol Nurs 2013;29: 232e237. 70. LoBiondo-Wood G, Brown CG, Knobf MT, et al. Priorities for oncology nursing: the 2013 national survey. Oncol Nurs Forum 2014;42:67e76. 71. Vardy J, Wong K, Yi QL, et al. Assessing cognitive function in cancer patients. Support Care Cancer 2006;14: 1111e1118. 72. Bender CM, Pacella ML, Sereika SM, et al. What do perceived cognitive problems reflect? J Support Oncol 2008;6:238e242. 73. Kilbiger G, Kirsh KL, Wall JR, Passik SD. My mind is as clear as it used to be: a pilot study illustrating the difficulties of employing a single-item subjective screen to detect cognitive impairment in outpaients with cancer. J Pain Symptom Manage 2003;26:705e715. 74. Poppelreuter M, Weis J, Kulz AK, et al. Cognitive dysfunction and subjective complaints of cancer patients. a cross-sectional study in a cancer rehabilitation centre. Eur J Cancer 2004;40:43e49. 75. Shilling V, Jenkins V. Self-reported cognitive problems in women receiving adjuvant therapy for breast cancer. Eur J Oncol Nurs 2007;11:6e15.
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76. Hermelink K, Kuchenhoff H, Untch M, et al. Two different sides of ’chemobrain’: determinants and nondeterminants of self-perceived cognitive dysfunction in a prospective, randomized, multicenter study. Psychooncology 2010; 19:1321e1328. 77. Mehnert A, Scherwath A, Schirmer L, et al. The association between neuropsychological impairment, selfperceived cognitive deficits, fatigue, and quality of life in breast cancer survivors following standard adjuvant versus high-dose chemotherapy. Patient Educ Couns 2007;66: 108e118. 78. Downie FP, Mar Fan HG, Houede-Tchen N, Yi Q, Tannock IF. Cognitive function, fatigue, and menopausal symptoms in breast cancer patients receiving adjuvant chemotherapy: evaluation with patient interview after formal assessment. Psychooncology 2006;15:921e930. 79. Reid-Arndt SA, Hsieh C, Perry MC. Neuropsychological functioning and quality of life during the first year after completing chemotherapy for breast cancer. Psychooncology 2010;19:535e544. 80. Weis J, Poppelreuter M, Bartsch HH. Cognitive deficits as long-term side-effects of adjuvant therapy in breast cancer patients: ’subjective’ complaints and ’objective’ neuropsychological test results. Psychooncology 2009;18:775e782. 81. Poppelreuter M, Weis J, Bartsch HH. Effects of specific neuropsychological training programs for breast cancer patients after adjuvant chemotherapy. J Psychosoc Oncol 2009;27:274e296.
Journal of Pain and Symptom Management 697
Original Article
Perceived Cognitive Function in Breast Cancer Survivors: Evaluating Relationships With Objective Cognitive Performance and Other Symptoms Using the Functional Assessment of Cancer TherapydCognitive Function Instrument Diane Von Ah, PhD, RN, and Eileen F. Tallman, BS, BA Department of Adult Health (D.V.A.), Indiana University School of Nursing; and Department of Radiology and Imaging Sciences (E.F.T.), Indiana University School of Medicine, Indianapolis, Indiana, USA
Abstract Context. Perceived cognitive impairment (PCI) has been shown to be one of the most common symptoms after breast cancer treatment. However, this symptom does not always correlate with objective cognitive performance and is often highly associated with other patient-reported symptoms. Objectives. Using a sample of breast cancer survivors (BCS), this study examined relationships among the Functional Assessment of Cancer Therapy-Cognitive (FACT-Cog) scale, a self-report questionnaire that measures PCI; impact on quality of life (QoL); comments from others (other); perceived cognitive ability (PCA); objective cognitive performance on tests of verbal memory, speed of processing, and executive functioning; and other symptoms (fatigue, depression, anxiety, and sleep disturbance). Methods. The BCS who were aged 40 years or older and at least one year post-chemotherapy treatment were enrolled. Participants completed questionnaires and a brief neuropsychological assessment. Results. A total of 88 BCS who were on average 56.7 (SD 8.5) years old and 5.3 (SD 4.1) years post-treatment participated; 94% reported clinically significant PCI. The PCI was significantly correlated with some objective measures of immediate and delayed verbal memory and executive function, whereas PCA was associated with all these measures. The PCI and PCA were both significantly associated with depressive symptoms, fatigue, and anxiety, but only PCI was related to poor global sleep quality. Conclusion. The PCA was highly correlated with objective neuropsychological performance and may be clinically useful in identifying problems with verbal memory and executive functioning in BCS. J Pain Symptom Manage 2015;49:697e706. Ó 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. Key Words Cognitive impairment, breast cancer survivor, symptoms, neuropsychological assessment
Introduction Breast cancer survivors (BCS) often report changes in cognitive function after cancer and cancer treatment.1e4 In fact, researchers have shown that perceived cognitive impairment (PCI) is one of their most prevalent symptoms over three phases of the
Address correspondence to: Diane Von Ah, PhD, RN, Department of Community and Health Systems, Indiana University School of Nursing, Indianapolis, IN 46202, USA. E-mail: [email protected] Ó 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.
disease.5 The PCI after cancer and cancer treatment, often referred to as ‘‘chemo brain’’ by BCS,1,3,6,7 has been associated with difficulties in everyday functioning and reported by survivors as problems with memory, attention, speed of processing, and decision making.4,8 PCI has been shown to have a significant
Accepted for publication: August 14, 2014.
0885-3924/$ - see front matter http://dx.doi.org/10.1016/j.jpainsymman.2014.08.012
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impact on BCS’ self-perceptions, social network, work ability, and overall quality of life (QoL).1,2,4,6,9 Cognitive impairment also has been documented among BCS using objective neuropsychological tests. Researchers have shown that cancer survivors perform more poorly on objective neuropsychological tests relative to healthy age- and education-matched women and to published norms.10e13 Although neuropsychological tests are considered the gold standard in assessing cognitive impairment, such tests are not always feasible or affordable.14 Administration of neuropsychological test batteries requires a trained and qualified professional and is often time intensive, which limits their use in practice.15 In addition, administration of large and lengthy neuropsychological test batteries may lead to conflicting test results because of fatigue, loss of attention, and decreased motivation.15,16 Concerns also have been raised in some studies that neuropsychological assessments are not always sensitive to the subtle cognitive impairment incurred by BCS.15 Accurate subjective reports of cognitive impairment, however, would be clinically useful in identifying survivors with subtle deficits.14 Although studies have not always supported a relationship between PCI and objective neuropsychological tests,17e22 subjective measures of impairment have been shown to correlate significantly with changes on magnetic resonance imaging that demonstrate impairment.23e25 In fact, Ferguson et al23 found that one BCS with substantial cognitive complaints had both structural changes (increased white matter hyperintensities) and functional changes (expanded spatial activation during a working memory task) compared with her nonaffected twin. Therefore, finding efficient screening tools capable of identifying patients with clinically significant cognitive impairment is needed for both research and practice. The Functional Assessment of Cancer Therapy Cognitive Scale (FACT-Cog, Version 3)14,25e28 is one of the most well-known and widely used self-assessment measures of cognitive concerns and has even been translated into other languages.29 This instrument was originally developed using cancer patient focus groups and oncology clinical experts. The FACT-Cog is unique in that it measures both cognitive concerns (impairment or deficiency) and cognitive abilities--two concepts that are distinct and independent of one another.14,30 Notably, the Patient Reported Outcomes Measurement and Information System (PROMIS, www.nihpromis. org), an initiative by the National Institutes of Health (NIH) to develop reliable and valid patient-reported symptoms measures, has identified both perceived cognitive concerns and cognitive abilities as concepts of interest in assessing cognition. The FACT-Cog, both the total score and more recently the subscale scores of
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PCI and perceived cognitive ability (PCA), has been widely used; however, little information is available regarding the relationship of this instrument and subscale scores with objective cognitive performance.14 More research is needed to understand these relationships, as well as relationships between the FACT-Cog and its subscale scores with other symptoms (anxiety, depression, fatigue, and sleep). In fact, although the FACT-Cog has been shown to be significantly correlated with other symptoms,26 researchers recently have identified that PCI may relate more to other clinical features such as depression and anxiety than PCA. These findings suggest that these subscales are tapping into distinct and separate constructs, supporting the need for further research examining the use of both subscales and their relationship to other clinical symptoms.30 Therefore, the purpose of this study was to explore the perceived cognitive functioning of BCS using the FACT-Cog and its subscale scores and their relationships to objective cognitive performance (verbal memory, speed of processing, and executive function) and to other symptoms (depression, fatigue, anxiety, and sleep).
Methods This study was part of a longitudinal, randomized controlled trial to test advanced cognitive training programs in BCS.31 All data used in this study were collected at one time at baseline assessment.
Procedure The BCS were recruited from a Midwestern cancer center and affiliated clinics. Women included in this study were aged at least 40 years or older, postmenopausal, and underwent at least 12 months postcancer treatment that had included chemotherapy. In addition, based on self-report and medical record review, participants were free of any psychiatric (including major depression) or neurological (encephalitis, traumatic brain injury, brain surgery, dementia, or Alzheimer’s disease) disorders. Women included in the study reported having cognitive problems since their diagnosis and treatment for breast cancer and were seeking treatment for them.
Measures Eligible and interested women were consented and completed subjective questionnaires that assessed demographic and medical information; perceived cognitive functioning; and symptoms of depression, fatigue, anxiety, and global sleep quality. They also completed a brief objective battery of neuropsychological tests; the battery was brief to minimize fatigue. The neuropsychological tests were administered by the same trained psychology graduate student at the academic health
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center in a quiet, private, and designated space for the assessments. The assessments took approximately 50 minutes to complete. Subjective and objective cognitive measures were administrated at the same appointment. All tests were administered in the same fixed order to reduce variability resulting from test presentation. Demographic and Medical Information. An investigatordeveloped questionnaire was used to collect demographic information including age, education, employment status, marital status, income, and medical information (stage of disease, time posttreatment, type of adjuvant therapy, use of antihormonal medications including tamoxifen and aromatase inhibitors). Medical information was validated by a medical record review. Perceived Cognitive Function. Perceived cognitive function was measured by the FACT-Cog,25,26 a 37-item measure designed to assess cognitive complaints in cancer patients. The FACT-Cog Version 3 includes negatively worded (e.g., I have had trouble concentrating) and positively worded (e.g., My mind is as sharp as it has always been) items. The FACT-Cog yields a total score and four subscale scores including: 1) PCI, 2) perceived impairments in QoL, 3) perception and comments from others, and 4) PCA. When rating PCI and comments from others (other), participants must rate on a five-point Likert scale (0 ¼ never to 4 ¼ several times a day) the frequency with which each phenomenon had occurred in the past seven days. The QoL and PCA are rated on five-point scales (from 0 ¼ not at all to 4 ¼ very much). Negatively worded items are reverse scored to create subscale scores, with higher scores reflecting fewer cognitive problems and better QoL. The FACT-Cog was developed through interviews with cancer patients and also validated with cancer patients including BCS.25 This instrument has demonstrated acceptable reliability in BCS14,25 and in this study, the Cronbach alpha was 0.86 for the total score, with subscale scores ranging from 0.77 to 0.86. Cognitive Performance. Cognitive performance was determined through the use of a brief battery of neuropsychological tests to measure immediate and delayed verbal memory, speed of processing, and executive function. The neuropsychological tests chosen for this study have been used in large clinical trials in both the well elderly32 and BCSs.17 Objective verbal memory (immediate and delayed) was assessed by two separate measures including the Rey Auditory Verbal Learning Test (AVLT) and the Rivermead Behavioral Memory Test (RBMT). The AVLT33 is a word list reading task commonly used to
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test verbal memory. Individuals are presented with a 15-item word list. Five learning trials are conducted and immediate recall is taken after each. An interference list precedes the short-term delayed recall of the initial list and after 30 minutes, a long-term delayed recall is taken. The score is the number of words recalled at each trial, with higher scores indicating better performance. The AVLT has evidence of construct validity when compared with other measures of verbal memory, such as the California Verbal Learning test34 and divergent validity with other neuropsychological tests such as the Trail Making Test, a measure of executive function.35 This instrument also has demonstrated sensitivity in identifying significant cognitive impairment in studies with BCS.18,36 The AVLT has strong reliability, with test-retest correlation coefficients for immediate memory ranging from r ¼ 0.79 to 0.84 and delayed memory r ¼ 0.74 to 0.77.37,38 The AVLT was selected over other tools (e.g., Wechsler Memory Scale-IV) for inclusion in NIH epilepsy neuropsychological common data elements39 and has been identified as an NIH Toolbox instrument.40 The RBMT Story Subtest41 is a story recall test used to assess verbal memory. Participants listen to a short passage that is read aloud and then asked to write down as much as they can remember immediately afterward and again after a 30 minute delay, producing immediate and delayed recall scores.42 Two stories were presented at each assessment and the average score was used, with higher scores indicating better performance. The RBMT has been validated with other verbal learning and memory tests, as well as by consistently demonstrating poorer scores for patients identified by therapists as experiencing memory deficits.43 The RBMT has demonstrated adequate test-retest reliability (r ¼ 0.60) in cognitively impaired populations.44 However, the main advantage for using this test is that it has been shown to reliably assess memory performance in BCS.17,45 Objective speed of processing was measured with the Symbol Digit Modalities Test (SDMT) oral response format.46 Participants were asked to substitute simple geometric shapes for numbers using a legend. Responses were reported orally over 90 seconds. The oral format has demonstrated moderate test-retest reliability (r ¼ 0.76)47 and adequate construct validity48 and has been used with BCS.36 Objective executive functioning was measured by the Controlled Oral Word Association (COWA).49 For this test, participants are asked to spontaneously produce words beginning with a given letter (C, F, L or P, R, W) for one minute. The participants also are instructed to refrain from using words with similar endings (i.e., love or loving), proper nouns, or numbers. High reliability for the COWA has been demonstrated (r ¼ 0.83) as well as significant test-
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retest reliability (r ¼ 0.74).50 Construct validity was demonstrated by statistically significant correlations between the COWA and two other neuropsychological assessments of executive function (Wechsler Adult Intelligence Scale-Similarities Test and Ruff Figural Fluency Test).51 This instrument has been used in cancer patients including BCS.17,36 Depressive Symptoms. The 20-item Center for Epidemiologic Studies Depression Scale (CES-D) assesses depressive symptoms over the past week (total score range 0e60, with higher scores indicating greater symptom burden).52 A score higher than 16 indicates high levels of depressive symptoms and has been used as a proxy for clinically significant depression in previous studies.52,53 The CES-D has shown strong correlation with other measures of depression and has strong internal consistency,53 and it has been widely used in cancer patients,53,54 including BCS.31,55 The Cronbach alpha in this study was 0.89. Fatigue. The Functional Assessment of Cancer Therapy-Fatigue (FACT-F)56 is a 13-item measure that asks respondents to rate symptoms of fatigue over the last seven days on a five-point scale ranging from zero (not at all) to four (very much so). Higher scores reflect lower fatigue. The FACT-F has strong internal consistency and test-retest reliability (r ¼ 0.90). Convergent validity has been demonstrated through high correlations with the Piper Fatigue Scale and Profile of Mood States-Fatigue Subscale (r ¼ 0.77 and 0.83, respectively). This instrument was designed and validated for cancer patients56 and has been used extensively with that population,57,58 including BCS.59,60 In this study, the Cronbach alpha was 0.94. State Anxiety. The 40-item Spielberger State-Trait Anxiety Inventory-State Subscale (STAI-S)61 has two subscales assessing state and trait anxiety. In this study, we assessed state anxiety because this has been correlated with cognitive functioning in other studies.62 The STAI-S comprises 20 questions that require participants to rate how they feel at the present time (‘‘at this moment’’) using a scale from one (almost never) to four (almost always). Higher scores indicate more anxiety. The STAI-S has demonstrated acceptable correlations (r ¼ 0.80) with other established anxiety measures and strong reliability (Cronbach alpha ¼ 0.93).63 This instrument has been widely used in cancer patients including BCS.64 The Cronbach alpha was 0.89 in this study. Sleep. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality and disturbances during the past week.65 The 19-item questionnaire includes items asking about usual bed time, wake time, number
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of actual hours slept, and number of minutes to fall asleep, all on Likert response scales. The tool produces a global sleep quality score based on seven component scores: sleep quality, latency, duration, efficiency, disturbance, use of sleep medications, and daytime dysfunction. Higher scores indicate poorer overall sleep quality.65 Psychometrics support reliability and validity among BCS.66,67 The Cronbach alpha was 0.72 in this study.
Statistical Analysis Characteristics of the sample were assessed with descriptive statistics including mean (M) and SD or frequency data. Pearson’s correlation coefficient was used to examine the relationships of the FACT-Cog, including the total score and all four subscale scores, to cognitive performance tests and other symptoms. To further explore relationships between the FACT-Cog subscale scores of PCI and PCA, respectively, and objective measures of cognitive functioning, we obtained partial correlations, controlling for the covariates of age, depressive symptoms, fatigue, anxiety, and sleep.
Results Sample Table 1 displays demographic and medical information about the sample. Briefly, 88 BCS who were aged 40e74 years (M ¼ 56.7, SD ¼ 8.5) participated. Most of these survivors were Caucasian (88.6%), married (59.1%), and most had some college education (M ¼ 15.7 years, SD ¼ 2.6). Most had Stage II disease; all had had chemotherapy, with only 25% having had radiation therapy; and slightly more than half (51.1%) were currently taking antihormonal medication (either tamoxifen or an aromatase inhibitor). Means and SDs for each of the neuropsychological tests and symptoms (fatigue, depression, anxiety, and sleep disturbance) have been reported in a study by Von Ah et al.31 However, to give a sense of the level of cognitive impairment incurred by these BCS, we compared their scores to published norms for the AVLT. Based on these published norms,68 we identified that 20e23% of the participants had clinically significant memory impairment in immediate and delayed memory, respectively (defined as 1.0 SD below the norm-based test). This finding is similar to our previous work, which noted a 17% impairment on the AVLT immediate and delayed memory tests.36
Relationships Among Perceived Cognitive Function, Cognitive Performance, and Symptoms Perceived Cognitive FunctiondTotal Score. The FACTCog total score was significantly related to immediate
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Table 1 Descriptive Statistics of the Sample Including Personal Characteristics and Medical and Treatment Factors (N ¼ 88) Parameters
Mean (SD)
Age, yrs 56.7 (8.54) Time post-treatment 5.3 (4.07) Ethnicity African American Caucasian Highest level education Less than high school High school diploma Some college Bachelor’s degree Some graduate school Master’s degree Doctoral degree Employment status Employed full time Employed part time Homemaker Retired Unemployed Other Marital status Single Single/living with partner Married Widowed Other Income No difficulty paying for basics Some difficulty A lot of difficulty Stage of disease 0 I IIA IIB IIIA IIIB Type of adjuvant therapy Radiation No radiation Chemotherapy Tamoxifen and aromatase inhibitor use Never used Tamoxifen current and past use Aromatase inhibitor I current and past use
n (%)
10 (11.4) 78 (88.6) 2 10 23 28 3 16 6
(2.3) (11.4) (26.1) (31.8) (3.4) (18.2) (6.8)
40 17 5 19 6 1
(45.5) (19.3) (5.7) (21.6) (6.8) (1.1)
22 1 52 5 8
(25.0) (1.1) (59.1) (5.7) (9.1)
70 (79.5) 15 (17.0) 3 (3.4) 4 22 32 19 8 3
(4.5) (25.0) (36.4) (21.6) (9.1) (3.4)
22 (25.0) 66 (75.0) 88 (100.0) 11 (12.5) 52 (59.0) 44 (50.0)
verbal memory on the AVLT (r ¼ 0.29; P < 0.01); delayed verbal memory, as assessed by the RBMT Paragraph Recall test (r ¼ 0.30; P < 0.01); and executive function using the COWA (r ¼ 0.24; P < 0.05). However, it was not related to the delayed verbal memory assessed by the AVLT (r ¼ 0.21, P < 0.08). In addition, perceived cognitive function (total score) was not significantly related to speed of processing as measured by the SDMT. The FACT-Cog total score also was significantly (P < 0.01) related to each symptom assessed, ranging from r ¼ 0.31 to 0.60 (Table 2). That is, more perceived cognitive problems were associated with more depressive symptoms, fatigue, anxiety, and poor sleep quality.
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Perceived Cognitive Impairment. Similar to the FACTCog total scores, significant relationships were found between PCI and, respectively, objective measures of immediate verbal memory (AVLT; r ¼ 0.25, P < 0.05), delayed verbal memory (RBMT; r ¼ 0.24, P < 0.05), and executive function (COWA; r ¼ 0.23, P < 0.05). However, no relationship was noted between PCI and the other tests of memory (RBMT immediate verbal memory and AVLT delayed verbal memory) or speed of processing. In addition, PCI was significantly and positively correlated with measures of depressive symptoms, fatigue, anxiety, and sleep problems (Table 2). Perceived Impairments on the QoL Subscale. There were no significant relationships noted with the subscale score of perceived impairments on QoL with any of the objective measures of cognitive performance. There were, however, significant relationships between QOL scores and depressive symptoms, fatigue, anxiety, and sleep, with coefficients ranging from r ¼ 0.33 to 0.49 (Table 2). Perception and Comments From Others Subscale. The FACT-Cog subscale of perceptions and comments of others was significantly (P < 0.01) related to one measure of immediate verbal memory (AVLT). In addition, the subscale was significantly (P < 0.05) related to both measures of delayed verbal memory, However, it was not related to speed of processing or executive function. This subscale was highly correlated with each of the symptom measures, with coefficients ranging from r ¼ 0.37 to 0.50. These relationships indicated that perceptions of cognitive concerns by others were related to depressive symptoms, fatigue, anxiety, and poorer sleep (P < 0.01; Table 2). Perception of Cognitive Abilities. As displayed in Table 2, PCA was significantly related to both measures of immediate verbal memory, with coefficients ranging from r ¼ 0.26 to 0.27. In addition, PCA was significantly (P < 0.05) related to delayed verbal memory on the RBMT. However, it was not significantly related to delayed verbal memory as measured by the AVLT. In addition, PCA was significantly related (P < 0.01) to executive function, but not to speed of processing. The PCA also was related to depressive symptoms, fatigue, and anxiety, with coefficients ranging from r ¼ 0.43 to 0.48. The PCA was not related significantly to global problems with sleep.
Relationships of PCI and PCA to Cognitive Performance, Controlling for Covariates Controlling for age, depression, fatigue, anxiety, and sleep, partial correlations were computed
0.17 0.10 0.02 0.17 0.26b 0.49a 0.29a 0.25b 0.13 0.29a 0.27a PCF total PCI QoL Other PCA Memory immediate (AVLT) Memory immediate (RBMT) Memory delayed (AVLT) Memory delayed (RBMT) Speed of processing Executive function Depression Fatigue Anxiety Sleep
AVLT ¼ Rey Auditory Verbal Learning Test; RBMT ¼ Rivermead Behavioral Memory Test; PCI ¼ perceived cognitive impairment; QoL ¼ impairment in quality of life; Other ¼ comments of others; PCA ¼ perceived cognitive ability. a P < 0.01. b P < 0.05.
0.54a 0.51a 0.47a 0.43a 0.43a 0.15 0.02 0.01 0.08 0.20 0.17 0.74a 0.55a
Anxiety Fatigue
0.60a 0.56a 0.49a 0.50a 0.48a 0.25b 0.09 0.19 0.11 0.19 0.19 0.73a 0.56a 0.53a 0.46a 0.48a 0.46a 0.14 0.04 0.09 0.02 0.22b 0.20 0.24b 0.23b 0.13 0.20 0.33a 0.36a 0.19 0.27b 0.23b 0.38a 0.10 0.11 0.04 0.08 0.15 0.51a 0.48a 0.52a 0.48a 0.30a 0.24b 0.09 0.24b 0.35a 0.51a 0.88a 0.44a
Depressive Symptoms Executive Function Speed of Processing Memory Delayed (RBMT) Memory Delayed (AVLT) Memory Immediate (RBMT) Memory Immediate (AVLT) Parameters
Table 2 Relationships Among Perceived Cognitive Function, Cognitive Performance, and Symptoms in Breast Cancer Survivors
0.21 0.17 0.04 0.22b 0.19 0.81a 0.39a
Sleep
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0.31a 0.29a 0.33a 0.37a 0.15 0.03 0.06 0.12 0.12 0.09 0.00 0.43a 0.53a 0.36a d
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between the measures of PCI and PCA, respectively, and all measures of objective cognitive function. After controlling for confounding factors, only PCI and delayed verbal memory were significantly correlated (r ¼ 0.29; P < 0.05). PCA, on the other hand, remained correlated with immediate verbal memory, delayed verbal memory, and executive functioning, with coefficients ranging from r ¼ 0.19 to 0.48.
Discussion The cognitive changes associated with cancer and cancer treatment are a complex and significant problem for cancer survivors.69 In fact, cognitive changes have been consistently identified by clinicians as one of the most persistent late effects of treatment, both distressing to patients and difficult to manage for clinicians.70 In an effort to identify and effectively treat this bothersome and lingering symptom, clinically useful assessment measures are needed. Therefore, the purpose of the present study was to examine one of the most widely used perceived cognitive function instruments and explore its relationship to objective cognitive performance as well as to other symptoms. Although there have been a number of studies examining the relationship between objective neuropsychological tests and perceived cognitive function, to our knowledge this is the first to use the current version of the FACT-Cog and its subscale scores, particularly PCI and PCA, and exploring their relationships to both objective cognitive performance and to other symptoms.17 The most interesting finding in this study was that the total FACT-Cog scores (perceived function) and, specifically, the subscale scores of PCI and PCA were correlated with objective measures of immediate verbal memory, delayed verbal memory, and executive function. This finding is important because there has long been a concern regarding the failure to find associations between subjective and objective measures of cognitive function in cancer survivors. To our knowledge, Vardy et al71 have been the only researchers to examine relationships between the FACTCog and objective cognitive assessments; in 29 patients with breast and colorectal cancer, they found no correlations. However, that study may have been limited by a lack of power, given the small sample size. In a recent review article, Hutchison et al17 examined 24 studies and found that only eight noted a correlation between perceived and objective cognitive function. These authors speculate that the disparate findings may be a result of methodological variations in both the subjective and objective assessments used. Similarly, Bender et al72 noted that the studies with contradictory results often used brief subjective measures; some having only
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one or two items, and they suggested that more comprehensive and multidimensional measures may be more sensitive to the subtle cognitive impairment incurred by cancer survivors. Other researchers, however, suggest that subjective cognitive measures are not identifying cognitive impairment, but rather are indicators of distress or depressive symptoms.8,15,21,73e75 To address this issue, we explored whether the relationships between subjective and objective cognitive function would remain after controlling for relevant demographic (age) and common correlated symptoms such as depressive symptoms, fatigue, anxiety, and sleep problems. We found that most of the relationships on the PCI (impairment) subscale were no longer significant but that the significant correlations between the PCA (ability) subscale and objective performance remained significant. These preliminary findings are significant. First, this work supports the work by Lai et al14,30 in the development of the FACT-Cog as a PROMIS measure conceptualizing PCI and PCA as two separate and distinct concepts. Second, these findings suggest that the negatively worded PCI items might be tapping into more of the negative affect (e.g., depressive symptoms, distress, and so on) than the positively focused ability items. In fact, researchers have noted that depression and negative affectivity may induce negative appraisals of cognitive function76 and thus, negatively worded or problemfocused items may be identifying negative affect vs. cognitive functioning. On the other hand, the positively framed PCA items, as hypothesized by Lai et al,30 may reduce the effects of negative emotional states, providing a valid measure of cognitive function. Finally, our results suggest that PCA may serve as an indicator of cognitive function in BCS. Similar results have been reported by Bender et al,72 who found a significant relationship between perceived cognitive functioning and measures of verbal memory using the RBMT in 31 BCSs. In the review by Hutchinson et al,17 six of the eight studies demonstrating correlations between subjective and objective cognitive function identified correlations between PCI and measures of memory.74,77e81 In addition, we identified only one other study that found a relationship between PCI and executive function. Poppelreuter et al74 noted such a relationship in 119 patients receiving cancer rehabilitation, although correlations were not significant when affective states were controlled. Although our results are preliminary, the data suggest that the FACT-Cog, and specifically the PCA (ability) subscale, may be a clinically useful tool to identify cognitive function. Future research is needed in larger, demographically and ethnically diverse samples of cancer patients.
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As anticipated, perceived cognitive function as measured by the FACT-Cog and subscale scores were significantly correlated with other symptoms including depressive symptoms, fatigue, anxiety, and sleep problems. Previous research has demonstrated that these symptoms are highly correlated in BCSs.5 Future work is needed to identify whether these affective states predict PCI or whether the recognition of cognitive impairment is accompanied by these affective symptoms. One of the major limitations of this study is that it was conducted with BCS who were reporting cognitive concerns, which may have created sampling bias and limit generalizability of the results. This study also was limited by the small homogeneous sample of mostly Caucasian women who were well educated. Further research is needed in a larger and more diverse sample of cancer survivors that includes those with and without cognitive concerns to confirm the results presented. Importantly, this work needs to include a diverse set of cancer survivors because most of this work has been conducted with BCS. In addition, to improve the clinical utility of these instruments, future research is needed to establish cutpoints on the FACT-Cog and subscales of PCI and PCA for cognitive impairment so that clinicians and researchers can identify clinically significant cognitive impairment.
Conclusion Identifying a measure that can recognize subtle cognitive impairment in cancer survivors is important to advance clinical practice and research in this area. Despite the limitations, the results of this study suggest that the FACT-Cog, and specifically the subscales of PCI (impairment) and PCA (ability), may be clinically useful in identifying BCS with cognitive impairment.
Disclosures and Acknowledgments This study was supported by the Robert Wood Johnson Foundation Nurse Faculty Scholar Program (#64194, Principal Investigaor [PI]: Von Ah); American Cancer Society Institutional Research Grant (#84-00225, PI: Von Ah); Indiana University School of Nursing Center for Enhancing Quality of Life in Chronic Illness; and the Mary Margaret Walther Program of the Walther Cancer Institute (#0097.01, PI: Von Ah). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Robert Wood Johnson Foundation, which funded this trial. The funding agency had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.
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References 1. Boykoff N, Moieni M, Subramanian SK. Confronting chemobrain: an in-depth look at survivors’ reports of impact on work, social networks, and health care response. J Cancer Surviv 2009;3:223e232. 2. Munir F, Burrows J, Yarker J, Kalawsky K, Bain M. Women’s perceptions of chemotherapy-induced cognitive side affects on work ability: a focus group. J Clin Nurs 2010;19:1362e1370. 3. Myers JS. Chemotherapy-related cognitive impairment: the breast cancer experience. Oncol Nurs Forum 2012;39: E31eE40. 4. Von Ah D, Habermann B, Carpenter J, Schneider BL. Impact of perceived cognitive impairment in breast cancer survivors. Eur J Oncol Nurs 2013;17:236e241. 5. Bender CM, Ergyn FS, Rosenzweig MQ, Cohen SM, Sereika SM. Symptom clusters in breast cancer across 3 phases of the disease. Cancer Nurs 2005;28:219e225. 6. Myers JS. Cancer- and chemotherapy-related cognitive changes: the patient experience. Semin Oncol Nurs 2013; 29:300e307. 7. Mitchell T, Turton P. ‘‘Chemobrain’’: concentration and memory effects in people receiving chemotherapy - a descriptive phenomenological study. Eur J Cancer Care 2011;20:1e10. 8. Pullens MJ, De Vries J, Roukema JA. Subjective cognitive dysfunction in breast cancer patients: a systematic review. Psychooncology 2010;19:1127e1138. 9. Mitchell T. The social and emotional toll of chemotherapy patients’ perspectives. Eur J Cancer Care 2007;16: 39e47. 10. Jim HS, Phillips KM, Chait S, et al. Meta-analysis of cognitive functioning in breast cancer survivors previously treated with standard-dose chemotherapy. J Clin Oncol 2012;30:3578e3587. 11. Stewart A, Bielajew C, Collins B, Parkinson M, Tomiak E. A meta-analysis of the neuropsychological effects of adjuvant chemotherapy treatment in women treated for breast cancer. Clin Neuropsychol 2006;20:76e89. 12. Jansen CE, Miakowski C, Dodd M, Dowling G, Kramer J. A meta analysis of studies of the effects of cancer chemotherapy on various domains of cognitive function. Cancer 2005;104:222e233. 13. Falleti MG, Sanfilippo A, Maruff P, Weih L, Phillips KA. The nature and severity of cognitive impairment associated with adjuvant chemotherapy in women with breast cancer: a meta-analysis of the current literature. Brain Cogn 2005; 59:60e70. 14. Lai J, Butt Z, Wagner L, et al. Evaluating the dimensionality of perceived cognitive function. J Pain Symptom Manage 2009;37:982e995. 15. Jansen C. Cognitive changes associated with cancer and cancer therapy: patient assessment and education. Semin Oncol Nurs 2013;4:270e279.
Vol. 49 No. 4 April 2015
impairment following chemotherapy for cancer: a systematic review. Cancer Treat Rev 2012;38:926e934. 18. Schagen SB, van Dam FS, Muller MJ, et al. Cognitive deficits after postoperative adjuvant chemotherapy for breast cancer. Cancer 1999;85:640e650. 19. Cull A, Hay C, Love SB, et al. What do cancer patients mean when they complain of concentration and memory problems? Br J Cancer 1996;74:1674e1679. 20. Jenkins V, Shilling V, Fallowfield L, Howell A, Hutton S. Does hormone therapy for the treatment of breast cancer have a detrimental effect on memory and cognition? A pilot study. Psychooncology 2004;13:61e66. 21. Jenkins V, Shilling V, Deutsch G, et al. A 3-year prospective study of the effects of adjuvant treatments on cognition in women with early stage breast cancer. Br J Cancer 2006;94: 828e834. 22. Paganini-Hill A, Clark LJ. Preliminary assessment of cognitive function in breast cancer patients treated with tamoxifen. Breast Cancer Res Treat 2000;64:165e176. 23. Ferguson RJ, McDonald BC, Saykin AJ, Ahles TA. Brain structure and function differences in monozygotic twins: possible effects of breast cancer chemotherapy. J Clin Oncol 2007;25:3866e3870. 24. Deprez S, Amant F, Yigit R, et al. Chemotherapyinduced structural changes in cerebral white matter and its correlation with impaired cognitive functioning in breast cancer patients. Hum Brain Mapp 2011;32:480e493. 25. Wagner L, Sweet J, Butt Z, et al. Measuring patient selfreported cognitive function: development of the functional assessment of cancer therapydcognitive function instrument. J Support Oncol 2009;7:W32eW39. 26. Jacobs SR, Jacobsen PB, Booth-Jones M, Wagner LI, Anasetti C. Evaluation of the functional assessment of cancer therapy cognitive scale with hematopoietic stem cell transplant patients. J Pain Symptom Manage 2007;33:13e23. 27. Wagner L, Lai JS, Cella D, Sweet J, Forrestal S. Chemotherapy-related cognitive deficits: development of the FACT-Cog instrument. Ann Behav Med 2004;27(Suppl 10). 28. Deprez S, Amant F, Smeets A, et al. Longitudinal assessment of chemotherapy induced structural changes in cerebral white matter and its correlation with impaired cognitive function. J Clin Oncol 2012;30:274e281. 29. Joly F, Lange M, Rigal O, et al. French version of the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) version 3. Support Care Cancer 2012;20: 3297e3305. 30. Lai JS, Wagner LI, Jacobsen PB, Cella D. Self-reported cognitive concerns and abilities: two sides of one coin? Psychooncology 2014; [Epub ahead of print]. 31. Von Ah D, Carpenter JS, Saykin A, et al. Advanced cognitive training for breast cancer survivors: a randomized controlled trial. Breast Cancer Res Treat 2012;135:799e809. 32. Jobe JB, Smith DM, Ball K, et al. ACTIVE: a cognitive intervention trial to promote independence in older adults. Control Clin Trials 2001;22:453e479.
16. Ouimet LA, Stewart A, Collins B, Schindler D, Bielajew C. Investigation of neuropsychological screen for chemo-fog. Oncol Rev 2011;5:205e213.
33. Rey A. L’examen psychologique dans les cas d’encephalopathie traumatique. Arch Psychol 1941;28:286e340.
17. Hutchison AD, Hosking JR, Kichenadasse G, Mattiske JK, Wilson C. Objective and subjective cognitive
34. Stallings GA, Boake C, Sherer M. Comparison of the California Verbal Learning Test and the Rey Auditory Verbal
Vol. 49 No. 4 April 2015
Cognitive Function in Breast Cancer Survivors
Learning Test in head-injured patients. J Clin Exp Neuropsychol 1995;17:706e712. 35. Magalhes S, Malloy-Diniz LF, Hamdan AC. Validity convergent and reliability test-retest of the Rey Auditory Verbal Learning Test. Clin Neuropsychiatry 2012;9:129e137. 36. Von Ah D, Harvison K, Monahan P, et al. Cognitive function in breast cancer survivors compared to healthy age- and education-matched women. Clin Neuropsychol 2009;23:661e674. 37. Knight RG, McMahon J, Skeaff M, Green TJ. Reliable change index scores for persons over the age of 65 tested on alternate forms of the Rey AVLT. Arch Clin Neuropsychol 2007;22:513e518. 38. Geffen GM, Butterworth P, Geffen LB. Test-retest reliability of a new form of the auditory verbal learning test (AVLT). Arch Clin Neuropsychol 1994;9:303e316. 39. Loring D, Bauer RM. Testing the limits: cautions and concerns regarding the new Wechsler IQ and memory scales. Neurology 2010;74:685e690.
705
52. Weissman MM, Sholomskas D, Pottenger M, Prusoff BA, Locke BZ. Assessing depressive symptoms in five psychiatric populations: a validation study. Am J Epidemiol 1977;106:203e214. 53. Radloff LS. The CES-d scale. Appl Psychol Meas 1977;1: 385e401. 54. van Wilgen CP, Dijkstra PU, Stewart RW, Ranchor AW, Roodenburg JL. Measuring somatic symptoms with the CES-D to assess depression in cancer patients after treatment: comparison among patients with oral/oropharyngeal, gynecological, colorectal, and breast cancer. Psychosomatics 2006;47:465e470. 55. Ferguson RJ, McDonald BC, Rocque MA, et al. Cognitvebehavioral management of chemotherapy-related cognitive change. Psychooncology 2007;16:772e777. 56. Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E. Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J Pain Symptom Manage 1997;13:63e74.
40. National Institutes of Health. NIH toolbox auditory verbal learning test (Rey). 2013. Available at: http://www.nihtoolbox. org/WhatAndWhy/Cognition/EpisodicMemory/Pages/NIHToolbox-Auditor-Verbal-Learning-Test-(Rey).aspx. Accessed June 1, 2013.
57. Graziano F, Bisonni R, Catalano V, et al. Potential role of levocarnitine supplementation for the treatment of chemotherapy-induced fatigue in non-anaemic cancer patients. Br J Cancer 2002;86:1854e1857.
41. Wilson B, Cockburn J, Baddeley A. The rivermead behavioral memory test. England and Michigan: Thames Valley Test, Co. and National Rehabilitation Services, 1985.
58. Shafqat A, Einhorn LH, Hanna N, et al. Screening studies for fatigue and laboratory correlates in cancer patients undergoing treatment. Ann Oncol 2005;16: 1545e1550.
42. Lezak MD, Howieson DB, Loring DW. Neuropsycholgical assessment, 4th ed. New York: Oxford Unviersity Press, 2004. 43. de Wall C, Wilson BA, Baddeley AD. The extended Rivermead Behavioural Memory Test: a measure of everyday memory performance in normal adults. Memory 1994;2: 149e166. 44. Wilson BA. The assessment, evaluation and rehabilitation of everyday memory problems. New York: Psychology Press, 2014. 45. Paraska KK, Bender CM. Cognitive dysfunction following adjuvant chemotherapy for breast cancer: two case studies. Oncol Nurs Forum 2003;30:473e478. 46. Smith A. Symbol Digit Modalities Test. Los Angeles: Western Psychological Services, 1982. 47. Sbordone RJ, Saul RE, Purisch AD. Neuropsychology for psychologists, health care professionals and attorneys, 3rd ed. Boca Raton, FL: CRC Press, 2007. 48. Berrigan LI, Fisk JD, Walker LA, et al. Reliability of regression-based normative data for the oral symbol digit modalities test: an evaluation of demographic influences, construct validity, and impairment classification rates in multiple sclerosis samples. Clin Neuropsychol 2014;28:281e299.
59. Pinto BM, Rabin C, Abdow S, Papandonatos GD. A pilot study on disseminating physical activity promotion among cancer survivors: a brief report. Psychooncology 2008;17:517e521. 60. Tchen N, Juffs HG, Downie FP, et al. Cognitive function, fatigue, and menopausal symptoms in women receiving adjuvant chemotherapy for breast cancer. J Clin Oncol 2003; 21:4175e4183. 61. Spielberger CD, Gorsuch RI, Lushene RG. Manual for the state-trait anxiety inventory. Palo Alto, CA: Consulting Press, 1971. 62. McCracken LM, Iverson GL. Predicting complaints of impaired cognitive functioning in patients with chronic pain. J Pain Symptom Manage 2001;21:392e396. 63. Spielberger CD. Manual for the state-trait anxiety inventory (Form Y). Palo Alto, CA: Consulting Psychologists Press, 1983. € 64. OZalp G, Sarioglu R, Tuncel G, Aslan K, Kadiogullari N. Preoperative emotional states in patients with breast cancer and postoperative pain. Acta Anaesthesiol Scand 2003;47:26e29.
49. Benton AL, Hamsher KD. Multilingual aphasia examination. Iowa City, IA: AJA Associates, 1989.
65. Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989;28:193e213.
50. Ruff RM, Light RH, Parker SB, Levin HS. Benton controlled oral word association test: reliability and updated norms. Arch Clin Neuropsychol 1996;11:329e338.
66. Carpenter JS, Andrykowski MA. Psychometric evaluation of the Pittsburgh sleep quality Index. J Psychosom Res 1998;45:5e13.
51. Ruff RM, Light RH, Parker SB, Levin HS. The psychological construct of word fluency. Brain Lang 1997;57: 394e405.
67. Fortner BV, Stephanski EJ, Wang SC, Kasprowicz S, Durrence HH. Sleep and quality of life in breast cancer patients. J Pain Symptom Manage 2002;24:471e480.
706
Von Ah and Tallman
68. Uchiyama CL, D’Elia LF, Dellinger AM, et al. Alternate forms of the auditory-verbal learning test: issues of test comparability, longitudinal reliability and moderating demographic variables. Arch Clin Neuropsychol 1995;10:133e145. 69. Bender CM, Thelen BD. Cancer and cognitive changes: the complexity of the problem. Semin Oncol Nurs 2013;29: 232e237. 70. LoBiondo-Wood G, Brown CG, Knobf MT, et al. Priorities for oncology nursing: the 2013 national survey. Oncol Nurs Forum 2014;42:67e76. 71. Vardy J, Wong K, Yi QL, et al. Assessing cognitive function in cancer patients. Support Care Cancer 2006;14: 1111e1118. 72. Bender CM, Pacella ML, Sereika SM, et al. What do perceived cognitive problems reflect? J Support Oncol 2008;6:238e242. 73. Kilbiger G, Kirsh KL, Wall JR, Passik SD. My mind is as clear as it used to be: a pilot study illustrating the difficulties of employing a single-item subjective screen to detect cognitive impairment in outpaients with cancer. J Pain Symptom Manage 2003;26:705e715. 74. Poppelreuter M, Weis J, Kulz AK, et al. Cognitive dysfunction and subjective complaints of cancer patients. a cross-sectional study in a cancer rehabilitation centre. Eur J Cancer 2004;40:43e49. 75. Shilling V, Jenkins V. Self-reported cognitive problems in women receiving adjuvant therapy for breast cancer. Eur J Oncol Nurs 2007;11:6e15.
Vol. 49 No. 4 April 2015
76. Hermelink K, Kuchenhoff H, Untch M, et al. Two different sides of ’chemobrain’: determinants and nondeterminants of self-perceived cognitive dysfunction in a prospective, randomized, multicenter study. Psychooncology 2010; 19:1321e1328. 77. Mehnert A, Scherwath A, Schirmer L, et al. The association between neuropsychological impairment, selfperceived cognitive deficits, fatigue, and quality of life in breast cancer survivors following standard adjuvant versus high-dose chemotherapy. Patient Educ Couns 2007;66: 108e118. 78. Downie FP, Mar Fan HG, Houede-Tchen N, Yi Q, Tannock IF. Cognitive function, fatigue, and menopausal symptoms in breast cancer patients receiving adjuvant chemotherapy: evaluation with patient interview after formal assessment. Psychooncology 2006;15:921e930. 79. Reid-Arndt SA, Hsieh C, Perry MC. Neuropsychological functioning and quality of life during the first year after completing chemotherapy for breast cancer. Psychooncology 2010;19:535e544. 80. Weis J, Poppelreuter M, Bartsch HH. Cognitive deficits as long-term side-effects of adjuvant therapy in breast cancer patients: ’subjective’ complaints and ’objective’ neuropsychological test results. Psychooncology 2009;18:775e782. 81. Poppelreuter M, Weis J, Bartsch HH. Effects of specific neuropsychological training programs for breast cancer patients after adjuvant chemotherapy. J Psychosoc Oncol 2009;27:274e296.
