Self-directed physical activity intervention in older adults undergoing adjuvant chemotherapy for colorectal cancer: Design of a randomized controlled trial

Contemporary Clinical Trials 42 (2015) 90–97

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Self-directed physical activity intervention in older adults undergoing adjuvant chemotherapy for colorectal cancer: Design of a randomized controlled trial Grant R. Williams a,b,⁎, Kirsten A. Nyrop a,b, Allison M. Deal a, Hyman B. Muss a,b, Hanna K. Sanoff a,b a b

UNC Lineberger Comprehensive Cancer Center 450 West Drive, Chapel Hill, NC 27514, United States Department of Medicine, Division of Hematology-Oncology, University of North Carolina at Chapel Hill, NC 27599, United States

a r t i c l e

i n f o

Article history: Received 3 February 2015 Received in revised form 19 March 2015 Accepted 21 March 2015 Available online 28 March 2015 Keywords: Physical activity Fatigue Health related quality of life Colorectal cancer Geriatric oncology

a b s t r a c t Background: Colorectal cancer (CRC) diagnosis and treatment can have substantial detrimental impacts on health related quality of life (HRQOL) and physical function. This is especially true for older CRC patients and is of paramount concern in chemotherapy treatment decision making; yet, few studies to date have focused on understanding and managing fatigue in older CRC patients. We present the design of a study to evaluate the feasibility and impact of a home-based, selfdirected physical activity intervention on fatigue in older CRC patients receiving adjuvant chemotherapy treatment. Secondary aims pertain to intervention impact on HRQOL, physical function, and self-efficacy for managing fatigue. Methods/design: Multi-site, randomized controlled trial of physical activity intervention compared to usual care in a sample of older adults undergoing adjuvant chemotherapy for CRC. Forty CRC patients will be recruited and study questionnaires/assessments will be performed at baseline, 3 months, and after completion of adjuvant chemotherapy. The primary outcome is a comparison of the change in fatigue from baseline to 3 months between Intervention and Control arms. We will also compare changes in engagement in physical activity, HRQOL, physical function, and selfefficacy. Exploratory analyses will compare Intervention and Control arms with regard to changes in muscle mass and a biomarker aging that is known to increase during chemotherapy (p16INK4a). Discussion: If positive, findings from this pilot study would suggest the potential for improving the care of older persons with CRC undergoing adjuvant chemotherapy through a home-based physical activity intervention to manage fatigue, HRQOL, and physical function. Trial Registration: NCT02191969 © 2015 Elsevier Inc. All rights reserved.

1. Introduction Fatigue is a common and distressing symptom among adults with a cancer diagnosis [1–4]. Cancer-related fatigue is multifaceted and attributed to the disease itself, other systemic

⁎ Corresponding author at: University of North Carolina at Chapel Hill, Physician's Office Building, 170 Manning Drive, 3rd Floor, Campus Box 7305, Chapel Hill, NC 27599-7305, USA. Tel.: +1 1 919 627 3221; fax: +1 1 919 966 6735. E-mail address: [email protected] (G.R. Williams).

http://dx.doi.org/10.1016/j.cct.2015.03.008 1551-7144/© 2015 Elsevier Inc. All rights reserved.

disorders (e.g., anemia, infection), chronic pain, inactivity, and psychosocial disorders (anxiety, depression). It may also be attributed to specific cancer treatments, such as chemotherapy, during which an estimated 82 to 96% of patients report fatigue [5–10]. Fatigue in cancer patients is of clinical concern because it is associated with decreased physical activity, lower functional status, and impaired quality of life [11]. In older cancer patients, specifically, additional concerns are that long-lasting fatigue undermines function (physical performance, activities of daily living) which, in turn, can disrupt treatment regimens and increase the risk for institutional care [10,12–15]. Among older

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adults in general, fatigue is a self-reported indicator of aging and frailty, signaling decreased physiologic reserves for coping with stressors and increased risk for mortality [14,15]. Although 60% of all cancers are diagnosed in adults age 65 or older, few studies to date have focused on understanding and managing fatigue in older cancer patients [10,12]. The study reported here pertains specifically to fatigue among older (age ≥60) persons with a colorectal cancer (CRC) diagnosis. CRC is fourth among commonly diagnosed cancers in the U.S. and accounts for 8.2% of all new cancer cases [16]. As in most cancers, CRC is a disease of aging, with median age at diagnosis of 68 [16]. The 5-year survival rate is 64.7%, and there were an estimated 1.2 million colorectal cancer survivors in the U.S. in 2012 [16,17]. During chemotherapy for CRC, grade 3–4 fatigue ranges from 16% to 41% [8,18,19]. Both near- and longterm CRC survivors report fatigue levels that are higher than the general population [20,21]. For older CRC patients, the potential loss of physical function and independence is paramount in treatment decision-making [22], and patient and physician concerns about treatment related toxicity are often a reason for under treatment. Within the general population of adults with a cancer diagnosis, engagement in physical activity has the highest level of evidence for the management of fatigue [23]. Systematic reviews and meta-analyses of exercise interventions have documented both clinically and statistically significant benefits [24–26], and American Cancer Society guidelines specifically recommend physical activity both during and after cancer treatment [27]. However, in reviewing the literature we found most physical activity studies were conducted in breast cancer patients, post-treatment, and with little focus on older patients. The potential benefits of physical activity interventions in older CRC patients require further analysis. We have designed a pilot study to evaluate the feasibility and the impact of a home-based, self-directed physical activity intervention on fatigue in older patients (age ≥60 years) undergoing adjuvant chemotherapy for early stage colorectal cancer. Our overarching hypotheses are that people who undergo the physical activity intervention compared to those who do not will: (1) report less fatigue, (2) report higher health related quality of life (HRQOL), and (3) have less decline in physical function. 2. Methods 2.1. Design This study is a multi-site, randomized controlled trial of a moderate-intensity, self-directed physical activity intervention in older (≥ 60 years of age) CRC patients undergoing adjuvant chemotherapy (see Fig. 1). The study was prospectively registered with Clinicaltrials.gov, registration number NCT02191969, and approved by the protocol review committee of the UNC Lineberger Comprehensive Cancer Center and the institutional review board of the University of North Carolina (UNC) in 2014. 2.2. Study sample Forty CRC patients will be recruited through the North Carolina Cancer Hospital (NCCH) and community sites affiliated

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with the University of North Carolina Cancer Network (UNCCN). To be eligible for the study, patients must be age 60 or older with a diagnosis of stage II–III colon or rectal cancer and planned for treatment with adjuvant chemotherapy (see Table 1 for inclusion and exclusion criteria). Patients must be approved by their treating physician to engage in moderate-intensity physical activity. Patients who are unable to read English are excluded from the study, because various measures used in the study have not been tested or validated in non-English speaking populations.

2.3. Intervention The intervention is a physical activity program developed by the Arthritis Foundation (Walk With Ease/WWE) [28] that is evidence-based in both group and self-directed formats to reduce joint pain, stiffness and fatigue among adults with arthritis [29]. We use the self-directed format in our study because it is potentially highly scalable — no requirements for special facilities or equipment or trained personnel. The WWE goal is 150 min of walking per week, at a pace that is safe, comfortable, and sustainable. We have tested this format in previous studies of older cancer patients and have found the format safe and feasible [30]. Study participants in the Intervention group will receive a copy of the WWE workbook [28] and a 1-page flyer developed by the research team (Walk with Ease during chemotherapy treatment for colorectal cancer). They will be asked to walk at a safe and comfortable pace at least 30 min a day, five days a week (total of 150 min a week), throughout their chemotherapy treatment. The WWE program allows individuals to customize their goals, thereby creating a flexible “gateway” to increasing levels of physical activity over time. They are also asked to maintain a printed daily walking log (provided to them). Participants in the Control arm do not receive any literature or other guidance to engage in physical activity.

2.4. Recruitment and randomization Eligible patients who are planned for adjuvant chemotherapy and have an appointment scheduled for medical oncology will be identified through daily review of electronic medical records. On the day of their visit, written informed consent for participation in this study will be secured by study recruiters with the approval of the treating physician. Health Insurance Portability and Accountability Act (HIPAA) consent, a federal law enacted in 1996 to protect medical record privacy, will be requested to allow research personnel access to the patient's internal and external medical records in relation to their cancer diagnosis, treatments, and laboratory results. A randomization schedule developed by the study's biostatistician will be used to assign patients to Intervention or Control group. Stratified Block Randomization will be used with separate strata for each planned chemotherapy regimen (5FU/Capecitabine or FOLFOX) to ensure the different regimens are evenly distributed among both arms. Study recruiters and treating clinicians will be blinded to the randomization schedule, and the allocation is concealed until after baseline assessment completed and intervention assigned.

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Baseline assessment*

3 Month Assessment

Post Treatment Assessment*

Physical Activity Intervention (n=20) Age ≥60 Colorectal cancer with adjuvant chemotherapy planned (N=40)

Standard of care (n=20)

Initial muscle mass measure

Adjuvant Chemotherapy

Repeat muscle mass measure

*Includes all study assessments with exception of muscle mass measurements which are performed as part of routine care †Includes only patient reported outcome (PRO) measures (with exception of MOS physical health and

IADL measures) and Short Physical Performance Battery (SPPB) Fig. 1. Study design. *Includes all study assessments with exception of muscle mass measurements which are performed as part of routine care. †Includes only patient reported outcome (PRO) measures (with exception of MOS physical health and IADL measures) and Short Physical Performance Battery (SPPB).

3. Study outcomes All study outcomes – with the exception of instrumental activities of daily living (IADL), Timed Up and Go (TUG), Medical Outcomes Study (MOS) physical health, p16INK4a, and skeletal muscle mass measurements – are assessed prior to randomization (baseline), at midpoint during chemotherapy

Table 1 Exclusion and inclusion criteria. Inclusion criteria

Exclusion criteria

≥ Age ≥60 years (no upper age limit)

Other active, invasive malignancy requiring ongoing therapy or expected to require systemic therapy Already walking or engaging in other physical activity N120 min per week as documented via subject self-report

Diagnosis of stage II–III colon or rectal cancer planned for treatment with adjuvant chemotherapy scheduled as part of standard treatment A Able to read English

Approval from their treating physician to engage in moderate-intensity physical activity Patient-assessed ability to walk and engage in moderate physical activity

Unable to walk or engage in moderate-intensity physical activity One or more significant medical conditions that in the physician's judgment preclude participation in the walking intervention

(3 months), and at the end of chemotherapy (post treatment) (see Fig. 1). IADL, TUG, MOS physical health, p16INK4a, and skeletal muscle measurements will be assessed only at baseline and post treatment. An overview of assessments and measures are presented in Table 2. 3.1. Primary outcome measures 3.1.1. Fatigue Fatigue symptoms are assessed with the PROMIS (Patient Reported Outcomes Management Information System) Fatigue 7 Short Form measure [31]. This measure uses a 5-point Likerttype scale (1 = never, 2 = rarely, 3 = sometimes, 4 = often, 5 = always), with higher scores indicating higher levels of fatigue. The recall period for each question is “during the past 7 days”, which is a time frame well comprehended by patients. The seven items inquire about how often they feel tired, experience extreme exhaustion, run out of energy, fatigue limits work, too tired to think, too tired to take a bath/shower, and have enough energy to exercise strenuously. The global score for this measure will be the primary outcome for comparing changes in fatigue levels from baseline to 3 months between Intervention and Control arms. This measure will also be compared upon completion of chemotherapy. 3.1.2. Feasibility Feasibility will be measured by the proportion of Intervention participants who engage in at least 150 min per week of walking throughout adjuvant chemotherapy. Our program

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Table 2 Measures/assessments.

Primary outcome Physical activity Physical function

Quality of Life Potential mediators Biomarkers Adverse events

Investigations

Baseline

Midpoint

Post Chemo

PROMIS Fatigue short form 7a Self-Reported Walking questionnaire items Daily Walking Log⁎ Timed Up and Go (TUG) Instrumental Activities of Daily Living (IADL) MOS Physical Function Short Physical Performance Battery PROMIS Physical Function 10 Functional Assessment of Cancer Therapy — Colorectal (FACT-FCSI) PROMIS Pain Interference Short Form Outcomes Expectations for Exercise (OEE) scale Perceived Self-Efficacy for Fatigue Self-Management (PSEFSM) Expression of p16INK4a (biomarker of aging) Sarcopenia evaluation (CT scan) Recorded and graded using National Cancer Institute Common Terminology for Adverse Events Version (NCI CTCAE v4)

X X X X X X X X X X X X X X X

X X X

X X X X X X X X X X X X X X X

X X X X X X

X

⁎ Daily walking log is only collected in participants in the intervention group.

will be considered feasible if at least 40% of the Intervention participants achieve the 150 min target. Engagement in walking will be assessed through two measures. Participants in the intervention group will be asked to maintain a daily record of total minutes they walk for exercise or pleasure throughout their chemotherapy. These entries will be used to calculate weekly averages of total walking minutes. All participants will also be asked by questionnaire at baseline, 3 months, and end of chemotherapy (1) how many days a week they walked for exercise or pleasure and (2) how many minutes a day they walked for exercise or pleasure, and the two measures will be multiplied for total minutes of walking per week. 3.2. Secondary outcome measures Secondary outcomes will be assessed through various measures of physical function and HRQOL. We will also gather data on adverse events, chemotherapy completion rates, and variables that may mediate the association between physical activity and self-reported fatigue, physical function, and quality of life. Adverse events will be recorded according to the National Cancer Institute Common Terminology for Adverse Events Version (NCI CTCAE v4), and the study's principal investigator will provide ongoing monitoring of patient safety with periodic reporting to the Data and Safety Monitoring Committee (DSMC). 3.2.1. Physical function Physical function will be measured objectively by the TUG test [32] and Short Physical Performance Battery (SPPB) [33]. The TUG is a performance test of physical mobility and measures how long it takes the patient, in seconds, to stand up from a standard arm chair, walk a distance of approximately 10 ft, turn, walk back to the chair, and sit down again. The SPPB is a measure of lower extremity function and includes walking speed over 4 m, time to complete five chair-stands, and a balance test. The balance testing includes timed measures of semi-tandem, side by side, and tandem stances. Each SPPB measure is scored from 0 to 4 (0 = unable to perform and 4 = highest ability to perform) and then summed for a total score ranging from 0 to 12, with higher scores indicating better lower body function.

We will use three patient-reported measures of physical function. The PROMIS-Physical Function 10 [34] measure consists of 10 items that use a 5-point Likert-type scale ranging from “not at all” to “cannot do” for 5 questions and “without any difficulty” to “unable to do”. Items pertain to activities such as walking more than a mile, climbing stairs, bending/kneeling/ stooping, toileting, and personal hygiene. Instrumental activities of daily living (IADL) will be measured using the OARS (Older Americans' Resources and Services) Multidimensional Functional Assessment Questionnaire [35]. This is a 7-item measure that inquires about the ability to use a telephone, get to places out of walking distance, shopping for necessities, preparing meals, doing housework, taking medications, and handling money, with higher scores reflecting higher disability. The 10item physical function measure of the Medical Outcomes Survey (MOS) [36] is the third self-reported measure, with lower scores reflecting higher disability.

3.2.2. Quality of life Quality of life will be assessed through the Functional Assessment of Cancer Therapy — Colorectal (FACT-FCSI) and the PROMIS—Pain Interference Short Form 6b (PROMIS-PI SF6b). The FACT-FCSI is a 19-item form specifically designed for use in colorectal cancer that includes 16 toxicity-specific symptom scales (energy, pain, weight loss, stomach cramps, fatigue, meeting family needs, appetite, sleep quality, nausea, hair loss, bowel control, diarrhea, constipation, numbness/ tingling, temperature sensitivity, bothersome side effects) and 3 scales of QOL (worries about getting worse, ability to enjoy life, content with quality of life). Response options are on a 5-point Likert-type scale (0 = not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, 4 = very much). The scale includes questions that are particularly relevant for the treatment colorectal cancer, including measures of neuropathy related to oxaliplatin administration. The PROMIS-PI SF-6b uses a 5-point Likert-type scale ranging from “not at all” to “very much” and a 7 day recall period. Six items inquire how much pain interfered with respondent's enjoyment of life, ability to concentrate, daily activities, recreational activities, tasks away from home, and socializing with others.

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3.2.3. Potential mediator variables Two scales are used to assess potential mediating variables that may be associated with compliance with the physical activity intervention and ability to self-manage fatigue — Outcome Expectations for Exercise (OEE) [37] and Perceived Self-Efficacy for Fatigue Self-Management (PSEFSM) [38,39]. The OEE consists of 9 statements about the benefits of exercising, with response options from 1 (strongly disagree) to 5 (strongly agree). Suggested benefits of exercise include feeling better physically, feeling less tired, strengthening bones, and improving endurance in performing daily activities. The PSEFSM is a 6item scale that uses a 10-point Likert-type scale ranging from “not at all confident” to “totally confident.” Items inquire “how confident you” are in doing a variety of activities — controlling fatigue, regulating activity so as not to aggravate fatigue, doing something to help yourself feel better if feeling fatigued, managing fatigue during daily activities, managing fatigue so that you can do things you enjoy, and dealing with the frustration of fatigue.

each patient and normalized using each patient's height (in meters) to produce a Skeletal Muscle Index (SMI) (cm2/m2). 4. Statistical analysis 4.1. Sample size We will enroll a total of 40 patients and assume an attrition rate of 15%. A final sample size of 17 participants in each study arm will have 80% power to detect a difference in mean changes of 6 in PROMIS-Fatigue between baseline and 3 months (for example, the difference between a Control group mean change of 10 and an Intervention group mean change of 4), assuming the common standard deviation is 6 using a two group t-test with a two-sided 0.05 significance level. A clinically meaningful difference on the PROMIS-F scale has been shown to be about 3 points [45]. We anticipate a large increase in fatigue scores for the Control arm (~10) and a smaller yet meaningful increase (~4) in the Intervention group.

3.3. Exploratory measures

4.2. Statistical analyses

Two biomarkers will be measured for exploratory outcomes at baseline and after completion of chemotherapy. The first is a novel biomarker of aging — the senescence tumor suppressor p16INK4a located on human chromosome 9p21.3. Our research team has found that the expression of p16INK4a RNA increases exponentially with chronological aging and is accelerated by smoking and physical inactivity [40]. Recent results have shown a 75% absolute increase in expression of p16INK4a – equivalent to the increase observed over 14.7 years of chronological aging – in a cohort of patients with breast cancer treated with adjuvant chemotherapy, raising concern about the gerontogenic effects of chemotherapy [41]. For our study of CRC patients, expression of p16INK4a will be measured in CD3+ lymphocytes. Human peripheral blood will be labeled with anti-CD3 microbeads before being purified for T cell population using AutoMACS pro separator (Miltenyi Biotec, San Diego, CA). T cells with purity of more than 90% will be used for RNA extraction and subsequent Taqman quantitative reverse-transcription polymerase chain reaction to measure p16INK4a transcripts [40]. The second exploratory measure is an assessment of skeletal muscle mass. Sarcopenia, the age-related loss of skeletal muscle mass, is more prevalent in older as compared to all other adults and is a hallmark of frailty and subsequent disability [42]. Sarcopenia is associated with decreased life expectancy and increased chemotherapy toxicity in various cancer types [43]. Sarcopenia can be easily measured using cross-sectional imaging obtained as part of routine oncologic care [44]. For our study, muscle mass will be measured on standard of care CT scans for colorectal cancer staging and surveillance using the third lumbar vertebrae (L3) as the standard landmark and two consecutive CT images extending from L3 to the iliac crest will be used to measure muscle cross-sectional area. The baseline CT scan will be performed within 60 days of initiation of chemotherapy and the follow up imaging assessment will be performed per surveillance guidelines at one year after initial surgery. Skeletal muscle will be identified and quantified using Hounsfield unit thresholds (−29 to +150). Cross sectional area (cm2) of the total musculature will then be computed for

For the primary objective, the change in PROMIS-Fatigue from baseline to 3 months will be compared between Intervention and Control groups using a two group t-test. Fatigue levels at baseline, 3 months and end of chemotherapy will be reported using means, standard deviations, medians, and ranges. Adherence to the physical activity program in the Intervention arm will be reported using descriptive statistics based on data gathered from questionnaire responses and daily walking logs. We will report the percentage of patients able to meet the recommended level of 150 min of physical activity per week at three time points, and walking log data will be used to chart weekly averages throughout chemotherapy. For our objective of feasibility, we will calculate the proportion of participants in the Intervention group that are able to achieve at least 150 min per week of walking throughout adjuvant chemotherapy based on average minutes per week of walking obtained from the walking log. Intention-to-treat analysis will be conducted to measure the influence of physical activity on fatigue measures over time. Accordingly, we will investigate potential contamination between the two study arms — primarily, evidence of increased physical activity in the Control arm. In the event of substantial contamination, we will conduct an exploratory ancillary analysis of the entire sample, to compare fatigue levels among participants who report increased physical activity during chemotherapy at 3 months with participants who report no change or decreased physical activity. Secondary outcome measures of physical function, HRQOL, OEE, and PSEFSM will be described at all time points using means, standard deviations, medians, and ranges. Changes from baseline to follow up time points will be reported and comparisons between the groups will be made using two group t-tests for continuous measures and Fisher's Exact tests for categorical measures. Correlation coefficients and linear regression models will be used to assess the association between outcomes measures of fatigue, physical function, and QOL with the walking measures. We will investigate the potential

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mediators of OEE and PSEFM using the methods described by Baron and Kenny [46]. For the exploratory objectives, we will report p16INK4a expression and muscle mass measurements at all time-points and compare changes between groups using two group t-tests. The association of baseline p16INK4a with changes in fatigue, physical function, and quality of life measures will be made using correlation coefficients. Differences in these measures will be explored by sarcopenia status using two group t-tests. 5. Discussion This pilot study aims to assess the feasibility and estimate the effect of a home-based, self-directed physical activity intervention on cancer-related fatigue during adjuvant chemotherapy in older adults with early stage CRC. If positive, findings from this study would suggest this physical activity intervention may minimize the effect of chemotherapy on fatigue as well as HRQOL and physical function of older CRC patients, potentially enabling a larger proportion of patients to receive potentially curative chemotherapy. If the results are promising, our findings would also suggest that a very minimalist intervention – encouraging older CRC patients to walk during chemotherapy and providing low-cost supporting materials (WWE workbook, flyer and printed walking diary) – could be effective in this patient population. This important finding would be the basis for a larger more definitive trial to test the intervention in a larger population under real world conditions in busy oncology clinics. The WWE program is a physical activity intervention originally developed by the Arthritis Foundation that has been

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recently adapted for older adults with cancer. Our first study was a pilot test to see if the home-based walking program was feasible in postmenopausal breast cancer patients who were on an adjuvant aromatase inhibitor (AI) and were experiencing non-arthritis joint pain, stiffness, or achiness. In our sample of 20 patients with a mean age of 70 (range 65–87), the proportion walking 150 min/week increased from 21% to 50% between baseline and 6 weeks (end of intervention) (p b 0.001) and there were positive trends in the reduction of joint stiffness (p = 0.07) [30]. For a second study, we recently completed recruitment of breast cancer patients age 60 or older who were undergoing adjuvant chemotherapy treatment. In this sample of 22 patients, mean age 68 (range 60–79), the proportion walking 150 min/week was 41% Week 1, 54% Week 2, 32% Week 3, 45% Week 4, 50% Week 5, and 45% Week 6 (manuscript in progress). In both studies, patients received a one-time explanation of the walking goal of 150 min/week, a copy of the WWE workbook, and materials developed by the research team summarizing potential benefits from daily walking for symptom management. Study participants were also asked to maintain a daily walking diary, which had been described as motivational in post-walking interviews with AI study participants. These pilot studies in breast cancer patients provided preliminary evidence of safety, feasibility, and promise for this walking study in older adults undergoing adjuvant chemotherapy for CRC. The National Comprehensive Cancer Network's (NCCN) Practice Guidelines in Oncology: Cancer-Related Fatigue include physical activity among their recommendations for CRC management [9]. The evidence for this recommendation comes from RCTs – by our count approximately 70 RCTs – testing physical

Table 3 Randomized controlled trials of physical activity interventions among colorectal cancer patients that report fatigue outcomes. Author (year)

N, Mean age (SD or range)

Treatment stage

Fatigue measures, outcomes

Physical activity intervention

Bourke (2011) [47]

N = 18 Age 69 (52–80)

Post-surgery and post-chemotherapy, 33% had received chemotherapy; recruited 6–24 months post-operative

12 weeks — Supervised plus self-directed (home based) diet and exercise; control: standard care

Courneya (2003) [48]

N = 102 Age 60 (±10.7)

64–68% had received chemotherapy; recruited up to 3 months post-resection

FACT-Fatigue [57]; between group difference at endpoint — p = .005 (d = .56) Control baseline 42 (+/−9) end 43 (+/−6) Intervention baseline 43 (+/−7) end 48 (+/−4) FACT-Fatigue [57]; No significant intervention effects at 16 weeks

Hawkes (2013) [49]

N = 410 Age 65 (±10.8)

Lin (2013) [50]

N = 45 Age 56.5 (±10.3)

20.5%(I)–26.8%(C) were currently receiving chemotherapy; an additional 39.5 (I)–41.5 (C) had received chemotherapy; recruited within 12 months of diagnosis 100% during chemotherapy

Pinto (2013) [51]

N = 46 Age 57 (±9.7)

I = Intervention, C = Control.

Post-treatment; 83% had received chemotherapy

FACIT-Fatigue [57] No significant intervention effects at 24 weeks

Fatigue Symptom Inventory (FSI) [58] No significant intervention effects at 12 weeks FACIT—Fatigue [57] No significant intervention effects at 12 weeks

16 weeks — Home based; initial fitness consultation, personalized exercise prescription done at home, weekly telephone calls for adherence; wait list control 24 weeks — Home based telephone-delivered health coaching; handbook; motivational postcards; pedometer; newsletter; control: usual care, newsletter 12 weeks — Supervised group, aerobic and resistance training; control: usual care

12 weeks — Home based; initial in-person exercise instruction; physical activity log; pedometer; weekly telephone counseling; weekly survivorship tip sheets; control: weekly telephone administration of symptom questionnaire; weekly survivorship tip sheets

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activity interventions among adults with a cancer diagnosis that include fatigue as a primary or secondary outcome. However, of these numerous trials, only six were focused exclusively or primarily on colorectal cancer patients, as shown in Table 3 [47–51]. (Several other fatigue-focused trials include CRC patients but do not report separate results for each cancer type, thereby making it impossible to discern potentially important differences in fatigue outcomes among different cancer types.) Two trials listed in Table 3 had supervised physical activity interventions, requiring special facilities/equipment and trained personnel. The other three were home-based interventions; however, these interventions also include activities that pose scalability challenges in the U.S. health care system — initial fitness consultation, personalized exercise prescription, or initial in-person exercise instruction, weekly telephone calls, motivational postcards, and newsletter. Only one study showed statistically significant differences between Intervention and Control groups in fatigue scores at the end of the intervention period [47]; the other four reported non-significant findings. This brief overview of the CRC literature shows that the evidence for fatigue management through physical activity is mixed among adults with a CRC diagnosis. A further concern is that the average age of participants in three studies [48,50,51] is below our target population of 60 or older and the age range in the largest of the six studies [49] is only 65 to 68. A specific focus on older patients is a known gap in the physical activity-cancer related fatigue literature [12]. To address this gap, we have designed an RCT that evaluates the feasibility and estimates the impact of a pragmatic physical activity intervention in a sample of older adults undergoing adjuvant chemotherapy treatment for colorectal cancer. There is a well-established risk reduction in an initial diagnosis of CRC with increased physical activity — as much as 24% in both men and women [52]. Physical activity may also reduce the risk of CRC recurrence [53] and improve disease-specific and overall survival for men and women [54–56], which underscores the importance of an active lifestyle for adults with a CRC history. The outcomes emphasized in our study could further underscore the importance of physical activity during CRC treatment by lessening chemo-toxicities — negative impacts on fatigue, physical function, and HRQOL. Improving the tolerability of adjuvant chemotherapy may allow more patients to receive curative therapy and reduce the long-term negative sequelae of treatment in older CRC patients. Moreover, exploratory analysis of the effect of physical activity on p16INK4a expression and muscle mass measurements during adjuvant chemotherapy for CRC will make a significant contribution to the literature. Acknowledgements Funding provided by the University Cancer Research Fund of the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill and the John A. Hartford Foundation. Sponsors were not involved in any elements of the study design. References [1] Hofman M, Ryan JL, Figueroa-Moseley CD, Jean-Pierre P, Morrow GR. Cancer-related fatigue: the scale of the problem. Oncologist 2007; 12(Suppl. 1):4–10.

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