Support Care Cancer (2016) 24:481–497 DOI 10.1007/s00520-015-2927-y

REVIEW ARTICLE

Modifiable factors and cognitive dysfunction in breast cancer survivors: a mixed-method systematic review Ashley Henneghan 1

Received: 31 January 2015 / Accepted: 31 August 2015 / Published online: 29 September 2015 # Springer-Verlag Berlin Heidelberg 2015

Abstract Purpose It is unknown why some breast cancer survivors experience cancer-related cognitive impairments (CRCI) after cancer treatment, and modifiable risk factors for CRCI remain to be explicated. This mixed-method systematic review synthesizes quantitative and qualitative evidence for relationships between modifiable factors and CRCI in breast cancer survivors who receive chemotherapy as part of their treatment. Methods Keyword Searches of PubMed/Medline, PsychINFO, and CINAHL were performed for January 2005 through June 2015. Studies that provided data on associations between modifiable biological, behavioral, environmental, and psychosocial factors and cognition were included. Results Twenty-two quantitative studies and five qualitative studies were identified after applying inclusion and exclusion criteria yielding evidence for significant relationships among modifiable biological (inflammatory cytokines), behavioral (sleep quality, physical activity), and psychosocial (stress, distress, affect) factors and CRCI. Conclusion Many women unfortunately experience CRCI after breast cancer chemotherapy, with limited treatment options available to improve cognitive function. This review synthesizes current evidence to support the associations between modifiable factors and CRCI and can inform research to evaluate these factors prospectively. The clinical implications of these findings suggest that lifestyle factors such as physical activity, stress management, and sleep quality may be appropriate targets for behavioral interventions to improve

* Ashley Henneghan [email protected] 1

University of Texas at Austin, 1710 Red River, Austin, TX 78701, USA

cognitive function following breast cancer chemotherapy; however, further research is necessary. Keywords Breast cancer . Survivors . Cognition . Modifiable factors . Mixed-method systematic review

Introduction Advances in breast cancer treatment have resulted in lower rates of mortality and a growing breast cancer survivor cohort [1]. Among these breast cancer survivors are those who experience cancer-related cognitive impairments (CRCI), often a result of chemotherapy treatment. Indeed CRCI, defined here as perceived or objective Bproblems with memory, executive functioning, and attention/concentration^ [2, p 102], has mostly been evaluated in breast cancer survivors [2, 3]. Evidence is emerging that cognitive changes, namely lower than expected neuropsychological performance and selfreported cognitive dysfunction, are related to breast cancer treatment [2]. Cognitive function is of course intimately tied to daily activities and a person’s identity; therefore, the consequences of CRCI can be pervasive [4–8]. In fact, cancer survivors have reported this symptom as the most devastating and feared side effect of cancer treatment [4, 5] because it hampers independence and social role performance [6, 7] including negatively impacting work ability and productivity [8]. Meta-analyses suggest that breast cancer survivors experience deficits in the cognitive domains of verbal and visuospatial abilities [9], executive functioning, and processing speed [10, 11] compared to controls. Additionally, a systematic review reports that breast cancer survivors experience greater perceived cognitive difficulties than age-matched controls [12]. More recently, researchers have used structural and functional neuroimaging techniques to investigate the neural

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substrates of CRCI in breast cancer survivors, consistently reporting subtle and diffuse brain changes in survivors exposed to chemotherapy including decreased gray matter volume, decreased white matter integrity [13, 14], and patterns of neural hypo or hyperactivation [15] in comparison with those not exposed to chemotherapy or age-matched controls [16, 17]. The etiology of CRCI, including the neural substrates, remains unclear; however, the leading candidate mechanisms include direct and indirect neurotoxic effects of chemotherapy [18–20]. It is now recognized that CRCI is likely multifactorial [21, 22], and several treatment-related and individual risk factors have been identified in those vulnerable to CRCI including older age [23], lower cognitive reserve [24], positive apolipoprotein E (APOE) E4 allele genetic carrier status [9, 25], postmenopausal status [26], higher chemotherapy dose [27, 28], type of chemotherapy (e.g., doxorubicin) [26, 29], less time since chemotherapy [3], and tamoxifen use [30]. Although these distinct risk factors for CRCI have been identified, the underlying mechanisms for CRCI are not completely understood. Furthermore, these risk factors are largely unmodifiable or unavoidable when faced with breast cancer. A substantial body of research supports the relationships between CRCI and depression, anxiety [31–33], and fatigue [11, 12, 34, 35], which are modifiable emotional, or mood-related, factors and potential targets for interventions. This research suggests the important possibility that researchers should also consider modifiable biological, behavioral, environmental, and psychosocial factors (i.e., factors that can be manipulated with behavioral or pharmaceutical interventions) that may impact CRCI factors that have not been extensively evaluated in breast cancer survivors. The aim of this review is to synthesize the qualitative and quantitative evidence found in the literature for associations between modifiable biological (e.g., inflammatory markers, stress hormones), behavioral (e.g., sleep or exercise), environmental (e.g., physical environments, access to health care), and psychosocial (e.g., stress, distress, affect) factors and cognition (both perceived and objective) in breast cancer survivors. The literature on depression, anxiety, and fatigue and cognitive dysfunction will be excluded, since this body of research has previously been reviewed and synthesized as described above. In the present review, Bbreast cancer survivor^ refers to those with breast cancer from time of diagnosis to death. The specific research questions guiding this review are as follows: (1) What relationships have been identified among modifiable biological factors and perceived and objective cognitive dysfunction in breast cancer survivors?; (2) What relationships have been identified among modifiable behavioral factors and perceived and objective cognitive dysfunction in breast cancer survivors?; (3) What relationships have been identified among modifiable environmental factors and perceived and objective

cognitive dysfunction in breast cancer survivors?; (4) What relationships have been identified among modifiable psychosocial factors and perceived and objective cognitive dysfunction in breast cancer survivors? This review represents an adaptation of Kang et al.’s integrated biobehavioral model. This model is comprehensive, including clusters of individual (e.g., age, gender), environmental (e.g., access to health care), psychosocial (e.g., stress, social support), and behavioral (e.g., physical activity, diet) factors that can impact biological responses (e.g., immune changes) both individually and in combination, ultimately influencing health-related outcomes (e.g., cognitive function) [36]. The model posits that biological factors typically mediate the influence of various individual, behavioral, environmental, and psychosocial factors on health-related outcomes. Because the model offers conceptual and propositional flexibility, it was adapted for this review as shown in Fig. 1. Individual factors were not included in this adaptation because in the context of this model, the individual factors are not modifiable.

Methods Data sources and search Two primary methods were used to locate relevant studies: (1) key word search and (2) manual ancestry searches of the most recent systematic and meta-analytic reviews of breast cancer and cognition research [9, 11, 12]. PubMed/MEDLINE, CINAHL, and PsycINFO were searched with the following keywords for January 2005 through June 2015: breast cancer, breast neoplasms, cognition, cognition disorders, antineoplastic combined chemotherapy protocols, chemotherapy, adjuvant, combined modality therapy, cognitive effects, cognitive dysfunction, cognitive function, cognitive impairment, memory, cognitive deficit, and chemotherapy care. A science instruction librarian at the author’s university reviewed the chosen databases and search terms prior to the search being conducted. Study selection and data extraction Inclusion criteria for the studies were as follows: (1) the sample consisted of breast cancer survivors; (2) the majority of the sample (>50 %) received chemotherapy as part of their treatment; (3) cognitive function (or dysfunction) was a primary outcome of the study; (4) correlational data were provided on modifiable biological (e.g., immune changes), behavioral (e.g., physical activity, diet), environmental (e.g., access to health care), psychosocial (e.g., stress, social support), or and a cognitive outcome (neuropsychological assessment or self-report) in

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Fig. 1 Theoretical model adapting the integrated biobehavioral model for CRCI in breast cancer survivors

quantitative studies, or cognitive dysfunction attributed to similar modifiable factors was discussed in qualitative studies; (5) the article was in English; and (6) the study presented primary research. Exclusion criteria were as follows: (1) correlational data were confounded by populations other than breast cancer survivors who received chemotherapy (e.g., healthy controls); (2) data were collected pretreatment, because this was not the focus of the review; (3) only imaging data were presented; (4) studies were done with animals or in vitro; (5) studies were case studies; (6) studies were methodological or psychometrically focused; and (7) data involved correlations between anxiety, depression, and/or fatigue and cognition which are already explicated in the literature [11, 12, 31–35]. The search strategy and methodology are depicted in Fig. 2. Fig. 2 Search flowchart created using http://prisma. thetacollaborative.ca

The author extracted the following data from articles reviewed: first author and year of publication; study objective; population; study setting; design; modifiable factors; cognitive outcomes; and key findings (see Table 1). Data were synthesized into factor groups (environmental, biological, behavioral, psychosocial) using Pluye et al.’s complementary method [37].

Risk for bias appraisal criteria Few methodologies exist for appraising both qualitative and quantitative studies; therefore, an appraisal of risk for bias was conducted according to criteria adapted from Pluye et al. [37] (see Table 2). This methodology has been utilized in several other mixed-method systematic reviews [38–40].

PubMed/Medline Jan 2005 5 to June 201 15 263 citations

PsychINF FO Jan n 2005 to Ju une 2015 87 citatio ons

CIN NAHL Jan 2005 to June 20155 156 ccitations

352 non-dup plicate citations scrreened

Inclusion//Exclusion Criteriaa Applied

278 articles excluded after ttitle/abstractt screen

74 articles retrieved

Inclusion/E Exclusion Criteria applied

27 articless included

47 aarticles excluuded afterr full text scrreen

To assess the influence of glucocorticoid and ovarian disruption on cognitive function in survivors of breast cancer

To evaluate the effect of chemo induced inflammatory response on breast cancer patients’ cognitive function

To examine the association of perceived cognitive impairments with gray matter density and working memory-related MRI brain activation in breast cancer survivors

To determine whether or not there is a significant relationship between recent chemo exposure in women with early stage breast cancer and proinflammatory cytokines

Andreano, 2012 [26]

Cheung, 2015 [41]

Conroy, 2013 [42]

Ganz, 2013 [5]

Biological factors

Quantitative studies

Objective

Observational cohort study T1: 0–3 months postprimary treatment T2: 6 months later T3: 12 months later

Multimodal MRI (imaging) study

Indianapolis— community

Breast cancer survivors 3–10 years after chemo (n=24) Mean age 57.8 (9.6) Stage I–IIIb Doxorubicin-based chemo Age and education matched controls (n=23) Los Angeles— community

Multi-centered prospective cohort T1 (before chemo initiation) T2 (6 weeks after T1) T3 (12 weeks after T1)

Singapore—cancer institutions

Breast cancer patients (n=99) Mean age 50.5 (8.4) Stage I–III Anthracycline chemo (70.7 %)

Early stage breast cancer survivors (n=49) Age 49.9 (8.5) 92 % Stage I–II Anthracycline Chemo (29 %)

Experimental (manipulation of physical stressor) T1 (anytime during Lupron treatment) T2 (1 week after T1)

Design

California—breast cancer clinic

Setting: Geographic and clinical

Breast cancer patients on Lupron to prevent recurrence (n=20) Stage unspecified 70 % chemo Controls (n=20)

Population: Age Stage Chemo

Data extraction for quantitative and qualitative articles

First author, year

Table 1

Inflammatory markers (biological): regular sensitively ELISA for soluble TNF Receptor type II (sTNF-RII)

Oxidative damage (biological): modified alkaline Comet assay of oxidative DNA damage

Inflammatory markers (biological): immunoassay kit for interleukins [IL-1β; IL-2; IL-4; IL-6; IL-8; IL10]; granulocytemacrophage colony stimulating factor [GM-CSF]; interferon [IFN-γ]

Cortisol (biological): salivary cortisol ELISA

Modifiable factors (category)—measure

∫

Memory (SR): SMQ

Perceived cognitive function (SR): MASQ; FACT-Cog

Processing speed, response speed, memory, and attention performance (NP) Cognitive Stability Index (Headminder) Perceived global cognitive (SR): FACT-Cog version 3

Immediate and delayed memory (NP): WMS III subtests-verbal paired associates; logical memory—Story A [emotionally charged story] and Story B [weather report)]

Cognitive outcome (SR or NP)—measure

€

At T1 significant negative correlation between sTNF-RII and SMQ (r=−0.21, p=0.05) controlling for age, BMI, radiation exposure, and depression

No significant relationships between oxidative damage and perceived cognitive impairments (MASQ, FACT-Cog) Increased oxidative damage was related to lower gray matter density (r=−0.5, p=0.011) in breast cancer survivors

IL-1β was associated with 0.78 decrease in response performance (p=0.023) Higher concentration of IL-4 was associated with better response speed performance (p=0.022) Higher concentrations of IL-1β and IL-6 were associated with more perceived cognitive disturbances (p=0.018; p=0.001) Every unit increase of IL-4 was associated with 0.95 increase in FACT-Cog total score (p=0.022)

Controls (T2) recall for story A was significantly positively correlated with salivary cortisol levels (r=0.54, p<0.05, df=9) No significant correlations between cortisol and recall in the breast cancer patients at any time—suggesting reduced glucocorticoid responsiveness

Key findings

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Cross-sectional

Cross-sectional

California—Stanford area community

California—Stanford area community

Breast Cancer Survivors (n=19) Mean age 55.1 (8.4) Stages I–III Various chemo regimens Age-matched controls (n=17)

Breast cancer survivors (n=20) Mean age 54.6 (6.5) Stage 2.12 (0.72) 100 % chemo

To evaluate metabolite concentrations as well as cognitive performance in breast cancer survivors and age-matched controls

To investigate the relationships between hippocampal structure, verbal memory performance, and peripheral cytokines in breast cancer survivors

Kesler, 2013 [47]

Secondary analysis of randomized control trial T1: 1st 0–2 cycles of chemo T4: after 2 more cycles of chemo

Design

Kesler, 2013 [48]

University of Rochester and 2 other sites

Setting: Geographic and clinical

Breast cancer patients receiving chemo: Group 1 (n=27, age 52.85 (8.64); AC/CAF chemo) Group 2 (n=27, age 50.18 (9.62), CMF chemo) Stage unspecified

Population: Age Stage Chemo

To compare levels of IL-6, IL-8, and MCP-1 in patients receiving doxorubicin-based chemo with levels in those receiving a combination of CMF chemo and their relationships with cognitive complaints

and how these markers interact with other behavioral symptoms

Objective

Janelsins, 2012 [54]

First author, year

Table 1 (continued)

Inflammatory marker: (biological): high sensitivity multiplexed sandwich immunoassay IL-6, IL-8, IL-1-, IL_12, IL-1-beta, IL-β, IFNγ, TNFα

Neural metabolites (biological): magnetic resonance spectroscopy (choline [Cho]; myoinositol [mI]; Nacetylaspartate [NAA]/ Cho and NAA/mI ratios)

Inflammatory markers (biological): ELISA-IL-6, IL-8, monocyte chemo-attractant protein [MCP-1]

Modifiable factors (category)—measure

∫

MMQ was significantly related to mI (r=−0.55, p<0.02) and Cho (r=−0.62, p<0.005) in the breast cancer group No significant correlations between Cho, mI, NAA/Cho, NAA/mI and the BRIEF or between NAA/Cho, NAA/mI and MMQ in either group A significant interaction between IL-6 and TNFα on the HVLT-R was reported in the chemo treated breast cancer survivors (β=−2.46, p=0.006) MMQ not associated with cytokines Perceived memory (SR): MMQ Memory performance (NP): HVLT-R

In the AC/CAF group: Changes in MCP-1 from T1 to T2 significantly correlated with difficulty concentrating (r=−0.498, p<0.05) and forgetfulness (r=−0.466, p<0.05) Both IL-8 and IL-6 were positively correlated with all the items (p=NS) In the CMF group: IL-6 was negatively correlated with all 5 items (p=NS) IL-8 was positively correlated with all but difficulty thinking (p=NS) MCP was positively correlated with all items except heavy headed (p=NS)

Significant negative correlation between change in SMQ and change in sTNF-RII from T1 to T3 (r=−0.34, p=0.04)

Key findings

Perceived memory (SR): MMQ, BRIEF Cognitive performance (NP): HVLT-R, WAIS-IV, WCST

Perceived global cognition (SR): Fatigue Symptom Checklist (5 yes/no questions): heavy headed, muddled thoughts, difficulty thinking, difficulty with concentration, forgetfulness

€ Cognitive outcome (SR or NP)—measure

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To explore EEG biofeedback as a potentially restorative intervention for post chemo cognitive impairments in breast cancer survivors

To explore the changes in perceived attention function in women with breast cancer over time (2 years)

To examine the relationship between self-reported exercise, cardiorespiratory fitness, and cognitive function in early breast

Chen, 2012 [45]

Crowgey, 2014 [43]

To examine relationships following adjuvant chemo between proinflammatory cytokines, regional cerebral metabolism and cognitive complaints in early stage breast cancer patients To identify whether decline in cognitive functioning after chemo is associated with health/disease, treatment, and psychosocial variables

Objective

Alvarez, 2013 [56]

Behavioral factors

Vearn-combe, 2009 [50]

Pomykala, 2013 [44]

First author, year

Table 1 (continued)

Pilot study Quasi-experimental Participants served as own wait list control

Prospective observational study (12 time points from before surgery to 24 months after) Cross-sectional

Taiwan—3 hospital sites

North Carolina—Duke Medical Center

Newly diagnosed breast cancer patients (n=200), stage I–IIIb 83 % received chemo ER+, HER−, breast cancer patients (n=37), Stage IA–IIIC Doxorubicin containing chemo

Observational cohort T1 (pre-chemo) T2 (1-month post chemo)

Australia—several hospitals

Breast cancer survivors (n=136) Age 49.38 (7.92) Stage I–III Various types of chemo Breast cancer survivors with no chemo (n=21)

Ohio—community setting

Observational cohort study Baseline: 0–3 months post primary treatment T2: 6 months later T3: 12 months later

Los Angeles—community

Breast cancer survivors (n=33) Stage 0–IIIA (59 % Stage 2) 69.6 % chemo, 35 % anthracycline

Female Breast Cancer Survivors with self-reported cognitive impairments (n=23) >40 years stage unspecified 100 % chemo

Design

Setting: Geographic and clinical

Population: Age Stage Chemo

Psychomotor speed (NP): Finger Tapping and Symbol Digit Coding Reaction time (NP): Stroop Test

Attention (SR): AFI

Sleep (behavioral): GSDS

Exercise (behavioral): GLT-EQ; Cardiorespiratory fitness (behavioral): VO2peak

Perceived cognitive impairments (SR): FACT-Cog

Verbal memory (NP): Auditory Verbal Learning Test Visual memory (NP): WMSIII Working memory (NP): WAIS-III, Digitspan Processing speed (NP): Symbol Digit Modalities Test Attention (SR): TEA Executive function (NP): WAIS-III, Stroop, COWAT, Card Sorting Motor coordination (NP): Purdue Pegboard

Anemia (biological): whole blood hemoglobin

Sleep (behavioral): PSQI

Cognitive complaints in memory, high-level cognition, sensory motor, language/Communication (SR): PAOFI

€ Cognitive outcome (SR or NP)—measure

Inflammatory marker (biological): interleukin 6 (IL-6), soluble TNF receptor type II (sTNF-RII)

Modifiable factors (category)—measure

∫

Significant positive relationship between exercise behavior and visual memory (r=0.47, p=0.004)

Perceived attentional function significantly related to sleep disturbance across time points (r=−0.43 to −0.64, p<0.01)

Significant negative correlation between FACT-Cog quality of life subscale and PSQI sleep quality subscale (r=−0.56, p<0.01) Significant negative correlation between FACT-Cog quality of life subscale and PSQI sleep daytime dysfunction (r=0.42, p<0.05)

Declines in hemoglobin were associated with declines in verbal memory (r=0.20, p<0.02)

At baseline-significant positive correlation between total severity scores for PAOFI memory subscale and IL-6 levels (p=0.0287)

Key findings

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To compare the severity of perceived cognitive disturbances in Asian breast cancer patients receiving chemo and those not receiving chemo and to identify potential clinical and psychosocial factors associated with these difficulties

To explore the factors that determine self-reported cognitive functioning in breast cancer survivors

To examine the relationship between loneliness and

Hermelink, 2010 [57]

Jaremka, 2014 [46]

To identify and longitudinally examine a symptom cluster based on concurrent and correlated symptoms in women receiving treatment for breast cancer

cancer patients previously treated with chemo

Objective

Cheung, 2012 [51]

Psychosocial factors

Sanford, 2014 [49]

First author, year

Table 1 (continued)

Study 1 Unspecified setting

Study 1 part of a clinical trial

Prospective observational

Germany—multiple cancer centers

Breast cancer survivors without metastases part of multicenter clinical trial— randomized to standard dose (n=48, age 49.9 [8.9])) chemo and high dose chemo (n=53, age 47.1 [10.1])) Stage unspecified Study 1 breast cancer survivors (n=200)

Cross-sectional

Secondary analysis of longitudinal prospective study

Design

Singapore—cancer center

Chicago—outpatient oncology clinics

Setting: Geographic and clinical

Breast cancer patients receiving chemo (n=85, age 51 (9.2)) and not receiving chemo (n=81, age 54.1 (10.2)) Stage I–IV (75.3 % Stage II or III)

Breast cancer survivors (n=80) undergoing chemo Age 49.7 (9.2) Stage I–III

Population: Age Stage Chemo

Study 1

Negative and positive affect (psychosocial): PANAS

Emotional functioning (Psychosocial): EORTC QLQ-C30

Sleep (behavioral): PSQI Other symptom variables: anxiety: HADS-A And depression: HADS-D

Modifiable factors (category)—measure

∫

Lonelier breast cancer survivors reported more

Negative affect (assessed before start of chemo) increases cognitive complaints throughout the first year (EORTC-CFS, CI 95 % −0.85±0.69, p=0.015 and FEDA, CI 95 % −0.62±0.47, p=0.011) Positive affect did not show significant effects on the same measures Global cognition (SR): Cognitive Function Scale of EORTC-CFS Attention (SR): FEDA

Study 1

Perceived cognitive disturbances significantly correlated with emotional functioning (r=0.52. p<0.001) and anxiety (r = -0.58, p <.001) Emotional functioning were significant predictors of cognitive functioning (β=0.22, p<0.01)

PSQI, FACT-Cog, HADS-D, and HADS-A moderately highly correlated across 3 times points (absolute value rho 0.33 to 0.75, p<0.01) Individual correlations not provided by author

Trend towards significance for the relationship between memory composite and exercise (r=0.31, p=0.067) All other relationships were generally weak and nonsignificant

Key findings

Perceived global cognitive functioning (SR): FACTCog

Complex attention; cognitive flexibility; processing speed (NP): Symbol Digit Executive functioning: Shifting Attention Verbal memory: Four Part Continuous Performance Test Visual memory: Four Part Continuous Performance Test Composite memory: Four Part Continuous Performance Test Perceived cognitive function (SR): FACT-Cog

€ Cognitive outcome (SR or NP)—measure

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Mehlsen, 2009 [55]

Multiple factors

To examine if cancer patients receiving chemo differ in cognitive changes during treatment from cardiac

To compare cognitive effects of adjuvant tamoxifen and letrozole in postmenopausal women with early stage breast cancer within an RCT (double blind) To test the hypothesis that increased accessibility of the Bchemo-brain schema^ may influence the expression of cognitive complaints

Phillips, 2010 [58]

Schagen, 2009 [59]

To develop a brief, reliable self-report measure of work-related cognitive limitations in occupationally active breast cancer survivors

Aarhus University Hospital

Prospective observational T1 (0–7 days before chemo) T2 (4–6 weeks after last cycle of chemo

Cross-sectional

Netherlands—cancer institute

Breast cancer survivors (N=261) receiving survivorship care Stage unspecified 100 % received chemo

Breast cancer patients receiving chemo (n=34) Age 48.6 (8.0) Stage unspecified

Psychological distress (psychosocial): GHQ-12

Sub-study (crosssectional, 5 years after endocrine treatment) of a double blind RCT

Australia, Europe, New Zealand—cancer centers (n=11)

Breast Cancer Patients (n=120) Mean age 63.7 (7) Stage unspecified 59 % history chemo

Stress (psychosocial): Perceived Stress Scale Social support (psychosocial): Social

Positive affect (psychosocial): 5 items from PANAS

Job stress (psychosocial): 1 item: BHow often do you experience job stress at work (never, seldom, sometimes, often)?^

Merged data set, secondary analysis

Maryland—community

Breast cancer survivors from 2 studies (n=228) stage I–III 80.7 % received chemo

Working memory (NP): WAIS-III, Digit span Forward and Backward Response inhibition (NP): Stroop Test

Memory and concentration (SR): 2 items: the extent that memory problems and concentration problems happened lately

Global cognitive function (SR): FACT-Cog Perceived attention, concentration, memory, visual processing, language, executive functioning (SR): CSCW59 Psychomotor function, visual attention, working memory, visual learning, verbal learning (NP): set of computerized cognitive tests

Perceived cognitive impairment (SR): Chinese version of FACTCog Version 3

Memory concentration (SR): 3 item cognitive problems scale

Loneliness (psychosocial) UCLA Loneliness Scale

PTSD symptoms (avoidance and hyperarousal) (psychosocial): PTSD Symptom Inventory

Cognitive outcome (SR or NP)—measure

€

Modifiable factors (category)—measure

∫

Cross-sectional observational

Design

Shandong University Qilu Hospital

Age 51.48 (9.24) Stage 0–IIIA 61 % received chemo

cognitive function in breast cancer survivors using 3 samples (* only Study 1 reported here, studies 2a and 2b included healthy controls with breast cancer participants) To investigate how chemo and psychological factors are related to perceived cognitive impairment in Chinese patients with breast cancer

Setting: Geographic and clinical

Breast cancer patients who received chemo or were scheduled for chemo (n=202) Mean age 45.2 (8.0) Stage 0–IV

Population: Age Stage Chemo

Objective

Ottati, 2013 [8]

Li, 2014 [53]

First author, year

Table 1 (continued)

Baseline stress was the only significant predictor of general cognitive decline in the breast cancer

Significant negative relationship between positive affect and cognitive complaints (r=−0.23, p<0.001) Priming and preexisting knowledge were dichotomous variables and no correlations were reported between these variables and cognitive complaints, only ANOVA’s

No correlation was observed between cognitive measures and psychological distress

Job stress at work significantly correlated with FACT-Cog (r=0.43, p<0.001) and the CSCW59 (r=0.35, r<0.001)

Perceived cognitive impairment was negatively related to avoidance (r=−0.45, p<0.001) and hyperarousal (r=−0.57, p<0.001)

cognitive difficulty than less lonely survivors (b=0.03, t(177)=3.13, p=0.002) across different treatment types

Key findings

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To examine the psychosocial effects of chemobrain

To gather descriptions from multiethnic Asian breast cancer patients on their experiences and impact of

Cheung, 2012 [61]

To explore potential factors associated with perceived cognitive impairments in breast cancer survivors compare to controls

patients and healthy controls

Objective

Boykoff, 2009 [4]

Qualitative studies

Myers, 2015 [52]

First author, year

Table 1 (continued)

Ethnographic content analysis (part of exploratory pilot study) focus groups Qualitative descriptive 8 focus groups

Singapore—National Cancer Center

Breast cancer patients receiving chemo (N=43) Mean age 52

Cross-sectional

Design

Los Angeles—community

National wide through Oncology Nursing Society

Setting: Geographic and clinical

Breast cancer survivors (N=74) 40–59 years (65 %) Stage unspecified 77.6 % received chemo

Breast cancer survivors (n=317) Mean ages range 53.1– 62.3 for 5 groups of BCS Stage I–IV (majority stage II) Type of chemo unspecified Healthy controls (n=46)

All had CEF chemo Cardiac patients (n=14) Healthy controls (n=17)

Population: Age Stage Chemo

Mental activity (behavioral) Physical activity (behavioral)

Stress (psychosocial)

Women in the sample identified that they had more memory dysfunction in stressful situations such as job interviews Many women (56 %) attributed cognitive changes to lack of mental and physical activity 26 % attributed cognitive

Memory

Cognitive changes

In the chemo group: Perceived cognitive impairments were associated with sleep disturbance (r=−0.32, p<0.0001) AFI was associated with sleep disturbance (r=−0.32, p<0.0001) Perceived cognitive impairments were associated with distress (r=−0.40, p<0.0001) AFI were associated with distress (r=−0.40, p<0.0001) Exercise moderated the negative effect of BMI on perceived cognitive impairments in the chemo group (F(3,133) =3.1, p=0.03)

patients (odds ratio: 1.3, p<0.01) Social support and sleep quality were not significant predictors of cognitive decline

Processing speed (NP): WAIS-III Executive functioning (NP): Shifting Attention Verbal memory (NP): Rey Auditory Verbal Learning Test; Wechsler’s Memory Scale-III immediate and delayed Visual memory (NP): RCFT immediate and delayed Visuospatial ability (NP): RCFT Verbal fluency (NP): Word Fluency-animals, Bf^, Bn^ Perceived cognitive function (SR): AFI; FACT-Cog

Support Questionnaire of Transactions Sleep quality (behavioral): PSQI

Distress (psychosocial): MD Anderson Symptom Inventory Sleep disturbance (behavioral) MD Anderson Symptom Inventory Exercise (Behavioral): Type, frequency, and duration of current exercise

Key findings

Cognitive outcome (SR or NP)—measure

€

Modifiable factors (category)—measure

∫

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To provide an in depth description of the experience of chemo-related cognitive impairment for women with breast cancer

To describe changes in cognitive function experienced by women who had undergone chemo and the strategies they used to overcome associated challenges

Myers, 2012 [60]

Player, 2014 [62] Breast cancer survivors (n=9) Age 39–67 Stage I–III 100 % chemo

Breast cancer survivors (n=18) 25–65 years old Stage I–IV Chemo (100 % doxorubicin and cyclophosphamide)

Stages I–IV (77 % stages II or III) 100 % received chemo (77 % either AC or FEC based) Breast cancer survivors (n=31) Oncology health providers (n=5) 47 (6) years old Stage I–III 100 % received chemo

Population: Age Stage Chemo

New South Wales— community

Kansas City—academic breast cancer survivor center

United Kingdom—cancer center

Setting: Geographic and clinical

Qualitative phenomenological study Semi-structured interviews

Part of a mixed methods study (combined qualitative and quantitative content analysis), interviewed 4 months after completing chemo Semi-structured interviews Qualitative descriptive (qualitative content analysis) Focus group and semistructured interviews

Design

Global cognitive function

Perceived global cognition

Exercise (behavioral) Sleep (behavioral)

Feeling overwhelmed (psychosocial)

Perceived global cognitive problems

Cognitive outcome (SR or NP)—measure

€

Distress (psychosocial)

Social support (psychosocial)

Modifiable factors (category)—measure

∫

All 9 participants attributed emotional feelings of being overwhelmed as a cause of their Bchemobrain^

11/18 participants reported that exercise was beneficial to their cognitive function Participants described that periodic naps (or rest) throughout the day helped to sharpen their focus

Participants perceived that an intervention targeted at coping with emotional stress associated with cognitive problems would be Bquite a bit useful^ to Bvery useful^

changes to lack of social support

Key findings

In the cognitive outcomes column—the bold represents the cognitive variable(s) in the study. The category of cognitive variable is in parentheses (neuropsychological [NP] or self-report [SR]), and the measure used for the cognitive variable is italicized

€

∫ In the modifiable factors column—the bold represents the modifiable factor(s) in the study. The category of modifiable is in parentheses (biological, behavioral, psychosocial), and the measure used for the modifiable factors is italicized

Outcome: SR self-rated, NP neuropsychological test performance; self-report measures: AFI Attentional Function Index, BAI Beck Anxiety Inventory, BRIEF Behavioral Rating Inventory of Executive Function, CSC-W59 Cognitive Symptom Checklist Work-59, FACT-COG Functional Assessment of Cancer Treatment Cognition, EORTC-CFS European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 version 3.0, FEDA Questionnaire of Experienced Deficits of Attention, GHQ-12 General Health Questionnaire- 12, GSDS General Sleep Disturbance Scale, GLTEQ Godin Leisure Time- Exercise Questionnaire, HADS Hospital Anxiety Depression Scale, PSQI Pittsburgh Sleep Quality Index, MASQ Multiple Ability Self-Report Questionnaire, MMQ Memory Questionnaire Ability Scale, PANAS Positive and Negative Affect Schedule, PAOFI Patient’s Complaints of Own Functioning Inventory, SMQ Squire Memory Questionnaire, TEA Test of Everyday Attention; neuropsychological tests: COWAT Controlled Oral Word Association Test, HVLT-R Hopkins Verbal Learning Test Revised, RCFT Rey Complex Figure Test, WAIS-IV Wechsler Adult Intelligence Scale 4th edition, WCST Wisconsin Card Sorting Test, WMS III Wechsler Memory Scale III

To examine the need for interventions related to perceived cognitive problems from the perspectives of cancer patients and healthcare staff

chemo associated cognitive changes

Objective

Munir, 2011 [63]

First author, year

Table 1 (continued)

490 Support Care Cancer (2016) 24:481–497

491

Treatments not specified

Clear description of treatment modalities Scales described

0

Does not fit

Clear description of treatment modalities (dose, intensity, density) Scales described, reliability of instruments stated and in acceptable range (>0.70), direction of scales stated

1

Fits the purpose of study

Treatment description

Reliability and validity of the review

Scales not described

To strengthen the reliability and validity of the review, the author did the following at two separate times: conducted the key word and ancestry searches, extracted the data, and appraised the risk for bias (to evaluate the intra-rater reliability).

Results Study characteristics Keyword search yielded a total of 27 studies from January 2005 to June 2015 that met the inclusion criteria. Ancestry searching yielded no additional citations. Of the total sample, 22 (81.5 %) were quantitative and 5 (18.5 %) were qualitative. Overall, 2599 breast cancer participants were represented in these articles (quantitative, n=2424; qualitative, n=175).

Sampling justification is appropriate

A process for checking validity/ trustworthiness is discussed

Sample

Trustworthiness

Criteria adapted from Pluye et al. [37]

Not discussed

Not discussed

Not appropriate

Discussed if applicable

Design

Framework

Criteria

Quantitative studies

Qualitative studies

Instrument

Criteria

Quantitative studies

Table 2

Risk for bias criteria

3

0

Sampling not discussed

1

Not random sample

2

Random sample (includes age, gender, socioeconomic status) Clear description of treatment modalities (type of chemo) Scales are clearly described, direction of scale is stated, previous validity and/or reliability discussed Random sample from 2+ settings Sample selection

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The average sample size for breast cancer participants in the quantitative studies was 111.09 (SD 91.05, range 19–317). From 51.2 to 100 % of the samples had a history of chemotherapy (mean 87.81 %), and 7 of 22 specified the type of chemotherapy that participants had received [5, 41–44, 54, 55]. In one study, participants’ breast cancer was stage I–II (4.5 %) [5], in 11, stage 0–III (50 %) [8, 41–50], in three, stage I–IV (13.6 %) [51–53], and in seven, the stage was not specified (31.8 %) [26, 54–59]. Twelve of the 22 studies (54.5 %) were conducted in the USA [5, 8, 26, 42–44, 47–49, 52, 54, 56]; nine (40.9 %) were conducted in other countries (the Netherlands, Denmark, Australia/Europe, Germany, Singapore, China, and Taiwan) [41, 45, 50, 51, 53, 55, 57–59]; and one (4.5 %) did not report the location of the data collection [46]. For those studies conducted in the USA, the settings were mainly within the community or in cancer clinics. Only one U.S. study was at a medical center [43]. For those conducted outside of the USA, all study settings were cancer centers, hospitals, or cancer institutes. Sixteen of the 22 studies (72 %) evaluated cognitive function using self-report measures [5, 8, 41, 42, 44–49, 51–54, 57, 59], and eight of the 22 (36 %) used neuropsychological performance to measure cognitive function [26, 41, 43, 47, 48, 50, 55, 58]. Qualitative studies The sample sizes for the qualitative studies ranged from 9 to 74; 77.6 to 100 % of the samples had received chemotherapy, and two studies specified the type of chemotherapy that participants received [60, 61]. In two studies, participants had a

492

history of stage I–III breast cancer [62, 63]; in two, stage I–IV [60, 61]; and in one, the stages were not specified [4]. Two of the studies were conducted in the USA [4, 60], and three were conducted in the UK [63], Australia [62], and Singapore [61]. Two of the five studies were conducted within the community [4, 62], and the other three were conducted in cancer centers [60, 61, 63]. Findings related to modifiable factors Quantitative and qualitative studies were found that provided data on associations between modifiable biological, behavioral, and psychosocial factors and cognitive function in breast cancer survivors. No studies were found in the literature that provided data on associations between modifiable environmental factors and cognitive function in breast cancer survivors. The findings from the quantitative and qualitative studies are synthesized and organized by factor groups (biological, behavioral, psychosocial) below. Biological factors Nine of the 22 (40.9.3 %) quantitative studies [5, 26, 41, 42, 44, 47, 48, 50, 54] presented data on relationships between biological factors and cognitive function. Two of these were conducted using the same longitudinal sample [5, 54]. The biological factors identified include stressrelated markers (both inflammatory cytokines [5, 41, 44, 47, 54] and cortisol [26]), hemoglobin [50], oxidative damage [42], and neural metabolites [48]. Most of the studies evaluated inflammatory markers in relation to self-reported cognitive function—all evaluated at least one biological marker in relation to memory, finding that higher levels of inflammatory markers were associated with lower perceived memory or memory performance (absolute values of these Pearson’s correlations ranged from 0.20 to 0.62 (p<0.05)). One study evaluated inflammatory markers in relation to neuropsychological memory performance, reporting significant relationships (p=0.006) [47]. Inflammatory markers were also significantly correlated with self-reported concentration problems [54] and global cognitive function [41, 44]. Another study reported that inflammatory markers were significantly associated with response performance. Only one study evaluated cortisol, finding that breast cancer survivors had a blunted cortisol response to stress and indicating that their stress response was overused and did not function optimally [26]. One study reported no significant relationships between oxidative damage, measured by oxidative DNA damage, and perceived cognitive impairments [42], and another reported that perceived memory was significantly related to two neural metabolites mI and Cho (r=−0.55 and r=−0.62, p<0.02) [48]. Inflammatory markers were the most researched biological factors studied in relation to CRCI. None of the qualitative studies mentioned biological factors as potential contributors to CRCI.

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Behavioral factors Six of the 22 (27.3 %) quantitative studies and two of five of the qualitative studies presented data on relationships between behavioral factors, mainly sleep [45, 49, 52, 55, 56] and exercise [43, 52, 60, 61], and cognitive function. Generally, in terms of sleep, as sleep quality decreased, cognitive function decreased; however, in one study, it was reported that sleep quality was not a significant predictor of objective cognitive decline [55]. In the quantitative studies, the absolute value of these correlations ranged from 0.33 to 0.75, all statistically significant at p<0.07. These studies mainly evaluated sleep quality in relation to self-reported cognitive function, including global cognition [49, 52, 56] and attention [45]. Participants in Myers’ study discussed the relationship between sleep and cognitive function, explaining that taking naps or increasing the amount of sleep, led to better focus [60]. In terms of the exercise, Crowgey et al. reported a significant positive relationship between exercise and visual memory (r=0.47, p=0.004), indicating that as self-reported exercise increased, cognitive function increased [43]. Similarly, Myers reported that exercise moderated the negative effects of higher body mass index on perceived cognitive impairments breast cancer survivors treated with chemotherapy [52]. Qualitative data also supports these findings—11/18 participants in Myers’ study perceived that exercise was beneficial to their cognitive function [60], and 56 % of 42 the participants in Cheung’ study attributed their cognitive changes to lack of physical activity [61].

Psychosocial factors Nine of the 22 (40.9 %) quantitative studies presented data on relationships between psychosocial factors and cognitive function, and four of the five qualitative articles discussed relationships between psychosocial factors and cognitive function. Most of these studies discussed relationships between poor emotional functioning and cognitive dysfunction. Significant relationships between distress [52], negative affect [57, 59], emotional wellbeing [51], stress [8], avoidance behavior and hyper-arousal [53], loneliness [46], and self-reported cognitive function were found, indicating that more emotional and social stress is associated with more cognitive dysfunction in breast cancer survivors. Two studies utilized a neuropsychological measure of cognitive function, one reporting a nonsignificant relationship between emotional distress and cognitive performance [58] and the other reporting that baseline stress was a significant predictor of cognitive decline but that social support was not [55]. The absolute value of these correlations ranged from 0.22 to 0.57 (p<0.01). In addition, emotional functioning [51] and negative affect [57] were both significant predictors of cognitive dysfunction. Similarly, participants in the qualitative studies most often associated emotional and situational stress with cognitive dysfunction [4, 62], attributed cognitive changes to lack of social support [61], and favored an

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intervention targeted at stress management to alleviate some of their cognitive problems [63]. Risk for bias appraisal The risk for bias appraisal identified a number of strengths as well as limitations in the studies reviewed here. Possible risk for bias scores could range from 0 to 9 for quantitative studies and 0 to 4 for qualitative studies—lower scores indicate major risk for bias and higher scores indicate minimal risk of bias. For quantitative articles, scores ranged from 3.5 to 8; the mean was 6.0 (SD 1.2), and the median was 6 (For the distribution of quality scores, see Fig. 3). Almost all of the quantitative studies were conducted with random samples, and 13 used samples from two or more settings. Only three studies described the type and dose of chemotherapy that participants had received, but all authors either specified that participants had a history of chemotherapy or stated the type of chemotherapy (e.g., anthracycline). Very few of the studies discussed the reliability of instruments used in their studies; therefore, scores on this criterion were generally lower. Most adequately described the instruments that were used, including the direction of the measurement and previously reported reliability or validity. Less variability in risk for bias was found in the qualitative studies. All five qualitative studies scored 3, because authors either did not discuss frameworks that guided the studies, did not describe sampling, or did not discuss the trustworthiness of their methods (For the distribution of quality score, see Fig. 3).

Discussion Summary of findings Specific discussion of biological, behavioral, environmental, and psychosocial modifiable factors, for CRCI other than in

Number of Studies

Risk for Bias Appraisal Scores 10 9 8 7 6 5 4 3 2 1 0

Quantitative Qualitative

0 1 2 3 3.5 4 4..5 5 5.5 6 6..5 7 7.5 8 8.5 9 Score

Fig. 3 Distribution of risk for bias scores. Note: The possible score range for qualitative articles was 0 to 4; for quantitative articles, it could range from 0 to 9. Different criteria were used to evaluate quantitative and qualitative articles, adapted from Pluye et al. [37]

literature on anxiety, depression, and fatigue is sparse. In order to understand the relationships between these factors and CRCI among breast cancer survivors who received chemotherapy, a mixed-method systematic review was conducted including both quantitative and qualitative studies. A biobehavioral model guided this review [36]. The review found that the data on associations between modifiable factors and CRCI in breast cancer were rarely the foci of the studies; rather, researchers provide only descriptive or ancillary data on these factors. In addition, none of the studies evaluated factors related to CRCI from a biobehavioral perspective, linking behavioral, environmental, and psychosocial factors to biological factors and subsequently to cognitive function. This review shows emerging evidence for significant relationships among modifiable biological (inflammatory cytokines), behavioral (sleep quality, physical activity), psychosocial (stress, distress, affect, and social support) factors, and CRCI (both self-report and neuropsychological performance). There was some evidence to support relationships among cortisol, neural metabolites, hemoglobin, loneliness, avoidance/ hyper-arousal, and CRCI (both self-report and neuropsychological performance). Risk for bias among these articles was low to moderate. The biological factors identified in this review are congruent with other findings in the literature linking overexpression of cytokines to CRCI [35, 64, 65]. More specifically, higher levels of peripheral cytokines are associated with worse cognitive dysfunction. A growing body of animal and human research indicates that high levels of circulating proinflammatory markers can access the brain and cause neurotoxic damage, resulting in a sequelae consisting of behavioral symptoms such as depression, sleep disturbance, fatigue, and cognitive dysfunction [17, 44, 64–67]. The behavioral factors in this review were also consistent with previous findings linking more exercise to improved cognitive function in older adults. There is evidence that physical activity is a significant mediator of cognitive decline in healthy older adults and is also associated with efficient cognitive functioning in the domains of executive functioning and attention control [68]. Similarly, the psychosocial factors identified in this review (stress and social isolation) support research findings that more chronic stress is associated with poorer cognitive function in other populations. A population-based study of adults 65 years or older (n=6207) reported significant independent relationships between perceived stress and cognitive scores and cognitive decline (p<0.001) [69]. In a study of breast cancer patients prior to start of adjuvant treatment, ReidArndt and Cox [70] reported significant relationships between perceived stress and immediate memory (r=0.43, p<0.01), delayed memory (r=0.43, p<0.01), verbal fluency (r=0.37 p<0.05), and attention (r=0.42, p<0.01). Quality and frequency of social interactions are also associated with

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cognitive functioning in other populations [71]—perceived social isolation is an established predictor of cognitive decline in older adults and is known to impair executive functioning in healthy adults [72]. The modifiable factors discussed in this review were mostly associated with self-report measures. In many of the studies, measures were either self-report or objective, not both. This is most likely because self-report cognitive impairment is rarely correlated with neuropsychological performance in cancer survivors [73]. Lack of association between self-report and neuropsychological evaluation among cancer survivors suggests that those who report CRCI may not be the same as those who perform worse on neuropsychological tests [57]. If this is true, factors contributing to subjective cognitive dysfunction may be different from factors contributing to neuropsychological dysfunction. It is known that the reporting of symptoms such as cognitive difficulties is strongly influenced by socio-demographic and psychological factors [57]. Historically, these factors (and those reported in this review) have been treated as confounders or covariates in CRCI-related research; however, since these factors are often significantly related to cognition, they could be contributing factors to CRCI and subsequently be appropriate targets for interventions for breast cancer survivors who have self-reported CRCI. It is also possible that these factors could contribute to neuropsychological deficits, but the findings of this review do not support it. The modifiable factors identified through this novel mixedmethod systematic review are especially relevant to breast cancer survivors who have completed adjuvant treatment, because reducing stress, increasing physical activity, improving sleep quality, and fostering supportive social relationships are all health promoting behaviors that survivors are encouraged to participate in to improve health-related outcomes [74, 75]. In fact, various organizations such as the American Cancer Society, World Cancer Research Fund, and the American College of Sports Medicine have issued guidelines that target diet and physical activity for cancer survivors [76]. It is known that health behaviors such as these reduce the chances for cancer recurrence or secondary cancers; improve quality of life; and reduce cancer-related symptoms such as CRCI [74, 76]. Most breast cancer patients are encouraged to maintain healthy behaviors during active treatment and continue behaviors into the survivorship phase of the disease. Unfortunately, survey data suggests that despite the evidence on positive outcomes associated with healthy behaviors, cancer survivors still report high levels of stress [77], are not meeting national guidelines for physical activity [78], and have extremely high rates of sleep disturbances [79]. Although the broad implications of healthy behaviors (congruent with the modifiable factors identified in this article) are well documented [75], the specific effects of these behaviors on CRCI in breast cancer survivors exposed to chemotherapy are not well understood,

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and further prospective research is necessary before clinicians should counsel survivors or intervene to modify these factors in order to improve cognitive function. Limitations and future research The studies reviewed here were largely heterogeneous and not without limitations. In addition, this review has limitations. First, the review was conducted by one person and could therefore be biased; however, systematic and rigorous methods were used to reduce such bias (as highlighted in the BMethods^ section). The author conducted the risk for bias appraisal on 100 % of the reviewed articles two separate times and found a strong intra-rater reliability (Kappa 0.84, p<0.001). The specificity of the research questions and purpose of this review limit the generalizability of the findings beyond breast cancer survivors treated with chemotherapy. The correlations and associations reported in this review were mainly from one point in time; therefore, causality cannot be inferred. Research is needed to identify modifiable factors that contribute to the vulnerability of some breast cancer survivors to CRCI. The correlations between inflammatory markers, sleep quality, physical activity, chronic stress, and social support need to be evaluated further to draw conclusions.

Conclusion More women are living beyond breast cancer treatment each year. Unfortunately, many of these women face unwanted late effects of cancer treatment for years after treatment ends, including CRCI. There is some evidence to suggest distinct unmodifiable risk factors for CRCI such as age and cognitive reserve; however, the underlying process for CRCI is not completely understood. It is possible that modifiable factors may too impact the underlying mechanisms of CRCI, and research on this topic is limited. Therefore, a mixed-method systematic review of the literature was conducted to identify and synthesize the evidence for associations between modifiable factors and CRCI. The findings indicate that relationships exist between inflammatory markers, sleep quality, physical activity, stress, social support, and cognitive function in breast cancer survivors who have undergone chemotherapy. Importantly, the majority of these factors can be influenced by healthy lifestyle behaviors that cancer survivors are encouraged to engage in. This review is the first step in building evidence to support the associations between such modifiable factors and CRCI; however, further research is needed before clinical recommendations can be made. The next logical step is to examine these relationships through a theoretical lens to provide foundational evidence for future prospective research studies to evaluate if these are indeed risk factors for CRCI.

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Support Care Cancer (2016) 24:481–497 Acknowledgments I would like to take this opportunity to express my gratitude and deep regard to Sharon A. Brown, PhD, RN, FAAN for sharing her expertise in critical literature reviews and guiding me during the course of this research.

14.

Disclosures Ashley M. Henneghan, MSN was supported by a Doctoral Degree Scholarship in Cancer Nursing, DSCN-15-072-01 from the American Cancer Society. The author of this manuscript has educational support from the Jonas Nurse Leaders Scholar Program and also serves on the Board of Directors of the Central Texas Oncology Nursing Society. The terms of these arrangements have been reviewed and approved by the University of Texas at Austin in accordance with its policy on objectivity in research.

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