Randomized Controlled Trial of Exercise to Reduce Cancer Related Fatigue in Women Undergoing Radiation Treatment for Breast Cancer
Phase: NA
Conditions: Cancer Related Fatigue
Sponsor: Hackensack Meridian Health

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TITLE: 
A Randomized Controlled Trial of Exercise to Reduce Cancer Related 
Fatigue in Women Undergoing Radiation Treatment for Breast Cancer 
PROTOCOL #: 
 
Pro2016-XXXX 
STUDY DRUG: 
 
N/A 
IND #: 
 
 
N/A 
SPONSOR:  
 
Hackensack University Medical Center 
PRINCIPAL 
 
INVESTIGATOR:  
Lucile Adams-Campbell, Ph.D. 
 
 
 
 
 
Lombardi Comprehensive Cancer Center 
 
 
 
 
 
Brett Lewis, M.D., Ph.D. 
 
 
 
 
 
Hackensack University Medical Center 
 
ORIGINAL  
PROTOCOL VERSION: 
Version 1.0 – 15 Feb 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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A Randomized Controlled Trial of Exercise to Reduce Cancer Related Fatigue in Women Undergoing 
Radiation Treatment for Breast Cancer 
Brett Lewis, M.D., Ph.D. (HUMC)  
 
Lucile Adams-Campbell, Ph.D. (LCCC) 
Loren Godfrey, M.D. (HUMC) 
 
 
Claudine Isaacs, M.D. (LCCC) 
 
Deena Graham, M.D. (HUMC) 
 
 
Chiranjeev Dash, M.D., Ph.D. (LCCC) 
Donna McNamara, M.D. (HUMC) 
Stan Waintraub, M.D. (HUMC) 
 
 
b. ABSTRACT 
 
Cancer related fatigue (CRF) is a common and debilitating side effect of radiotherapy in breast cancer patients. 
Physical activity interventions can attenuate CRF.  The proposed study is a randomized, controlled trial (RCT) 
of  exercise of structured moderate-intensity exercise intervention, delivered concurrently with radiotherapy, to 
reduce CRF and improve health-related quality of life among breast cancer patients. Eighty women with breast 
cancer scheduled to receive radiation therapy at HUMC will be randomized to one of the two trial arms:  1) a 
facility-based aerobic exercise utilizing a portable stationary pedal exerciser; or 2) a control group. Intervention 
arm participants will exercise at the hospital either before or after their radiation treatment. Assessments will be 
conducted at baseline, 4 weeks into radiation course, and at 4-week follow-up visit. The outcome variables are 
CRF, biomarkers of inflammation, and health-related quality of life.  The study will provide preliminary 
evidence on whether a short-term moderate-intensity exercise intervention might be effective in reducing CRF 
in women undergoing radiotherapy for breast cancer, and whether this effect is mediated by inflammation. 
c. Specific Aims 
The specific aims of this study are: (1) to test the efficacy of a structured, moderate intensity exercise 
intervention delivered concurrently with radiation therapy (RT) in reducing CRF among breast cancer patients; 
(2) to provide pilot data on the acceptability and adherence of the exercise intervention on women receiving 
treatment; and (3) to determine the impact of exercise on serum inflammation markers among women 
undergoing RT.     
d. Background 
Radiation therapy (RT) is frequently used in the treatment of early stage breast cancer.1 Adjuvant RT combined 
with partial mastectomy or lumpectomy is associated with better outcomes in early stage breast cancer as 
compared to surgery alone.2,3 RT delivered through conventional external beam radiotherapy or more targeted 
alternatives like intensity modulated RT (IMRT), is a well-established treatment modality for clinically 
localized cancer.4,5 However, RT has side effects associated with decreases in physical functioning and quality 
of life. 
 
Cancer related fatigue (CRF), defined as “a distressing, persistent, subjective sense of physical, emotional, 
and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent 
activity and interferes with usual functioning”, is one of the most debilitating side effects of RT.6-9 Nearly all 
breast cancer patients report fatigue as a consequence of treatment,10,11 and RT-related fatigue is reported in up 
to 80% of patients.1,6-8,12,13 Fatigue can limit a patient’s ability to care for herself and can decrease her quality of 
life.10,14 The severity of its occurrence may also impact treatment continuity.10,11 
 
 

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The etiology of RT-CRF is poorly understood. 14-17 Radiation exposure initiates a programmed response of 
normal tissue towards tissue remodeling, of which inflammation is an important component.18-20 Inflammation 
has been hypothesized as a potential cause of treatment-related fatigue14 as inflammatory markers such as 
cytokines have been positively associated with increases in fatigue during radiation treatment. 15,21,22 Although 
biological correlates of fatigue such as cytokine expression have been identified,14 elevations in individual 
cytokines are not consistently associated with fatigue and do not fully explain the occurrence of fatigue in 
patients who are treated with RT. 23  
 
 
Several studies have found that physical activity may be an effective intervention to enhance QOL in cancer 
survivors. 24-26 Physical activity has been reported to decrease fatigue, anxiety, and depression27-31, and to 
improve sleep among healthy adults30,31. More than one third of the decline in functional capacity experienced 
by cancer patients can be attributed to prolonged physical inactivity32.  Prolonged physical inactivity and 
sedentary lifestyle can lead to rapid losses in fitness, energy, and physical functioning33. Decreased physical 
activity may also worsen complaints of cancer related fatigue25. Aerobic exercise training has been found to 
significantly lower levels of fatigue in patients undergoing RT; however, the mechanism underlying this 
positive effect is unclear7,11,34-36.  Despite the uncertainty about the precise contributions of diverse mechanistic 
pathways and the timing of introducing an exercise regimen, enough evidence exists of the potential utility of 
increased exercise to warrant further controlled intervention studies.  
 
e. Methods, including statistical analysis 
Study Design 
This RCT targets women with breast cancer stages 0-IIIA scheduled to receive RT (no T4, N3, or M1 disease). 
After obtaining written informed consent, participants are randomized either to a structured moderate-intensity 
aerobic training exercise regimen concurrent with radiotherapy or to a control group. Endpoints are assessed at 
baseline, 4 weeks into the radiation course, and at the 4-week follow-up visit. In order to minimize loss to 
follow up, visits coincide with radiation appointments. Participants in the structured exercise group are 
instructed to use portable stationary pedal exercisers to achieve an exercise goal of 75 minutes/week of 
moderate-intensity exercise. All exercise sessions are supervised and conducted in the RT facility while patients 
are waiting for their RT or after their RT. Radiation therapy is typically administered on a five-times-weekly 
schedule, amounting to 15 minutes of exercise per weekday. Control group participants are asked to maintain 
their normal physical activity levels.  
 
Eligibility Criteria  
Eligibility for the study includes the following parameters: (1) women between the ages of 18 and 75 years; (2) 
histologically confirmed non-metastatic carcinoma of the breast (in situ disease or invasive); (3) radiation 
therapy naïve; (4) sedentary activity level at baseline, as defined by less than 60 minutes per week of modest 
physical activity based on 7-day physical activity recall questionnaire (5) ambulatory; (6) negative serum 
pregnancy test and not planning to become pregnant in the next three months; and (7) able to provide 
meaningful consent. Patients must have been deemed by their medical oncologist or internist that they “may 
participate in [this] exercise trial.” The exclusion criteria include the following: (1) younger than 18 or older 
than 75 years; (2) no histological confirmation of breast cancer; (3) prior breast, chest, or pelvic radiotherapy; 
(4) concurrent chemotherapy; (5) distant metastases; (6) physical limitations that contraindicate participation in 
low to moderate intensity exercise; (7) positive pregnancy test; (8) currently engaged in moderate to vigorous 
physical activity; and (9) psychiatric disorder which would render the participant unable to provide informed 
consent. Prior to randomization, participants are required to complete a physical activity readiness questionnaire 
(PAR-Q) that includes questions regarding physical and medical conditions that would preclude safe 
participation in an exercise program.  
 
Recruitment 

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Women with breast cancer stages 0-IIIA, who are scheduled to receive radiation therapy, will be recruited from 
the Department of Radiation Oncology at Hackensack University Medical Center (HUMC) and screened for 
eligibility by a study coordinator. Study coordinators will complete, in-person, the eligibility checklist 
(Appendix A) to confirm eligibility. The study coordinators will obtain informed consent (Appendix B), 
complete baseline and follow-up assessments, including demographic and treatment history, and will make 
study assignment as below, under “Randomization”.   
 
Randomization 
Participants will be randomly assigned to structured moderate-intensity aerobic exercise program or to the 
control group using a block randomization scheme. The study biostatistician (Kepher Makambi, Ph.D.) will 
generate the computer-based randomization sequence. The intervention assignment is placed in opaque 
envelopes and delivered to the study coordinator. After completing baseline assessments, eligible participants 
will be assigned to study arm by a study coordinator who will open the next one of the sequentially-numbered, 
sealed envelopes.  
 
Intervention 
Arm 1: Exercise Intervention Arm 
Participants randomized to the exercise intervention will be required to exercise before or after each radiation 
treatment session, on a five-treatment per week schedule. No special accomodations will be made to open the 
clinic on weather days or on extra days in the event of machine failure or patient unavailability. The exercise 
intervention will be administered at the radiation treatment facility in a room allocated for the study.  The 
exercise prescription consists of aerobic training utilizing the portable stationary pedal exerciser (Pedlar) which 
contains two cycling pedals mounted to a stationary block that allows patients to exercise while sitting. Pedal 
tension is adjusted to provide desired resistance. Exercise intensity is self-rated by participants, instructed that 
moderate intensity goal will “make you breathe somewhat harder than normal”. Participants may move and 
position the device to permit comfortable use while sitting in a chair.  Participants are required to perform 15 
minutes/day of aerobic exercise using the Pedlar device on radiation treatment days; during a standard radiation 
course, this will typically yield 75 minutes/week of aerobic time. Ten Pedlar devices have been approved for 
purchase for HUMC Department of Radiation Oncology through the Development Grant. Participants will 
record their activity on a daily basis on an exercise log (Appendix H). 
 
Arm 2: Control Arm 
Control group participants will be told to maintain their current daily activities and exercise habits for the 
duration of their treatment.   
 
Study retention and adherence 
All participants in the study undergo RT as scheduled by their physician. The exercise intervention does not 
interfere with dose or timeline of RT. No specific requirements are made herein regarding prone or supine 
positioning, utilization of standard fractionation or hypofractionation, use of cardiac blocking or for utilization 
or omission of boost phase of radiation. These treatment decisions are completely at the discretion of the 
treating radiation oncologist. Adherence to the exercise intervention is achieved by offering participants 
flexibility in scheduling daily exercise, either before or after radiation treatment. Adherence is recorded in daily 
participation logs. Logs document participant identification, date, and length of time utilizing the Pedlar device. 
Participant retention efforts include a $20 gift card incentive at baseline and one follow-up visit. 
 
Assessments 
Three assessments: at baseline, at 4-weeks into radiation course and at 4-week follow-up visit, will be assessed 
(see Table 1 below).   
 

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Table 1:  Baseline and Follow-up Assessments 
Assessment 
 
Screening 
Baseline (T0) 
4 weeks (T1) 
Follow-up visit 
(T2) 
Eligibility (Appendix A) 
X 
 
 
 
Informed Consent (Appendix B) 
X 
 
 
 
Demographics (Appendix C) 
X 
 
 
 
Medical history (Appendix C) 
X 
 
 
 
Medications (from MD Consultation Note) 
X 
 
 
 
Cancer and Treatment Summary (Appendix D) 
X 
 
 
 
Performance Status 
X 
 
 
 
Physical 
activity 
readiness 
questionnaire 
(Appendix C) 
X 
 
 
 
Physical activity recall questionnaire (Appendix 
E) 
X 
 
 
 
Blood tests for hematology (Appendix F) 
 
X 
 
 
Vital signs and anthropometrics (Appendix G) 
 
X 
X 
X 
FACIT-Fatigue (in Appendix C) 
 
X 
X 
X 
FACT-B HRQOL (in Appendix C) 
 
X 
X 
X 
Inflammation biomarkers (Appendix F) 
 
X 
X 
X 
Adverse events assessments 
 
 
X 
X 
Radiation Treatment Summary (by Treating 
MD) 
 
 
 
X 
 
Outcomes 
Primary outcomes 
CRF will be determined using the Functional Assessment of Chronic Illness Therapy (FACIT-Fatigue) survey 
instrument. The FACIT is a 13-item subscale developed to identify a finite set of concerns specific to fatigue. 
The responses to the 13 items on the FACIT-Fatigue questionnaire are each measured on a 4-point likert scale, 
with score ranging from 0 to 52. The FACIT-Fatigue scale has been validated in patients with cancer and 
showed excellent internal consistency and reliability.  The following biomarkers of inflammation will be 
assessed at the Hackensack UMC:  (1) High sensitivity CRP (hsCRP) - Serum hsCRP will be measured on the 
Vitros 5,1 FS Chemistry platform via an immunoassay with a reportable range of 0.10 -15.00 mg/L, and intra- 
and inter-assay CVs of 1.8-4.0%.  (2) Serum fibrinogen and (3) Ferritin will be measured using standardized 
clinical protocols. All assays have intra- and inter-assays coefficient of variations <10%.  We will collect CBC 
data at each blood draw for correlative and explorative purposes. 
 
 
Secondary Outcomes 
Cancer-related healthcare quality of life (HRQOL) among participants in the study will be measured using the 
Functional Assessment of Cancer Therapy (FACT) system questionnaires. The HRQOL measures four different 
domains (physical well-being, functional well-being, emotional well-being, and social/family well-being). 
FACT-B is a breast cancer specific module that will be used to reflect patients’ concerns; moreover, they are 
reliable, reproducible, and have been validated in numerous studies. Higher scores on the FACT questionnaires 
reflect higher QOL. Post hoc analysis will be performed to associate RT treatment parameters against 
differences in outcomes, including utilizing the following pre-specified parameters: heart V5, lung V20, 
utilization of supraclavicular field (yes/no), utilization of supraclavicular field with axillary coverage (yes/no). 
These will potentially be hypothesis-generating and no Bonferroni corrections will be applied. 

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Sample size Considerations 
In this study participants are randomized into two groups: a structured exercise intervention group and a usual 
care control group. It is expected that there will be two levels of fatigue measurements: at baseline and after the 
exercise intervention. Our sample size calculation is based on analysis of covariance (ANCOVA) comparing 
mean fatigue score differences between the two intervention arms at the end of intervention, adjusting for 
baseline. In our exercise intervention study (Dash et al, unpublished data, mean fatigue scores of 42.53 
(SD=9.35) and 37.12 (SD=9.42) were reported for the intervention and control arms, respectively. In the same 
study, the correlation coefficient between baseline and after intervention fatigue scores was calculated as 0.64. 
With the above guidelines and a level of significance of α=0.05 (two-sided), we will use randomize 40 
women/arm to obtain statistical significance between the arms with 90% power for the overall ANCOVA F-
ratio.  
 
Statistical analysis 
Baseline characteristics will be compared between the two intervention groups using two-sample t-test or 
Wilcoxon rank-sum test depending on whether the t-test assumptions are satisfied or not. Suitably transformed 
variables will be used when necessary. Categorical variables will be compared between the two groups using 
chi-square tests or Fisher’s exact test. The major analytical tool for addressing the specific aims of this study is 
linear mixed modeling for repeated measures. Study endpoints will be measured three times in each participant 
in the study, and it is expected that measures on the same individual will be correlated. We will also examine 
whether the variance of repeated measures changes over time. An appropriate correlation structure will be 
selected depending on whether there is a trend of variance with time or not. For each outcome measure of 
interest, a linear mixed repeated measures model will be fit to evaluate the main effects of time, study group, 
and group-by-time interaction. Known confounders and other covariates will be included in the linear mixed 
models if their individual bivariate associations with both the group variable and outcome are significant at 10% 
level. 
 
We hypothesize that participants in the intervention group will have lower average fatigue scores compared to 
the usual care group after the intervention. For Aim 1 and Aim 3, “change scores” will be defined as the difference 
between baseline score and 4 week, (end of radiation treatment) score. Change scores will be compared between 
the two groups using t-test or Wilcoxon rank-sum test. An ANCOVA model will be utilized to assess group 
differences in change scores adjusting for covariates including age. We hypothesize that participants in the 
structured exercise intervention group will have lower levels of fatigue (Aim 1) and lower levels of inflammatory 
biomarkers (Aim 3) compared to baseline at follow-up visits as compared to the usual care control group. We 
hypothesize that there will be at least partial normalization of both the fatigue levels reported and the 
inflammatory biomarkers to baseline by the 4-week follow-up visit. Linear mixed models as described above will 
be used to compare fatigue scores and inflammatory biomarkers levels over time across the study groups. For 
Aim 2, we will report rates of acceptability and adherence at baseline and end of intervention. We will use the 
binomial test to compare acceptance and adherence rates between the two intervention arms. Baseline and end of 
intervention acceptability levels evaluated using the Wilcoxon sign-rank test or McNemar’s test (or generalized 
McNemar’s test) for numerical and categorized outcomes, respectively. 
 
A Graduate Research Assistant (GRA) will assist with data collection for the survey data.  The GRA will collect 
log data of the women exercising using the Pedlar device. There is an hourly reimbursement for GRA labor 
without incentive. This has been approved via the Development Grant. 
   
f. Significance  
This study will contribute to the literature on the role of concurrent radiation treatment and moderate-intensity 
exercise in reducing cancer-related fatigue and improving HRQOL among breast cancer patients undergoing.  

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This study will also provide pilot data on the correlation of inflammatory markers with exercise-related changes 
in fatigue and other HRQOL measures in breast cancer patients undergoing RT. The strengths of this study 
include the use of an “in-office” easy to use exercise intervention that reduces participant burden, the timing of 
exercise inception that coincides with RT inception, and use of biomarkers.  
 
g. Future Plans   
It is our intent to seek external federal funding in the area of symptom management utilizing exercise 
interventions. Data from this study will be combined with a similar pilot study conducted at Georgetown 
MedStar Washington Hospital Center among 30 African-American breast cancer survivors undergoing radiation 
therapy. The combined data will result in a stronger and substantive preliminary data to support a larger and 
more definitive trial on exercise interventions to reduce fatigue and improve quality of life among breast cancer 
survivors undergoing radiation therapy. The pilot data on biomarkers of inflammation will also allow us to 
propose innovative biomarker endpoints for the exercise intervention in an effort to elucidate pathways 
associated with CRF and lower HRQOL among radiation therapy patients. 
 
 
 
 
 
 

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