Understanding the Post-Surgical Non-Small Cell Lung Cancer Patient's Symptom Experience
Phase: NA
Conditions: Fatigue, Self Efficacy, Quality of Life, Physical Activity, Lung Cancer, Non-Small Cell Lung Cancer
Sponsor: University of Nebraska

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TITLE PAGE 
 
PROTOCOL TITLE 
 
Managing Fatigue Using Virtual Reality for Post-Operative Lung Cancer Patients: 
Understanding the Post-Surgical Non-Small Cell Lung Cancer Patient’s Symptom Experience 
National Cancer Institute, National Institutes of Health Grant Award # (R01 CA 205025) 
 
 
Principal Investigator 
 
Amy Jude Hoffman, MSN, PhD, RN 
E: amyj.hoffman@unmc.edu 
P: 616-826-7820 
 
Secondary Investigators 
 
Ann Berger, PhD, APRN, AOCNS, FAAN 
Co-Investigator 
E:aberger@unmc.edu 
P: 402-559-4957 
 
Karin P. Trujillo, MD 
Co-Investigator 
E: ktrujillo@unmc.edu 
P: 402-559-4389 
 
Kevin Kupzyk, PhD 
Co-Investigator and Statistician 
E: kevin.kupzyk@unmc.edu 
P: 402-552-7262 
 
Participating Personnel (Consultants) 
 
Dr. Ruth Ann Brintnall, PhD, AOCN, APRN-BC 
Associate Professor Emeritus, Kirkhof College of Nursing, Grand Valley State University 
Grand Rapids, MI 
 
Dr. Lee W. Jones, PhD 
Attending Physiologist, Department of Medicine, Memorial Sloan Kettering Cancer Center 
New York, NY 
 
Dr. Lorraine Robbins, PhD, RN, FNP-BC, FAAN 
Associate Professor, College of Nursing, Michigan State University 
East Lansing, MI 
 
Dr. Alexander von Eye, PhD 
Professor Emeritus, Psychology Department, Michigan State University, East Lansing, MI 
Professor, University of Vienna, Austria 

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Team Science Multi-Institutional Study 
 
Historical Introduction of the Study: Managing Fatigue Using Virtual Reality for Post-Operative Lung 
Cancer Patients 
 
Historically, the Lead Site for this National Cancer Institute (NCI), National Institutes of Health (NIH) R01 3-arm 
randomized controlled trial (RCT) was Michigan State University. The NCI sponsored grant was officially 
awarded to Dr. Amy Jude Hoffman, PhD, RN, at Michigan State University on April 1, 2018. Dr. Hoffman, the 
Principal Investigator, received Michigan State University Institutional Review Board (IRB) approval to initiate 
the grant on September 21, 2017. Please see the attached 45 CFR 46.118 Designation Determination IRB 
approval letter that was sent to NCI with Dr. Hoffman’s NCI “Just In Time” request. 
 
The NCI honored Michigan State University (MSU) IRB’s approval via the 45 CFR 46.118 Designation 
Determination mechanism for the R01 which allows the researcher to open up a Contracts and Grants Account 
to spend funds immediately while doing the prep work to include an IRB, as well as completing the Clinical 
Trials Gov applications, hiring personnel, and preparing to initiate the grant. Note that approaching human 
subjects is only commenced after an IRB application is approved. Likewise, Dr. Hoffman’s prior NCI R21 2-arm 
RCT grant award (CA164515) received a 45 CFR 46.118 Designation Determination, and NCI provided an 
immediate Notice of Award for the grant funds to be accessed to allow for the preparatory work for the grant to 
be implemented and funded right away. Again, human subject activity is only commenced after an IRB 
application is approved. 
 
A mechanism such as the 45 CRF 46.118 Designation Determination approval by MSU IRB consequently 
allowed for the issuance of a Notice of Award by the NCI ensuring the award of the grant and its optimal 
initiation and implementation prior to approaching human subjects. Again, human subject activity would 
commence only after the initial approvals were received, again in this case, an IRB application and review at 
Michigan State University. 
 
Last, note that Dr. Hoffman’s NCI-NIH Grant (R01 CA205025) was relinquished from Michigan State University 
and is being transferred from Michigan State University to the University of Nebraska Medical Center with 
subsequent official paperwork sent to NCI to transfer the grant to the UNMC in June 2018. The NCI is ready to 
transfer and provide a Notice of Award (R01 CA205025) for the grant pending IRB approval and the NCI is 
requesting a September 1, 2018, start date. 
 
Dr. Hoffman was honored and grateful to join UNMC July 1, 2018, and at that time was completing the processes 
for the institutional grant transfer and was grateful for the support by the UNMC Sponsored Programs 
Administration, the UNMC IRB, and the UNMC College of Nursing. Currently, Dr. Hoffman is completing an IRB 
application to be submitted soon to UNMC IRB. NCI is requesting a September 1, 2018, start date to release 
this grant. Dr. Hoffman will provide a copy of the UNMC IRB to the Scientific Review Committee at UNMC and 
the Fred and Pamela Buffet Cancer Center as well 
 
Lead Institution: The University of Nebraska Medical Center 
 
Five Performance Sites to Include: 
McLaren Greater Lansing Hospital, Lansing, MI 
Munson Medical Center, Cardiothoracic Surgeons of Grand Traverse, Traverse City, MI 
Nebraska Medicine, Omaha, NE 
Spectrum Health, Grand Rapids, MI 
Sparrow Hospital, Lansing, MI 

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Historical Background of the Michigan Performance Sites 
 
Historical Background: McLaren Greater Lansing Hospital, Sparrow Hospital, and Spectrum Health are the 
founding institutions that started the Team Science with Dr. Hoffman. These three institutions started and 
completed the NCI-NIH feasibility and pilot 2-arm RCT (R21 CA164515) work. Additionally, these three 
performance sites worked collaboratively to streamline IRB processes and resources while ensuring protection 
of human subjects. The NCI-NIH is most excited about these performance sites [McLaren Greater Lansing 
Hospital, Spectrum Health, and Sparrow Hospital] during their feasibility and pilot work (RCT R21 CA164515) 
and this was well noted by comments made by the R01 Scientific Review Panel and NCI Program Officer, Dr. 
Ann O’Mara, PhD, RN. In addition, Dr. O’Mara would consult with Dr. Hoffman to learn from her team’s 
success in the recruitment of participants from a very complex patient population, the post-surgical non-small 
cell lung cancer population. This consultation was requested by Dr. O’Mara since other institutions with NCI 
grant awards could learn from our success in recruitment since Team Science proved difficult in processes to 
support participant recruitment in other institutions. Dr. Hoffman also was contacted by clinical researchers 
from various institutions such as Cleveland Clinic, Harvard School of Medicine, Duke University Medical 
Center, and Memorial Sloan Kettering to consult on optimization of Team Science to ensure the success of 
their study. 
 
Consequently, the R01 RCT application submitted to NCI supported by the feasibility and pilot work was well 
received and this enthusiasm for these performance sites led to the awarding of this current NCI-NIH award 
April 1, 2018. Cardiothoracic Surgeons of Grand Traverse at Munson Medical Center was added in the 
original R01 RCT submission and was also excited to collaborate in Team Science through a streamlined IRB 
approach. We are excited about adding Nebraska Medicine with Dr. Karin Trujillo, MD, to this important 
program of research since Dr. Hoffman with great enthusiasm joined The University of Nebraska Medical 
Center July 1, 2018. 
 
Brief Introduction of the Michigan Performance Sites 
 
McLaren Greater Lansing Hospital – Lansing, MI: A founding institution of this program of research led 
by Dr. Hoffman, McLaren is an award winning 389-bed hospital part of the McLaren Health Care network 
serving the greater Lansing area for over 100 years. McLaren was one of our primary recruiting sites for our 
recently completed RCT (R21 CA164515) and both McLaren and our team are looking forward to working 
together in research again. McLaren Lung Cancer Institute at McLaren Greater Lansing Hospital provides a 
multidisciplinary, patient centric approach with the goal to reduce “door to therapy” time via a team of experts 
including a dedicated Patient Navigator Program to ensure seamless, coordinated care, along with any 
necessary resources. In 2014, McLaren Health Care completed the acquisition of the Barbara Ann Karmanos 
Cancer Institute, a designated comprehensive cancer center by the National Cancer Institute. McLaren Health 
Care, a fully integrated health care network of 12 hospitals and 350+ facilities serving the state of Michigan, 
including the merged acquisition of the Barbara Ann Karmonos Cancer Institute (NCI-designated comprehensive 
cancer centers), elected Dr. Hoffman to serve on the McLaren’s Executive Leadership Research Advisory Board 
to fully engage all disciplines to advance research in their organization. 
 
Munson Medical Center (MMC) and Cardiothoracic Surgeons of Grand Traverse —Traverse City, MI: 
MMC is a 391-bed nonprofit hospital serving as northern Michigan’s regional referral center. Cardiothoracic 
Surgeons of Grand Traverse is affiliated with MMC supplying cardiothoracic surgery expertise to MMC and 
supporting the proposed study as the participant recruitment site. Three thoracic surgeons from this practice will 
be supporting the study. Relative to MMC, it is the largest of the nine Munson Health Care system hospitals 
located throughout northern Michigan with 510 physicians and 3,700 employees. Munson Medical Center was 
nd 
ranked 62  nationally among 4,667 hospitals, was one of just two percent of hospitals in the country. 

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Sparrow Hospital – Lansing, MI: A founding institution of this program of research led by Dr. Hoffman, 
Sparrow is an award winning 676-bed hospital serving as mid-Michigan’s only level 1 trauma center and 
Michigan’s only member of the Mayo Clinic Care Network. Sparrow served as one of our primary recruiting sites 
for our two-arm RCT (R21 CA164515) and we are planning to continue the proposed study seamlessly initiating 
the previously established working relationship. Sparrow Cancer Center is expanding and will be opening a new 
state-of-the-art Cancer Center in 2017, the Herbert-Herman Cancer Center, to play an expanded role with 
Sparrow’s continuing relationship with the Mayo Clinic Care Network. In addition, Sparrow Hospital achieved 
Magnet designation via the American Nurses Credentialing Center in 2014. Sparrow incorporates a 
multidisciplinary approach in their lung and chest clinic reducing the time from diagnosis to treatment and 
improving the quality of care for patients. 
 
Spectrum Health – Grand Rapids, MI: A founding institution of this program of research led by Dr. 
Hoffman, Spectrum Health was recognized among American’s 50 Best Hospitals for two years consecutively 
from 2015-2016. Spectrum was one of our primary recruiting sites for our recently completed RCT (R21 
CA164515) and we are looking forward to working together in research again. Spectrum Health Cardiothoracic 
Surgery located in the Fred and Lena Meijer Heart Center opened in 2004 at Spectrum Health. The Fred and 
Lena Meijer Heart Center has become a leader in heart care and lung care in the region, state and nation and 
remains the only hospital in Grand Rapids that provides open-heart surgery and heart and lung transplant. The 
Fred and Lena Meijer Heart Center covers eight stories and 330,000 square feet, has 164 patient beds, has a 
medical staff of more than 50 specialists, and serves more than 8,500 inpatients each year. Spectrum Health 
hosts the Lemmen-Holton Cancer Pavilion that provides a full range of comprehensive oncology services for a 
variety of cancer diagnoses. Opened at Spectrum Health in 2008, the six-story, 284,000 square-foot pavilion 
provides outpatient cancer services treating more than 70% of all new adult cancer cases within the Kent County 
region of western Michigan alone. Integrated within the Lemmen-Holton Cancer Pavilion is the Lung Mass and 
Cancer Multispecialty Team Clinic. The Lung Mass and Cancer Multispecialty Team is comprised of diverse 
certified oncology providers to provide a faster path to diagnosis and treatment. Spectrum Health is also 
recognized for Magnet Status by the American Nurses Credentialing Center. 
 
ABSTRACT 
 
Persons with non-small cell lung cancer (NSCLC) report significantly more unmet supportive care needs than 
other cancer populations, yet they are among the most vulnerable and least studied. Two of the most prevalent 
unmet supportive care needs include overcoming fatigue and attaining adequate exercise to meet physical 
demands of daily living. Cancer-related fatigue (CRF) is a prevalent, persistent, and distressing symptom in the 
NSCLC population. CRF correlates with greater severity of 15 other symptoms, leading to lower physical 
function for persons with NSCLC. Among 13 core symptoms across 3,106 breast, colorectal, prostate, and 
lung cancer patients, persons with lung cancer were the most symptomatic, with moderate to severe fatigue 
being reported with the greatest prevalence. While surgery is the standard curative treatment for NSCLC, no 
formal guidelines exist for post-surgical rehabilitation. We propose a randomized controlled trial (RCT) of a 
novel rehabilitative intervention for persons with NSCLC after surgery. Our intervention promotes 
self-management of CRF and tests the intervention’s impact on CRF severity and fatigability with analysis by 
age. Our preliminary data included a two-arm RCT (R21 CA164515) incorporating the proposed intervention, 
where we exceeded goals for recruitment (67%), retention (97%), adherence (93%), and acceptability. 
Our 6-wk exercise intervention demonstrated preliminary efficacy in significantly reducing CRF severity and 
fatigability as compared to usual care, with mean CRF levels restored to levels lower than pre-surgery. The 
exercise group’s functional performance exceeded usual care. No adverse events were reported; participants 
had a mean age of 67 with a mean of 8 comorbid conditions. Our long-term goal is to develop interventions to 
increase perceived self-efficacy for CRF self-management in order to improve CRF, symptom status, functional 
status, and quality of life (QOL) for persons with NSCLC. Our objective in this application is to determine the 
efficacy, optimal timing, and sustainability of our innovative home-based exercise intervention. This study has 
the potential to transform the current standard by providing a rehabilitative exercise intervention after surgery. 
The intervention is home-based, self-paced, and builds in duration upon discharge from the hospital after 

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surgery. Aim 1: Determine efficacy by comparing the immediate intervention group with wait-list control (usual 
care) and attention control by age. Aim 2: Determine efficacy of initiating the exercise intervention 6 wks post- 
discharge and compare results with the immediate intervention group for all ages. Aim 3: Determine the 
immediate intervention’s sustainability by analyzing 3a) rates of extension, adherence, and retention; 3b) 
acceptability; and 3c) efficacy of primary and secondary outcomes. IMPACT: Our results will provide a novel 
exercise intervention, and its optimal timing, and fills the gap for a vulnerable population by providing a 
practical, portable, and low-cost means of reducing CRF severity and fatigability that is enjoyable and 
applicable to nearly all post-thoracotomy lung cancer patients. 
 
Section 1.0 Objectives 
 
Persons with non-small cell lung cancer (NSCLC) report significantly more unmet supportive care needs than 
other cancer populations, yet they are among the most vulnerable and least studied.1,2 Two of the most 
prevalent unmet supportive care needs include overcoming fatigue and attaining adequate exercise to meet 
physical demands of daily living.1-6 Cancer-related fatigue (CRF) is a prevalent, persistent, and distressing 
symptom in the NSCLC population.7-16 The Principal Investigator has identified CRF as a priority symptom that 
correlates with greater severity of 15 other symptoms, leading to lower physical function and quality of life 
(QOL) for persons with NSCLC.17 Likewise, among 13 core symptoms across 3,106 breast, colorectal, 
prostate, and lung cancer patients, Cleeland et al. found that persons with lung cancer were the most 
symptomatic, with moderate to severe fatigue being reported with the greatest prevalence.18 To compound this 
problem, while surgery is the standard curative treatment for NSCLC, no formal guidelines exist for 
post-surgical rehabilitation.8,19-21 
To address this need, we propose a novel rehabilitative exercise intervention for persons with NSCLC 
after surgery. Our intervention promotes self-management of CRF to reduce CRF severity and fatigability 
(fatigue associated with activity, an indicator of functional capacity) with analysis by age. This randomized 
controlled trial (RCT) addresses the NCI Clinical Trials Planning Meeting priority need for longitudinal studies 
of exercise interventions that address CRF that are practical, portable, safe, and independent of climate, and 
that use motivation for intervention uptake.22 In support of this application, we conducted a two-arm RCT 
(R21 CA164515) incorporating the proposed intervention and exceeded goals for recruitment (67%), retention 
(97%), adherence (93%), and acceptability.23,24 Our 6-wk exercise intervention demonstrated preliminary 
efficacy in significantly reducing CRF severity and fatigability, compared to usual care, restoring mean CRF to 
levels lower than pre-surgery. The exercise group’s mental and physical functional performance exceeded 
usual care with no adverse events. Participants had a mean age of 67 and mean of 8 comorbid conditions. 
 
Our long-term goal is to develop interventions to increase perceived self-efficacy (PSE), perception of 
ability, for CRF self-management as a means of improving functional status and quality of life for persons with 
NSCLC.25 Our objective in this application is to determine the efficacy, optimal timing of initiation, and 
sustainability of our 6-wk home-based exercise intervention. The significance of this study is that it targets two 
of the most troublesome unmet needs, fatigue and lack of exercise, in an understudied, vulnerable population 
with the potential to transform the current standard of care by providing a rehabilitative exercise intervention 
after surgery. The proposed research advances the field by providing both an intervention for CRF self- 
management and evidence for its optimal initiation and sustainability, which currently does not exist for the 
post-thoracotomy NSCLC population. Our exercise intervention is guided by a theoretical approach (tested by 
the PI) incorporating self-efficacy theory to strengthen a person’s ability to manage their CRF and walking 
ability.17,26 The exercise intervention is innovative in its timing and approach in providing self-paced exercise 
to a vulnerable post-surgical NSCLC population upon discharge from the hospital. The Nintendo’s Wii Fit Plus 
is used to provide light-intensity, virtual reality walking and balance exercise that departs from the status quo 
and transcends barriers to exercise, as demonstrated by our R21 RCT retention and adherence outcomes. 
 
This study employs a three-arm RCT for persons undergoing NSCLC surgery with participants being 
randomly assigned to an immediate (post-hospital discharge) exercise intervention group, a wait-list control 
group (6 wks usual care [wks 1-6] and 6 wks exercise [wks 7-12]), or a 6 wk attention control group (wks 1-6). 

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Primary Outcome: Cancer-Related Fatigue (Severity and Fatigability). 
 
Secondary Outcomes: Severity of Other Symptoms; PSE for CRF Self-Management, Walking, and Balance; 
Functional Performance; and Quality of Life (QOL). 
 
Aim 1: Determine efficacy of three groups by comparing: 1) immediate exercise intervention group; 
2) a wait-list control group; 3) an attention control group by age. Hypothesis 1: The exercise intervention 
group will outperform wait-list and attention control on all primary and secondary outcomes at wk 6 for all ages. 
 
Aim 2: Determine efficacy of initiating the exercise intervention 6 wks post-discharge and compare 
results with the immediate intervention group by age. Hypothesis 2: The immediate exercise intervention 
group will improve for all ages at a greater rate and magnitude than the wait-list group for all outcomes. 
 
Aim 3: Determine the immediate exercise intervention’s sustainability by analyzing a) rates of 
extension, adherence, and retention; b) acceptability; and c) efficacy of primary and secondary 
outcomes. Hypothesis 3: The exercise intervention will be acceptable with >50% extending at wk 6 and >70% 
adherence and retention at wk 12, with improved primary and secondary outcomes at wk 12. 
 
IMPACT: Our results will provide a novel, practical, portable, low-cost, and enjoyable exercise intervention 
with important information on its optimal timing and sustainability to fill the gap regarding approaches that are 
applicable to nearly all post-thoracotomy lung cancer patients for reducing CRF severity and fatigability.20,22,27-32 
 
Section 2.0 Introduction 
Significance 
2A) OVERALL SCIENTIFIC PREMISE 
Fatigue remains a prevalent and distressing symptom in post-surgical NSCLC patients.15,16,33 Exercise has 
been shown to be effective in treating CRF.20,34 However, research investigating the effect of exercise on CRF 
is limited in the post-surgical NSCLC population as these patients are excluded from studies due to complex 
medical issues.27-29,32,35 To date, while surgery is a standard curative treatment for NSCLC, no guidelines exist 
for post-surgical rehabilitation.8,36-38 The results of our two-arm RCT (R21 CA164515) targeting CRF severity 
and fatigability via exercise for patients transitioning from hospital to home sets the premise for the proposed 
research, which holds considerable promise to improve post-surgical management of CRF.23 Our two-arm R21 
RCT exceeded goals for retention (97%), adherence (93%), and acceptability with no adverse effects despite 
participants having a mean age of 67 and a mean of 8 co-morbid conditions.23,24 Our 6-wk exercise intervention 
demonstrated preliminary efficacy in significantly reducing CRF severity and fatigability as compared with usual 
care, with mean CRF levels restored to levels lower than pre-surgery.23 Limited evidence exists on the optimal 
timing and sustainability of an exercise intervention targeting CRF for the post-surgical NSCLC population.30,31 
The proposed RCT investigates efficacy, optimal timing, and sustainability to provide an effective exercise 
intervention for rehabilitation of the post-surgical NSCLC population. 
 
2B) CRITICAL NEED 
Adults with multiple comorbid conditions and complex treatment plans, such as those with NSCLC, are 
vulnerable during the transition from hospital to home.39-42 In a study of 888 persons with varied cancer 
diagnoses from initial diagnosis to two years after diagnosis, having a lung cancer diagnosis was found to be a 
strong independent predictor of reporting a higher number of unmet needs as compared to all other cancer 
diagnoses combined.2 The most frequently unmet supportive care needs are managing fatigue and physical 
deterioration, performing activities of daily living, and receiving support to exercise.1-6,43 Likewise, greater levels 
of supportive care needs are associated with greater symptom distress and worse physical functioning.1 
Fatigue is a prevalent, severe, and debilitating cancer symptom in persons with lung cancer. Fatigue is 
the most common distressing and unmanaged symptom in persons with cancer.13,44-50 In a 2013 study among 

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3,106 ambulatory patients with breast, prostate, colorectal, or lung cancer with nearly 75% receiving treatment, 
fatigue was the most prevalent and severe symptom in each group.18 Persons with lung cancer were most 
symptomatic, with nearly 30% rating 5 of 13 symptoms’ severity as moderate or severe. Moderate or severe 
fatigue was more prevalent in persons with lung cancer than in persons with breast, prostate, or colorectal 
cancer.18 In 2014, Wang and colleagues reported that among persons with solid tumors receiving cancer 
treatment, having lung cancer was one of the most important contributors to moderate to severe fatigue.10 As 
shown in a 2011 national study of 4,512 cancer survivors, fatigue is persistent even one year post-diagnosis 
and after treatment.51 Also, > 25% of the participants reported having high symptom burden more than one 
year after diagnosis, with persons with lung cancer reporting high symptom burden with fatigue having the 
greatest impact on health-related QOL.51 Longitudinal studies of post-surgical NSCLC patients also report 
persistent and/or worsening of CRF, other symptoms, physical functional status, and QOL.8,11,14,21,52,53 
An intervention must be applicable to patients of all ages. Oksholm et al. report few age-related 
differences among 270 persons undergoing surgery for lung cancer, noting that fatigue and multiple symptoms 
are highly prevalent in both younger (< 65) and older (> 65) patients.54 While fatigue is a major issue among all 
ages, fatigue is prevalent in older adults (> 65) and interferes with activity, leading to loss of independence.55 
Among older adults void of mobility limitations or disability, fatigue when performing activities such as walking 
(fatigability) is predictive of activity limitations, functional decline, and disability.56-59 In persons 75-80 yrs old, 
sustained fatigue was found to be a strong predictor of mortality.60 With 67% of persons diagnosed with lung 
cancer aged 65+ at time of diagnosis,61 and fatigue identified as a priority symptom, it is critical to have an 
intervention that is effective and applicable to lung cancer patients of all ages.15,16,20 Results of our R21 RCT 
indicate the exercise intervention was beneficial for both younger (<65) and older (> 65) patients with CRF 
severity of both groups improving by a mean of 3.3 (scale 0-10, 10 = most severe) over their corresponding 
control groups post-intervention. 
 
2C). SIGNIFICANT CONTRIBUTION 
Our study incorporates a transdisciplinary, novel exercise intervention relevant for all ages that 
addresses CRF self-management to improve CRF severity and fatigability for a vulnerable population 
during a critical transition in their treatment.22 This study proposes a highly accessible solution to meet the 
unmet rehabilitative support needs62 targeting CRF via a PSE-enhancing exercise intervention to improve CRF 
severity and fatigability, other symptoms’ severity, and functional performance. This study helps meet the 
priority need identified in the NCI Clinical Trials Planning Meeting22 and 2014-2018 Oncology Nursing Society 
Research Agenda63 for implementation of longitudinal exercise trials for safe interventions that are practical, 
portable, independent of climate, and using motivation as a key factor for uptake. The proposed research is 
based on Principles of the Transitional Care Model,40-42,64 which underpins the approach to the implementation 
of the proposed intervention. The Transitional Care Model provides a continuum of care including pre- and 
post-surgical screening and engagement, management of symptoms using education for the promotion of self- 
management, health care team and patient collaboration, continuity of care from hospital to home, and 
postsurgical coordination of care while maintaining relationships in a transdisciplinary approach. A tested 
theoretical framework from the synthesis of the Theory of Unpleasant Symptoms65,66 and Bandura’s Self- 
efficacy Theory67 guides the intervention’s design and testing (Fig 1)17,23,26 and provides insight into how a 
person’s PSE for self-managing symptoms influences performance of those behaviors. Hoffman and 
colleagues17 found that for persons with cancer, including lung cancer, targeting CRF severity directly and 
indirectly through PSE for CRF self-management is important to functional status. Thus, we hypothesize that 
patient characteristics are influencing factors of symptoms and functional status. 

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A key characteristic is age and its influence on CRF severity and fatigability. Symptoms affect PSE. Symptoms 
and PSE affect CRF self-management behaviors. The performance of CRF self-management behaviors affects 
symptoms and functional status.68 Two dimensions of functional status are functional capacity (one’s maximum 
potential to perform activities) and functional performance (daily activities in the normal course of their lives).68 
This study investigates effects of an exercise intervention on CRF severity and fatigability, with fatigability 
indicated by a person’s functional capacity that enables or restricts functional performance.68 The effect of CRF 
self-management behaviors on CRF severity and fatigability ultimately affect quality of life, a “person's sense of 
well-being that stems from satisfaction or dissatisfaction with the areas of life that are important to him/her." 
The results of our two-arm R21 RCT indicate that our exercise intervention is feasible, acceptable, safe, 
and enjoyable, while providing significant improvements in CRF severity and fatigability for the 
intervention group versus the control group.23,24 Likewise, our home-based intervention removes barriers to 
exercise for a patient population that has significant health and logistical barriers to exercise.24,30,69 Our 
participants confirmed that the exercise intervention fills the gap in post-thoracotomy rehabilitation and meets 
their needs by providing a means to overcome the barriers to exercise they experience.35 
 
2D) EXPECTED BENEFITS 
Lung cancer is the most common cancer worldwide (1.8 million cases/year, NSCLC accounting for ~85% of 
cases).70 The 5-year survival rate for lung cancer is 55% for cases detected early70 with surgery being the best 
curative treatment; CRF is reported as the most prevalent and distressing symptom in this population.35,52,71 
This research addresses a glaring knowledge gap in how to rehabilitate and treat CRF in this sizeable, high 
acuity cancer population.8,35 Based on existing evidence, 72-75 results of our single-arm pilot (no control 
group)76,77 and two-arm R21 RCT,23 we expect the benefits of this study to confirm that post-surgical NSCLC 
patients will find the exercise intervention effective in reducing CRF severity and fatigability (functional 
capacity). Further, we expect the exercise intervention group will outperform the attention control and wait-list 
control groups by age for other symptoms’ severity; PSE for CRF self-management; PSE for walking; PSE for 
balance; functional performance; and QOL. We expect the wait-list exercise intervention group’s CRF severity 
and fatigability to improve, but not as significantly as the immediate exercise intervention group. We also 
expect >50% of the immediate exercise intervention group to extend 6 more wks, with adherence and retention 
rates of >70% at wk 12, with improved primary and secondary outcomes at wk 12. Once this exercise 
intervention’s effectiveness is further demonstrated, the intervention will provide a practical and portable 
means to treat CRF severity and fatigability for NSCLC and other vulnerable populations transitioning from 
hospital to home. 
 
Innovation 
2E) TRANSFORMING THE STATUS QUO 
This study is the first extensive study to target and analyze by age a priority symptom, fatigue and its 
associated fatigability, in a vulnerable, underserved post-thoracotomy NSCLC population during their 
transition from hospital to home. Our proposed research builds on the results of our single-arm pilot and 

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two-arm RCT. The approach executes transitional care principles to address a high-risk, high-cost, high- 
volume patient population and their most critical reported unmet needs. We will assess the timing and the 
corresponding sustaining effects of the exercise intervention in order to help define its optimal delivery. 
This is also the first large-scale RCT of post-surgical NSCLC patients to test a highly accessible, home- 
based, light-intensity exercise intervention that incorporates PSE-enhancing strategies. It utilizes an 
enjoyable approach through virtual reality (using the Nintendo Wii Fit Plus), which may offset the effects of 
unpleasant symptoms to facilitate exercise. By using an entertaining light-intensity exercise intervention, in the 
home, with a PSE-enhancing approach, we expect to transcend exercise barriers and provide a safe, practical, 
inexpensive, and portable means to effective CRF self-management and improved CRF severity and 
fatigability. No exercise intervention studies for the post-surgical NSCLC population have utilized fatigability to 
measure effectiveness of a fatigue intervention. This is important, given that fatigability is the degree of fatigue 
associated with activity of any kind and is a measure of the impact fatigue has on functional capacity that 
influences functional performance. Thus, without a fatigability measure, it is difficult to determine the 
effectiveness of an intervention for fatigue.68,78 
 
2F) LIMITATIONS & BARRIERS OF STATUS QUO ADDRESSED 
Studies on exercise interventions for post-surgical NSCLC patients are very limited. Currently, there are 
no guidelines for routine rehabilitative support for persons with NSCLC after surgery.8,19,21,38 The optimal 
exercise program for persons with NSCLC recovering from surgery is not known.37,79-83 In 2012, three 
systematic Cochrane reviews of the general cancer population indicated that exercise can be beneficial for the 
management of CRF and health-related QOL. This benefit was seen from cancer diagnosis, through active 
treatment, and post-treatment, with treatment including surgery, chemotherapy, radiation therapy, and/or 
hormone therapy.27-29 However, all three reviews recommended caution when interpreting these positive 
results because the majority of the studies were conducted on the breast cancer population, who are typically 
less vulnerable, younger, and have minimal comorbid conditions. 
 
2G) Our pilot data suggest that our exercise intervention is effective in removing the post-surgical 
NSCLC population’s significant barriers to exercise while the exercise intervention’s minimal exclusion 
criteria maximize its applicability. To date, the eligibility criteria for exercise interventions in post-surgical 
NSCLC patients have excluded much of the post-surgical NSCLC population: These criteria eliminate patients 
with common comorbid conditions; require moderate-to-vigorous exercise intensity; have been structured, and 
inpatient or facility-based; have not reported adherence rates while exhibiting poor rates of retention.30,31,69,72,84- 
87 In our R21 RCT, the proposed intervention showed preliminary efficacy in improving fatigue severity and 
fatigability while removing the barriers to exercise through light-intensity, home-based, self-paced, self-efficacy 
enhancing attributes that were highly acceptable, resulting in high retention rates.23,24 Our research addresses 
NCI recommendations for high-priority research focused on overcoming barriers to implementation and 
strategies to increase uptake and effect size of interventions like exercise, to promote CRF management.22 
 
2H) TRANSFORMING POST-THORACOTOMY REHABILITATION THROUGH INNOVATION 
It is difficult to determine how to exercise vulnerable, post-thoracotomy NSCLC patients and keep 
them exercising.29-31 The latest Cochrane reviews on exercise interventions on health-related QOL, including 
fatigue during/after active cancer treatment, recommend research investigating how to sustain positive effects 
of exercise over time. These reviews recommend research to determine the central attributes of exercise 
(mode, intensity, frequency, duration, timing) for cancer patients other than breast cancer.27-29 The Cochrane 
review of non-invasive interventions for improving well-being and QOL in lung cancer patients recommends the 
development of interventions focused on symptom self-management to promote functional ability.88 
Recommendations were made to test the feasibility and effectiveness of non-invasive interventions for the lung 
cancer population “within real life settings as opposed to the sometimes artificial setting of a research study.”88 
 
• 
Our proposed study couples self-efficacy theory67,89 with an innovative approach using virtual reality 
gaming technology, implemented in the comfort of the patient’s home to help sustain exercise by providing a 

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convenient and enjoyable means of exercise.29 We learned in our single-arm pilot, which was corroborated in 
our follow-up two-arm RCT that participants found the proposed exercise program enjoyable and “the right type 
of exercise at the right time” for their body and mind to recover.76,77 
 
The challenge has been to determine how to exercise a post-thoracotomy patient who is typically 
deconditioned, as demonstrated by reduced exercise capacity related to a sedentary lifestyle, the 
surgery itself, and multiple comorbid conditions.75,90 This deconditioning is exacerbated by the debilitating 
effects of the thoracotomy procedure and its sedentary recovery, with further reductions in exercise capacity 
upon initiation of adjuvant chemotherapy and/or radiation therapy.90 In our RCT, 21 of 37 exercise intervention 
participants were prescribed walkers on discharge. After 6 wks, all exercise participants, including those who 
required a walker pre-surgery, no longer needed walkers. Conversely, 6 of 35 control group participants were 
prescribed walkers at discharge, with 4 needing their walker at the end of the study. Also, 9 of 37 intervention 
participants were discharged with oxygen therapy. After 6 wks of exercise, only 4 required minimal oxygen for 
vigorous activities. Conversely, 6 of 35 in the control group required oxygen at discharge with 3 requiring 
oxygen for activities of daily living post study. Our team developed a prospective approach by incorporating an 
innovative exercise intervention that disrupts the debilitating deconditioning spiral by providing vulnerable 
patients a means to safely exercise after the transition from hospital to home.76,91,92 
 
 
2I) Introduction to the Approach 
By designing services for the hospital-to-home transition, we provide health care continuity and avoid 
preventable poor outcomes among high-risk patient groups. To date, exercise interventions for post- 
surgical NSCLC patients have been facility-based, utilizing conventional equipment with moderate- to high- 
intensity exercise.72,81,84,85 Studies have not addressed the critical post-surgical hospital-to-home transition, 
leaving patients without a plan to address symptoms such as CRF severity and associated fatigability.8 
Naylor’s39,42 work demonstrates that adults with multiple comorbid conditions and complex treatment plans are 
vulnerable during the hospital-to-home transition. Naylor also demonstrated that designing services for this 
transition provides health care continuity and prevents poor outcomes among high-risk patient groups.93 
 
2J) Research suggests that light-intensity exercise may improve functioning and QOL and may be an 
alternative to higher-intensity exercise programs for deconditioned populations with comorbid 
conditions.94,95 In our R21 RCT, we found that light-intensity (<3.0 METs) was practical, as the intensity falls 
within their current prescribed physical activity level; it reduced CRF severity and fatigability as compared to 
the usual care group; and it was safe, with no adverse events reported. 
 
2K) Given that CRF is a multiple determinant construct,96 research suggests that integrating self- 
efficacy with physical exercise may be beneficial in ameliorating fatigue.97 To date, there have been no 
intervention studies dedicated to persons with NSCLC after surgery that have incorporated self-efficacy 
enhancing processes and light-intensity exercise to target CRF. According to Bandura,67(p.411) successful 
adoption and adherence to exercise even in healthy populations requires PSE to engage in exercise. 
Structuring an environment that can reduce exercise barriers with motivational supports is essential for the 
post-surgical NSCLC population. Bandura67 (407-421) states that before building a person’s PSE to exercise, 
barriers to exercise need to be removed. Exercise barriers include travel, timing, weather, and the belief that 
exercise is onerous, monotonous, and strenuous. Additional barriers include lack of knowledge, skills, and 
abilities to implement an exercise program. NSCLC patients have added barriers of symptoms such as CRF 
that prevent daily activities. Bandura67 (p.147) states that a change in environment can instantly alter what 
preoccupies one’s thinking. Studies show that unpleasant sensations are offset by competing pleasant 
sensations, hypothesizing that the brain is limited to how many sources of information it can process at one 
time.98-101 Researchers hypothesize that while a patient is engaged in a pleasant activity, there is less attention 
available to process unpleasant sensations, providing relief of the unpleasant sensation and augmenting the 
pleasant sensation.98,102 The proposed intervention virtually transports the patient to enjoyable environments 

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overcoming barriers to exercise by introducing an attention strategy to self-attract pleasant thoughts, relieving 
the unpleasantness of unwanted symptoms.67 (p.147) 
 
2L) Generating evidence to determine key exercise intervention attributes and optimal timing is critical. 
Exercise is an effective means for treating CRF.20,29,32,71,82 However, research investigating exercise in the lung 
cancer population following surgery is limited, with heterogeneity of exercise programs.27,29 Limited evidence 
can be found showing the most essential attributes to making exercise effective (mode, intensity, frequency, 
duration, timing).27,29 We expect that light-intensity exercise initiated immediately after hospital discharge will 
positively affect CRF severity and fatigability, but the optimal timing of exercise initiation is not known.27,29 
Generating evidence to determine optimal intervention timing is critical, given that the post-surgical lung cancer 
population experiences significant symptom burden decreased functional status, and QOL.8,10,15,16,18,52,54,103 
Consequently, obtaining symptom data from participants who initiate the exercise intervention: a) immediately 
upon returning home after surgery and b) 6 weeks after returning home will 
provide insight into the recovery process and the importance of exercise 
timing on CRF severity and fatigability.76,77 With diminishing health care 
resources, it is important to understand how and when to apply resources to 
optimize outcomes.22 
 
2M) Exercise interventions must be sustainable to ensure continued 
use/effectiveness throughout the post-thoracotomy NSCLC 
population’s survivorship trajectory.104 Sustainability is defined as the 
continued use beyond the initial implementation of the intervention for the 
continued achievement of desirable outcomes for the intended 
population.104-106 Little research has been conducted with the post-thoracotomy lung cancer population on how 
to sustain changes in exercise behaviors and their associated effects over time for CRF, functional status, and 
QOL.27-29,69 Cochrane reviews27-29 state that research is required to investigate how to sustain these positive 
effects and determine the attributes that lead to success—a key goal of intervention science—to understand if 
investments are leading to longer-term beneficial outcomes.104 The design of the proposed exercise 
intervention combines recommended attributes identified as potential motivators to promote a sustained 
exercise intervention in the cancer population. These exercise motivators include but are not limited to: use of 
self-efficacy theory to create intrinsic demand for the intervention;29,89 use of a home-based approach30 with 
service delivery, including face-to-face contact followed up with phone contact;107 use of informational 
motivators such as activity logs; portable heart rate monitors and pedometers; and expert consultation 
provided by qualified health care providers.82 
 
PRELIMINARY WORK 
2N) Two-Arm R21 RCT Pilot Published 201723,24 
Purpose. Examine feasibility, acceptability, and preliminary efficacy of a rehabilitative intervention for CRF 
severity, fatigability, PSE for fatigue self-management, other symptoms’ severity, PSE for walking & balance, 
and functional performance for post-surgical NSCLC patients. 
Fig 2: RCT Participant Demographics 
Mean age = 67 yrs (range 32-89 yrs) 
56% female 
74% married 
56% retired 
29% employed outside home 
89% White 
7% Black (n = 5) 
4% American Indian (n=3) 
19% did not complete HS 
43% completed HS only 
28% some college or post-HS training 
10% college and/or post-grad 

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Methods. Participants (Figs 2, 3) were randomly assigned prior to surgery to intervention group (IG) (n = 37) 
or usual care group (UCG) (n = 35). The IG performed prescription-based virtual reality walking and balance 
exercise using the Nintendo Wii in their home. The 6-wk light-intensity exercise intervention was self-paced, 
gradually building in duration upon hospital discharge after NSCLC surgery. A nurse called the participant 
within 24 hrs post-surgical hospital discharge to screen for readiness to start the intervention. A home visit to 
start exercise was scheduled within 4 days of discharge. The nurse made a second home visit at the start of 
wk 2 and phone visits at the start of wks 3-6, with additional visits on participant request. Both home and phone 
visits supported participants by providing PSE-enhancing CRF self-management interventions to support 
exercise and adjust the exercise prescription 
. 
Aim 1 Results (feasibility, acceptability, safety) Recruitment. 
We recruited 67% of eligible participants, exceeding our goal 
of 50%. Also, recruiting goals of N=64 were exceeded: 72 
participants completed the study, recruited from one hospital 
site in west Michigan and two hospitals in mid-Michigan. 
Retention, adherence, acceptability, & adverse events: 
Retention was assessed by measuring percentage 
completing the program from first phone visit after surgery to final 
data collection at wk 6. Even though this vulnerable population had 
a mean of 8 comorbid conditions, the goal of 70% retention was 
exceeded: 97% of participants completed the intervention. 
Adherence was measured by computing percentage 
participating in the intervention that adhered to the 
recommended intervention. The goal of 70% adherence was 
exceeded, as 37 participants adhered to their prescribed 
exercise at a rate of 93%. Acceptability was assessed via a 
15-item questionnaire providing feedback in multiple areas. 
The 37 participants gave a mean rank of 5.6 (scale 0-6, 6 = 
highest acceptability) exceeding our goal of a mean positive acceptability score of 4. Participants stated that 
the intervention was enjoyable and effective in helping control their fatigue. A proposed improvement was after 
10 mins of walking with the Wii, participants wanted the option to walk outside or in another venue; this is now 
incorporated in our proposed intervention. No adverse events were reported. 
 
Aim 2 Results (preliminary efficacy of exercise intervention) Preliminary efficacy was assessed by comparing 
results of the IG (N=37) with the UCG (N=35). Primary outcomes were CRF severity, fatigability, and PSE for 
CRF self-management. Effect sizes were calculated using Cohen’s d mean difference methods by calculating 
the mean difference between IG and UCG divided by SD of the UCG (more conservative). 
 
Cancer-related Fatigue Severity was measured using the Brief Fatigue Inventory108 with data collected pre- 
and post-surgery, upon return home from hospital, and at the end of each wk for 6 wks. Results (Fig 4) 
indicate on a scale of 0-10 (10 = most severe), IG and UCG pre-/post-surgery values show no significant 
difference. At wk 6, a significant difference was found between the IG (M=0.7, SD 0.7) and UCG (M=4.0, SD 
2.0) [t (42) = -9.3, p<.001; 95% CI -4.0 to -2.6; d = 1.7]. The IG’s wk 6 CRF severity (M=0.7, SD 0.7) showed 
significant recovery from post-surgery (M=4.1, SD1.9) [t (36) = 9.9, p <.001; 95% CI 2.7 to 4.1; d = 1.8], 
restoring to a CRF severity lower than pre-surgery levels (M=2.2, SD 2.0) 
[t (36) = 4.4, p<.001; 95% CI 0.8 to 2.1; d = 0.7]. 
 
PSE for CRF Self-Management measured by the PSE for Fatigue Self-Management Instrument109 shows 
(Fig 5) on a scale of 0-10 (10 = greatest PSE) the IG’s PSE for CRF self-management improves from post- 
surgery (M=7.0, SD 2.0) to wk 6 (M=9.6, SD 0.7), while the UCG’s PSE decreased from post-surgery (M=7.6, 
Fig 3: RCT Participant Clinical Characteristics 
Mean of 8 comorbid conditions (SD 4; range 0-17) 
Mean hospital stay= 8.8 days (SD 5; range 4-35) 
Surgery Type 
90% open thoracotomy 
10% video-assisted thoracoscopy (VATS) 
69% lobectomy 
17% wedge resection 
4% bi-lobectomy resection 
5% pneumonectomy resection 
5% other resections. 
Cell type following resection 
adenocarcinoma (63%) squamous (31%) 
Post-surgical cancer staging: 
stage I (62%) stage II (21%) stage III (11%) 
stage IV (3%) indeterminate (3%) 

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SD 2.6) to wk 6 (M=6.9, SD 2.1) resulting in a significant difference at wk 6 
[t (41.8) = 7.4, p<.001; 95% CI 2.0 to 3.5; d = 1.3]. 
 
Fatigability (fatigue with activity, indicator of functional capacity) was measured by the 6-min walk test 
(6MWT) pre-surgery and post-study, by assessing fatigue reported during the 6MWT and distance walked in 6 
mins.110 The IG’s wk 6, post-study fatigability decreased from pre-surgery while the UCG’s increased. IG’s 
fatigue during 6MWT (0-10, 10= most severe) decreased from pre-surgery (M=2.0, SD 1.7) to post- 
intervention (M=0.4, SD 0.8) while their distance walked 
increased by a mean of 15% (SD 15). Conversely, the 
UCG’s fatigability increased as their 6MWT fatigue 
increased from pre-surgery (M=1.5, SD 1.8) to post 6 wks 
(M=3.1, SD 1.5) while their distance walked decreased by 
a mean of 21% (SD 19). The difference between the IG 
and UCGs’ fatigue during the post-study 6MWT was 
significant [t (50.9) = -9.3, p<.001; 95% CI -3.3 to -2.1; d = 
1.8) as was % change in distance walked post-study vs. 
pre-surgery 6MWT [t (70) = 9.0, p < .001; 95% CI 28 to 
44; d = 1.9]. 
 
15 Other symptoms’ (not including fatigue) frequency, 
severity, and interference levels were measured using the M.D. Anderson Symptom Inventory.111 Fig 6 shows 
number, severity, and interference from pre-surgery to wk 6, post-study for IG and UCGs. Mean # symptoms 
reported by the IG decreased from 8.4 (SD 2.4) post-surgery to 4.6 (SD 3.2) at wk 6 post-study, while the UCG 
reported a mean of 6.6 (SD 3.3) post-surgery and increased to 7.4 (SD 3.3) at wk 6, post-study, a significant 
difference between groups at wk 6 [t (70) = -3.7; p<.001; 95% CI -4.4 to -1.3; d = 0.9]. Likewise, mean 
symptom severity of the IG was 4.7 (SD 1.5) post-surgery and decreased to 2.1 (SD 1.0) at wk 6, while the 
UCG started equivalent to the IG post-surgery at a mean severity of 4.9 (SD 1.6) and only reduced to a mean 
level of 3.8 (SD 1.5) by wk 6, a significant difference between groups at wk 6 [t (61.2) = -5.6; p<.001; 95% CI - 
2.3 to -1.1; d = 1.1]. 
For mean symptom interference, the IG reported post-surgery mean 
interference of 3.3 (SD 2.1) decreasing to a level of 0.5 (SD 0.8) at wk 6, while the UCG reported a post- 
surgery mean interference of 4.5 (SD 2.8) and improved to an interference level of 2.9 (SD 2.3) at wk 6, a 
significant difference between groups at wk 6 [t (41.8) = -6.0; p< .001; 95% CI -3.2 to -1.6; d = 1.1]. 
 
Functional Performance was measured using the Medical Outcomes Short-Form-36 (SF-36)112 pre-/post- 
surgery and after wks 3 & 6. SF-36 uses norm-based scoring with physical and mental health components of 
the SF-36 scored to have the same mean (50) and 
SD (10) in the general U.S. population, with 
component scores ranging from 20 to 70. The 
Mental Health component of the IG (Fig 7) 
consistently improved from a mean pre-surgery 
level of 48.2 to 57.5 at wk 6 (exceeding national 
norm of 50). Conversely, the UCG’s mean Mental 
Health component scores dropped after surgery 
and stayed relatively flat for wks 3 & 6 (47.4 and 47 
respectively). Physical Health component scores 
dropped for both groups post-surgery, with IG’s 
improving from post-surgery 30.2 to a wk 6 of 45.2. 
The UCG improved at a much slower rate, starting 
at post-surgery level of 32.7 and improving to 38.8 
at wk 6 post-study. 

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Implications of Preliminary Work. Results justify efficacy testing with a larger sample, attention control 
group, and focus on optimal timing and sustainability of the exercise intervention. The proposed intervention 
retains all pilot components, incorporating participant feedback to add exercise flexibility with/without the Wii 
after achieving 10 mins/day of continuous walking for 5 days/wk. 
 
Section 3.0 Eligibility Criteria 
 
The research proposed for this application is a randomized controlled trial (RCT) to determine the efficacy, 
optimal timing, and sustainability of an innovative home-based exercise intervention for post-surgical non-small 
cell lung cancer (NSCLC) patients after discharge from the hospital. This exercise intervention is designed to 
enhance perceived self-efficacy (PSE) for cancer-related fatigue (CRF) self-management to improve CRF 
severity and fatigability (fatigue associated with activity, an indicator of functional capacity) to augment the 
rehabilitation of persons of all ages with NSCLC after surgery. 
 
No special vulnerable populations will be studied. 
 
Eligibility. Based on results of our R21 RCT, we will use criteria shown for participation in this study: 
 
Inclusion Criteria. 1) Women and men at least 18 years of age with suspected NSCLC to be confirmed after 
surgery; 2) Karnofsky Performance Status score of at least 70%, which provides functional impairment 
classification, universally used in oncology, and is scored from 0% (dead) to 100% (no complaints); 3) Thoracic 
surgeon approval pre- and post-surgery; 4) Medically stable comorbid conditions allowing for NSCLC surgery 
clearance; 5) Has phone access capability; 6) Able to speak and write English; 7) Able to hear and speak for 
phone interviews; 8) Owns a television; and, 9) Lives within 2 hours driving distance of recruitment site. This 
study includes both men and women since lung cancer remains the second most common, newly diagnosed 
solid tumor and accounts for more deaths than any other cancer regardless of gender.61 While the average age 
of persons with lung cancer at diagnosis is 70 years, age alone is not a reason to deny persons with NSCLC 
access to curative-intent surgical intervention since lung resection remains the best treatment option.114 
Consequently, persons 18 years of age and older and diagnosed with lung cancer will be eligible to participate. 
While 99.8% of persons diagnosed with lung cancer are at least 35 years of age upon diagnosis,155 those 
younger than 35 years of age will also need to recover from surgery, including meeting the needs of managing 
CRF and exercise.16 In addition, most exercise interventions conducted in the cancer population have excluded 
persons with comorbid conditions.29 Since the lung cancer population commonly has comorbid conditions, our 
research team included participants with medically stable comorbid conditions allowing the participant to be 
cleared for NSCLC surgery. The mean age was 67 (SD 9.9) years with a range in age from 32 to 89 years in 
our NCI-NIH two-arm RCT (R21 CA164515), with both the youngest and oldest participants completing the 
intervention. In addition the mean number of comorbid conditions upon entry into our two-arm RCT was 8 (SD 
3.9) with a range of 0 to 17 co-morbid conditions. Despite participants’ diverse ages from 32 to 89 years and 
having a mean of 8 comorbid conditions, there were no reported adverse events. Moreover, since cancer 
survivors are recommended to return to normal daily activities as quickly as possible after surgery,82 and the 
light-intensity exercise intervention mimics normal daily activities,118 persons with NSCLC with medically stable 
comorbid conditions are included to participate in the study. The proposed RCT in this application addresses 
the NCI Clinical Trials Planning Meeting priority need for longitudinal studies of exercise interventions that 
address CRF that are practical, portable, safe, independent of climate, and use motivation for intervention 
uptake.22 
Exclusion Criteria. 1) Severe impairment of sight, hearing, speaking; 2) Active treatment for malignancy 
within past 3 months (other than non-melanoma skin cancer or long-term hormonal treatment for common 
cancers such as breast and prostate if disease is stable; 3) Weight greater than 330 pound (weight capacity of 
the Wii balance board); 4) History of photosensitive seizures; 5) Any condition or disorder that would impede 
safe participation as directed; and 6) Plans to relocate outside the area during the study period or unable to 
fully participate. 

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Section 4.0 Registration Procedure 
Random Assignment. Randomization will be implemented after consent and before surgery. A random 
number table generated by our statistician will assign the participant to the IIG, WCG, or ACG. Blocking factors 
in the randomization scheme include participant’s age (< 65 or > 65 years) and functional capacity level 
(6MWT distance > 452 meters). 
 
Blocking Factors in the Randomization Scheme. Randomization will be implemented after consent and 
participants will be assigned to IIG, ACG, or WCG. This gives all participants an equal chance of being 
assigned to one of the three study groups. Blocking factors used successfully in the randomization scheme of 
our two-arm RCT (R21 CA164515) include the participant’s age (< 64 years or > 65 years) and functional 
capacity level (those that achieve six minute walk test [6MWT] distance > 452 meters). This is based upon the 
work of our oncology exercise consultant, Dr. Lee Jones, who found for persons with NSCLC that the 6MW 
distance provides important objective prognostic information relative to survival in that 452 meters was found to 
be the minimum distance achieved for those in the high capacity functioning group. 
 
 
 
 
Screening and Registering Participants. For prospective participants scheduled to undergo surgery for 
suspected NSCLC, the cardiothoracic surgeon’s office will: 1) Inform prospective participants about the 
availability of the study. 2) Provide prospective participants with an approved informed consent document and 
brochure that provides information about the study. 3) Provide prospective participants with information about 
contacting Dr. Hoffman for further information about the study and enrollment. 4) Obtain permission from the 
prospective participant for Dr. Hoffman to contact them if they wish for more information about the study. If the 
participant is eligible to participate in the study, the Dr. Hoffman or the nurse recruiter will give a copy of the 
informed consent form and an approved recruitment brochure providing an overview of the study. Potential 
participants will be given the opportunity to enroll when meeting with Dr. Hoffman or the nurse recruiter after 
given time to go through the consenting process and know they want to participate or they may elect to take 
the information home and decide at a later time. The consenting process includes time for patients to read over 
the consent document and ask questions prior to making any decision about participation. Contact information 
for the nurse recruiter will be provided as well. This will give the potential participant the ability to consider 
participation in the study out of the clinical environment. The nurse recruiter will call the potential participant at 
home to answer any questions and assess interest in participation after time is given to the potential participant 
to read and review material provided. If the potential participant expresses interest in participation either when 
initially presented the opportunity or after they have gone home, the nurse recruiter, will either begin the 
consenting process and enrollment or schedule a meeting to begin the enrollment process with both occurring 
in a designated private conference room at the participant’s convenience. Potential participants will be 
informed both verbally and in writing that participation is entirely voluntary and they may refuse to participate 
and withdraw from the study at any time. Potential participants will be assured that refusal to participate will in 
no way alter the quality of usual health care they receive. The patient will receive a copy of the consent with 
their signature. The study brochure provides the participant with the ability to contact the Principal Investigator 
to discuss participation in the study and to let the study team know that they are not interested in participating. 

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Section 5.0 Research Design 
5A) Introduction to the Research Design of Proposed Project 
We propose a three-arm, repeated measures RCT for persons undergoing NSCLC surgery as shown in Fig 8. 
The design provides for efficacy comparisons of outcome measures among the immediate (exercise) 
intervention group (IIG), the wait-list control group (WCG) usual care, and the attention control group (ACG) by 
age after 6 wks (Aim 1) through the measurement of primary and secondary outcomes. The design also 
provides for evaluation of the timing of the intervention (Aim 2) by comparing study outcomes of the IIG’s wks 
1-6 with those of the WCG’s wks 7-12 by age to account for time since surgery. Note that the timing of the data 
collection occurs near the time of the assessment during the week when the assessment is conducted. For 
example, if a participant has an unexpected visitor at their home and would like to have the data collector call 
the next day, then the data collector may call the next day. Unlike mice or non-human studies, we need to 
balance absolute timing against the needs of our human participants so we incorporate some flexibility 
required of our human participants when collecting data. Determining optimal timing to initiate an exercise 
program for post-surgical NSCLC patients is needed. We chose to start the WCG intervention at 6-wks post-
hospital discharge based on Leach et al.’s113 findings that 43% of the 66 postsurgical NSCLC patients in their 
study preferred to start an exercise program during adjuvant treatment. Also, 
adjuvant treatment (radiation and/or chemotherapy) commonly begins 4-10 wks after surgery, with nearly 30% 
of patients undergoing adjuvant treatment.114 Sustainability of the intervention (Aim 3) can be determined by 
offering the IIG the option to extend their exercise to 12 wks and calculating the percent that elect to extend, 
assessing acceptability, adherence, and retention while measuring primary and secondary outcomes for 
efficacy. Adverse events will be monitored to provide for safety (R21 RCT reported no adverse events). 
 
5B) Setting & Sample. The target sample will be recruited in 5 sites. We will continue the working 
relationships we built while conducting our R21 RCT with Spectrum Health, McLaren, and Sparrow Health. 
We will add Munson Healthcare and Nebraska Medicine Campus. Results from our R21 RCT show very 
large effect sizes between the exercise and usual care groups that are not expected to hold in this proposed 
study as we have additional sites with more diverse populations and two new study arms (ACG and WCG). 
Our sample size assessment for primary Aim 1 uses the expected CRF severity scores by age group shown 
in Table 1 (below) with CRF estimates from our R21 RCT for comparison. An exemplar multiple regression 
model was run with age distribution approximating the NSCLC population with 33% < 65 yrs and 67% > 65 yrs, 
model error standard deviation (SD) = 2.0. Comparable R21 results suggest a SD between 0.7 and 2.6 in 
these two age groups. With overall significance level at 5%, we computed the total sample size N to ensure at 
least 80% power in 4 pre-specified comparisons between IIG and ACG for ages <65 and > 65. With N = 180 
(60/group, 20 <65 yrs and 40 > 65 yrs) power to detect the expected CRF is shown in Table 2 (below) with the 
minimum sample size for each comparison. Based on our R21 RCT and previous cancer work,115 we will over- 
recruit to account for a conservative attrition rate of 20% (N = 225 = 180/0.8), and under plausible 
assumptions,116,117 conservatively provide for 90% compliance increasing for a total of N = 279 ≈ 
225/(0.9)(0.9)117 patients. 
 
 

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5C) Study Protocol 
 
The following protocol was used successfully in our R21 RCT with the addition of the WCG and ACG in the 
proposed study. Participants scheduled for NSCLC surgery will be identified by the surgeon’s office 
prior to surgery, recruited, and enrolled by the nurse recruiter. 
5C1) Study Interventions. 
 
5C1a) The exercise intervention is designed to promote regular, light-intensity walking and balance exercise 
< 3.0 metabolic equivalents (METs), which corresponds to usual activities of daily living.118 Combining walking 
with balance exercises has been found to have a positive effect on balance, and walking confidence and 
speed.119,120 Participants will perform warm-up exercises designed for this patient population. Walking should 
be comfortable and self-paced (e.g., they can stop instantly at any time unlike a treadmill). The Wii Fit Plus 
provides a virtual environment where the participant sees themselves, friends, and even their dog walking on a 
sunny day next to a stream, through a village with happy, familiar faces offering encouragement. As they walk 
in place in their home, they will see themselves taking a corresponding step in the virtual environment. We 
followed the American College of Sports Medicine (ACSM),37,80,82,121 American Heart Association (AHA),122 and 
American Cancer Society (ACS)79,83 principles of exercise prescription for duration (6 wks) and dosage (5 min 
increase per wk) for safe exercise prescription. Duration of walking will start at 5 mins/day, 5 days during wk 1, 
and will build by 5 mins/day each week with the goal of walking 30 mins per day during wk 6 (Appendix A1). 
Increase in walking duration will be assessed by the exercise nurse intervener at the start of each week. 
Duration will be increased 5 mins each week if participant’s PSE for attaining that duration is >70% on a 
0-100% scale (100% = high PSE).121 Gradually increasing walking duration promotes achievement of exercise 
goals, building PSE for CRF self-management and walking. Incorporating feedback from our R21 RCT, 
participants who can achieve a minimum of 10 mins continuous walking will be given the option to use the Wii 
or walk outside or at a place of their choice (mall, gym) to achieve their walking prescription. Participants will 
also perform Wii Fit-Plus balance exercises 5 days/wk for wks 1-6 (Appendix A1). Participants will self-select 
from a menu of predetermined Wii balance exercises, with each exercise taking less than 3 mins to complete. 
Balance exercises use a gaming format and scoring systems as motivation to improve performance. Exercises 
include downhill skiing, soccer, golf, and video game activities. Exercises use competitive and engaging 
formats, keeping users captivated so they forget they are exercising. Exercises provide encouragement that 
participants can partake in hobbies in which they may have thought they could never participate again. 
Participants will wear a pedometer to record their total steps/day. Pedometers will not be worn during exercise 
so non-intervention activity can be compared with the activity of the ACG and wks 1-6 of the WCG. Data are 
recorded in participant’s Daily Diary (Appendix A2). IIG participants receive the exercise intervention during 
wks 1-12 post-surgery and WCG participants will receive usual care, which is standard medical care from 
health providers for 6 wks after hospital discharge followed by the exercise intervention during wks 7-12. 
Safety: Inclusion criteria require that participants have phone access while exercising, should participant need 
assistance. Participants are provided safety criteria in the Daily Diary prior to start of each exercise 
intervention. Participants are taught to maintain a light-intensity dose of exercise by: 1) using portable pulse 
oximeter to ensure heart rate < 60% of heart rate reserve;37,80 2) ensuring perceived level of exertion is <3 on a 
scale of 0-10;37,79,80 and 3) ensuring they can talk and sing while exercising (Talk Test).37,80,121,123 Participants 
will document any symptoms/problems that occur during exercise intervention and any action taken in Daily 
Diary, for review by nurse. Nurse will be available by phone and can make a home visit to ensure participant 
safety. Note that no safety issues were reported in either the single-arm or the R21 RCT. 
 
5C1b) The attention control intervention is designed to provide general supportive cancer-related education 
that is not directly related to treating CRF. The following booklets published by the NCI will guide the delivery of 
planned, educational content, delivered weekly by the ACG nurse intervener as prescribed using the protocol 
in Appendix A3: 1) What You Need to Know About Lung Cancer; 2) Taking Time: Support for People with 
Cancer; and 3) Care for the Caregiver. The ACG participants will be matched to the IIG participants in the 

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exercise intervention in terms of frequency of visits (1 visit per wk); duration of visit (about 10 mins); and social 
interaction (one-on-one instruction from a nurse). Each booklet will be used over a 2-wk period with calls about 
10 mins. Nurse and patient will be given copies of each NCI booklet and phone scripts for each visit (Appendix 
A3). Highlights of each booklet will be pointed out following the script. While there is a sentence recommending 
exercise as a way to treat fatigue, and discussion on general nutrition provided in the “Taking Time: Support for 

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People with Cancer” brochure, fatigue and general nutrition will not be reviewed in the ACG intervention. 
Reading this recommendation is equivalent to what many health care providers tell their patients to do 
providing a systematic suggestion while our intervention is being tested over and above this suggestion. 
 
5C2) Study Procedures. IIG participants will have baseline data collected by the nurse recruiter. Following 
principles of transitional care,124 the exercise nurse intervener will engage the participant using protocol in 
Appendix A4 in the hospital post-surgery to review the exercise intervention and teach PSE-enhancing CRF 
self-management education (Appendix A5) that uses National Comprehensive Cancer Network Guidelines.125 
To ensure continuity, a primary nurse will be assigned to each participant. Data collectors will contact IIG by 
phone within approximately 24 hrs of discharge to collect data (if too ill, re-scheduled within approximately 3 
days of discharge) and at approximately the end of each week for 6 wks. The nurse will make a phone visit 
within approximately 24 hrs of post-surgical discharge to screen participant’s readiness to start exercise. 
Participants will be deemed ready to start if usual level of severity for key symptoms of pain, nausea, and 
dyspnea are rated < 4 on an 11-point scale (0-10, 10 = most severe). If participant is ready to exercise, a 
home visit will be scheduled to start exercise within approximately 4 days of discharge. 
When severity of a key symptom is rated > 4, nurse will intervene and contact participant’s surgeon’s office for 
recommendations. The nurse will repeat this step each day until participant is ready to start exercising. Once 
participant is ready, nurse will arrange home visit within approximately 3 days. The initial home visit will 
include connecting Wii to pariticipant’s TV, setting up Wii FitPlus log on password, teaching exercise 
intervention, and reinforcing CRF self-management education and exercise safety precautions. The nurse will 
follow-up with phone visit within approximately 24 hrs to answer questions and concerns, make a follow-up 
home visit at approximately the start of wk 2 of exercise, phone visits at approximately the start of wks 3-6, 
and additional visits per participant request. During visits, nurse will review IIG participant’s Daily Diary 
(Appendix A2) with participant and provide PSE-enhancing CRF self-management interventions (Appendix 
A6). These PSE-enhancing interventions include providing mastery and/or vicarious experiences; social 
encouragement; and reinterpretation of physical and psychological symptoms to support exercise program to 
adjust exercise prescription per guidelines. Participant uses Daily Diary to record weekly exercise activity and 
exercise-related symptoms or issues. IIG participants will be given the option to extend exercise for another 6 
wks to study wk 12. Data collection will continue on a weekly basis, culminating with a 6MWT at end of 
approximately wk 12. Nurse calls will continue weekly to prescribe balance exercises and advance walking 
prescription 5 mins each week, with goal of achieving minimum 30 min/day. Participants may extend beyond 
30 min/day with rate of increase no more than 5 min/day each wk, with participants’ PSE for attaining that 
duration > 70% on a 0-100% scale (100%=high PSE) (Appendix A1). 
 
5C2a) WCG participants will have baseline data collected pre-surgery by the nurse recruiter and receive a 
pedometer and instructions for recording total steps/day in Daily Diary (Appendix A7). The WCG nurse 
intervener (nurse) will visit in the hospital post-surgery to review study trajectory. Research staff will contact 
WCG by phone within approximately 24 hrs of discharge to collect post-surgery data (if too ill, data collection 
rescheduled within 3 days of discharge). Research staff will perform phone visits using protocol in Appendix 
A8 at the approximate end of wks 1-6 to control for staff interaction and data collection. During wk 6, an 
exercise nurse intervener will make a phone visit to screen participant’s readiness to start intervention as 
described for IIG participants. Once participant is ready to start, nurse will arrange home visit within 
approximately 3 days. The exercise intervention and procedures will be identical to those received by the IIG 
group during wks 1-6. Staff contact WCG by phone (if too ill, data collection re-scheduled within approximately 
3 days) to collect data at the end of approximately wks 7-12. 
 
5C2b) ACG participants will have baseline data collected pre-surgery by a nurse recruiter and receive a 
pedometer and instructions for recording total steps/day in Daily Diary (Appendix A7). The ACG nurse 
intervener will visit in the hospital post-surgery to review study trajectory, make a phone visit within 
approximately 4 days of post-surgical discharge to initiate the ACG intervention (Appendix A3), and make 
phone visits at the start of approximately wks 2-6. During visits, the nurse will deliver the ACG intervention. 
Data collectors will contact ACG by phone within approximately 24 hrs of hospital discharge (if too ill, re-
scheduled within approximately 3 days of discharge) and at the approximate end of each week for 6 wks to 

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obtain outcome measures. 

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5C3) Protocol Fidelity. Protocol fidelity will ensure consistency in design, dose, training, delivery, receipt, and 
enactment of the intervention (detailed procedural protocols in Appendix A3, A4).126,127 Design Fidelity. The 
intervention was designed based on tested Principles of the Transitional Care Model,40-42,64 and a tested 
theoretical framework, the Theory of Symptom Self-Management. Adherence to the theoretical underpinning 
will be evaluated by the PI through monthly team meetings and the use of intervention guidelines and protocols 
to include: Efficacy-Enhancing CRF Self-Management Intervention Guidelines (Appendix A6); Nurse Intervener 
Study Protocol for the IIG, ACG and WCG (Appendix A3, A4); and their respective Daily Diaries (Appendix A2, 
A7). A monthly team meeting will be held by the PI on use of these guidelines and protocols. Dose Fidelity. 
Dose of the intervention was designed following the principles of exercise prescription via the ACSM,37,80,82,121 
AHA,122 and ACS.79,83 Dose of the intervention for the IIG and WCG is defined in the Exercise Prescription 
Guidelines (Appendix A1). Likewise, dose of the ACG will be matched to the IIG in frequency, duration, and 
social interaction. The PI will train the interventionist on dosage and the IIG and WCG Daily Diaries and ACG 
Telephone Script Logs (Appendix A3) will be evaluated on a monthly basis. Training Fidelity. Initial orientation 
with standardized training manuals will be used to ensure the required skill level of the interventionists. 
Quarterly meetings will be led by the PI to maintain knowledge and prevent drift from original protocol. 
Delivery Fidelity. Weekly interventionists’ IIG and WCG logs and ACG logs documenting intervention delivery 
will be peer reviewed to standardize delivery and ensure protocol adherence. Logs and corresponding audio 
tapes will be randomly selected on a quarterly basis to ensure adherence with feedback provided regarding 
performance. Logs and tapes will be used to generate case studies for review in monthly team meetings. 
Receipt Fidelity. Daily Diaries for the IIG and WCG will be used to assess participant’s completion and 
understanding of the intervention as intended (Appendix A2). The script checklist documenting date, time, and 
minutes spent by the nurse with the ACG participant will document receipt of the intervention as intended 
(Appendix A3). Interventionist will review Daily Diaries and recorded prescriptions weekly (via a checklist) with 
the participant to ensure that the participant was able to understand the prescribed treatment activities. 
Enactment Fidelity. Interventionists will assess the level of intervention achieved on a weekly basis by the 
participant through the review of the participant’s Daily Diary that documents exercise completed to ensure the 
participant performed the intervention per prescription. 
 
Section 6.0 Measurement of Effect 
 
As earlier stated following our Specific Aims and Hypothesis, based on existing evidence,72-75 results of our 
single-arm pilot (no control group)76,77 and two-arm R21 RCT,23 we expect the benefits of this study to confirm 
that post-surgical NSCLC patients will find the exercise intervention effective in reducing CRF severity and 
fatigability (functional capacity). Further, we expect the exercise intervention group will outperform the attention 
control and wait-list control groups by age for other symptoms’ severity; PSE for CRF self-management; PSE for 
walking; PSE for balance; functional performance; and QOL. We expect the wait-list exercise intervention group’s 
CRF severity and fatigability to improve, but not as significantly as the immediate exercise intervention group. 
We also expect >50% of the immediate exercise intervention group to extend 6 more wks, with adherence and 
retention rates of >70% at wk 12, with improved primary and secondary outcomes at wk 12. 
 
Section 7.0 Study Parameters 
Measures for Aims 1-3. Aim 1 - Measurement IIG v. ACG and IIG v. WCG Comparisons. Table 3 depicts main 
study variables and corresponding measures embedded in the concepts of the theoretical framework in Fig 1 
(see measures Appendix B1-B9). All measures are administered to all participants using the schedule in Table 
3. Participant characteristics as depicted in Table 3 describe the sample. Age is a key biological variable. Given 
that lung cancer and CRF are significant problems for persons of all ages, and an exercise intervention must be 
applicable to patients of all ages, study variables will be analyzed for participants by age (< 65 and > 65). Also, 
this study includes men and women as lung cancer is the second most common diagnosed solid tumor with CRF 
a common symptom for both.128 All primary and secondary outcome measures have well established 
psychometrics, both validity and reliability, with internal consistency scores reported in Table 3 for the cancer 

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population including use in post-surgical NSCLC.23-24 All measures were used successfully in the R21 RCT 
without participant complaint about burden. The Karnofsky Performance Scale provides functional impairment 
classification, universally used in oncology, and is scored from 0% (dead) to 100% (no complaints).129 
 
Primary outcome measures include the Brief Fatigue Inventory (BFI) and Fatigability as shown in Table 3 
(below). The BFI measures CRF severity and its impact on daily life on an 11-pt scale (0-10, 10=most 
severe).23,76,108 Fatigability will be measured using the 6-min walk test (6MWT), which is a measure of sub- 
maximal functional capacity. It has been used successfully in persons before/after lung resection for 
cancer.23,75,76,130 Following the American Thoracic Society Guidelines,131 the 6MWT is relevant to measuring 
functional capacity to perform everyday activities.132,133 After completing the 6MWT, participants will be asked 
their average fatigue level during 6MWT using the Borg Scale.131 Fatigability will be calculated by dividing 
average level of fatigue by average 6MWT walking velocity measuring degree of fatigue associated with 
performing everyday activity. 
 
Secondary outcome measures are described in Table 3 (below) and include the following: M.D. Anderson 
Symptom Inventory Lung Cancer Module measures severity of 16 symptoms and symptoms interference on 
daily life on an 11-pt scale (0-10, 10= most severe and most interference).92,111 Perceived Self-Efficacy for 
Fatigue Self-Management Instrument (developed/tested by Principal Investigator) measures perception of 
ability to manage fatigue on an 11-pt scale (0-10, 10 = very certain).23,109 Self-Efficacy for Walking Duration 
measures a person’s perception to complete incremental 5-min periods of walking;23,134 and the Activities- 
Specific Balance Confidence Scale measures a person’s perception of balance during every day 
activities,23,135,136 using an 11-pt scale (0-100%, 100%= very confident). Daily Diary is a weekly diary that 
provides a structured design for participants to record their weekly exercise prescription and daily performance. 
All 72 two-arm R21 RCT participants used the Daily Diary to record their daily study-related physical activity 
including number of steps recorded (pedometer).23,137-140 Pedometers are valid and reliable measures of 
functional performance.141,142 Medical Outcomes Short Form-36 version 2.0 is a widely used measure with 
eight subscales that focus on physical and mental health components of functional performance. Subscale 
scores are linearly transformed, producing normative scores (0-100, 100 = higher functional status).23,112 Quality 
of Life Index Cancer version III measures level of satisfaction and importance of aspects of a person’s life 
producing an overall QOL score, with four domains: health and functioning; family; socioeconomic; and 
psychological and spiritual. Uses a 6-pt rating scale (1-6, 6 = very satisfied and very important).92,143 
 
Revision is underlined added on May 19, 2019: This includes the addition of three tools as follows in 
order. A revised Cover Page of the evaluations [Measurement Material] for the study is included to reflect 
this change. 
 
1) Added the Appendix 14: PROMIS Item Bank v 1.0 Sleep-Related Impairment-Short Form 8a. 
 
Justification: To assess sleep related-impairment since sleep disturbance is a frequent and severe symptom 
in the lung cancer population, found in the NIH, NCI R21 student that led to this current NIH, NCI R01study. 
For the duration of study participation, measurement will occur with participants pre-surgery, post-surgery, 
weeks 3, 6, 9, and 12. A summed score is calculated on 8 items taking 2 minutes to complete. The Sleep- 
Related Impairment-Short Form 8a has been psychometrically tested with internal consistency reliability at 
0.90 upwards. A copy of the tool is provided in this revision. 
 
2) Added the Appendix 15: Brief Pain Inventory (BPI). 
 
Justification: To assess pain since pain is highly correlated with cancer-related fatigue. The Brief Pain 
Inventory is a companion to the Brief Fatigue Inventory Tool and was used in the parent National Institutes of 
Health (NIH), National Cancer Institute (NCI) R21 study conducted by the Principal Investigator, Dr. Amy Jude 
Hoffman, that led to this current NIH, NCI R01 study. The BPI is brief as the title indicates, taking 5 minutes to 
complete, focusing on the severity of pain, impact of pain on daily living, sources of pain, pain 

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treatments/medications and amount of pain relief in the past 24 hours. For the duration of study participation, 
measurement will occur with participants pre-surgery, post-surgery, weeks 3, 6, 9, and 12. The tool has been 
psychometrically tested with internal consistency scores ranging from 0.77 to 0.91. A copy of the tool is 
provided in this revision. 
 
3) Added the Appendix 16: Perceived Self-Efficacy for Pain Self-Management Inventory (PSEPSM). 
 
Justification: To assess the certainty in performing pain-managing behaviors. The PSEPSM was used in the 
parent NIH, NCI R21 study that led to this current NIH, NCI R01 study. The PSEPSM Instrument is a self- 
report measure containing 6 items related to the certainty in performing pain-managing behaviors that takes 3 
minutes to complete. On an 11-point scale (0-10, 10 = very certain), respondents rate their certainty in 
performing pain-managing behaviors. For the duration of study participation, measurement will occur with 
participants pre-surgery, post-surgery, weeks 3, 6, 9, and 12. The PSEPSM has been psychometrically tested 
developed by the Principal Investigator, Dr. Amy Jude Hoffman, based on the Perceived Self-Efficacy for 
Fatigue Self-Management Tool with internal consistency of 0.92 in the surgical lung cancer population. A copy 
of the tool is provided in this revision. 
 
Note: In Table 3, a schedule is provided for collection of data. All time points such as Pre- & Post-
surgery and Weeks 1 – 12 are collected approximately at this time point. 
 
Table 3. Main Concepts, Variable, Measures, Collection Schedule, and Measurement Objective 
 

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Revision 5/19/2019. Updated Table with the following 3 measures added. 
 
Table 3. Main Concepts, Variable, Measures, Collection Schedule, and Measurement Objective 
 
Concept 
Variable 
Measure # Items 
Schedule 
Measurement Description 
(Cronbach’s alpha) 
Symptoms 
Sleep Impairment 
PROMIS v 1.0 Sleep-Related 
Impairment Short-Form 8a (8 
Items) 
Pre & Post- 
Surgery 
Weeks 3, 6, 9, 12 
Degree of sleep-related 
impairment. (0.90) 
Symptoms 
Pain Source, Pain 
Treatment, Severity and 
Interference Information 
The Brief Pain Inventory (4 
Severity Items; 7 Interference 
items; 4 Source Items) 
Pre & Post- 
Surgery 
Weeks 3, 6, 9, 12 
Degree of pain severity and 
impact of pain on every day. 
living. (0.77 to 0.91) 
Perceived Self- 
Efficacy 
Pain Self-Management 
The Perceived Self-Efficacy for 
Pain Self-Management 
Inventory (6 Items) 
Pre & Post- 
Surgery 
Weeks 3, 6, 9, 12 
Degree of pain self- 
management. (0.90) 
 
 
Aim 2 – Measures – WCG Delayed Intervention. At the start of wk 7, WCG will begin the intervention, 
concluding at  wk 12. Aim 1 study variables and measures (Table 3) will be analyzed for Aim 2 for wks 7-12 to 
compare with the IIG wks 1-6 outcomes. 
 
 
Aim 3 – Measures – IIG Intervention Sustainability. At the start of wk 7, IIG participants will be given the 
option to extend the intervention an additional 6 wks. We will measure the extension rate as % participants who 
elect to extend. Adherence to the intervention will be measured as % participating in the intervention who 
adhered to prescribed intervention. Weekly adherence will be calculated by taking number of times prescribed 
intervention was completed divided by total number of interventions prescribed for week. These data are 
recorded in the Daily Diary and will be confirmed by research staff reviewing recorded data in Wii Fit-Plus. 
Retention, measured as part of sustainment, will be calculated as % who elected to extend 6 wks who completed 
final data collection at wk 12. Based on our conceptual definition of sustainability, we will measure the extent 
to which components of the intervention were rated acceptable for continued use by participant. Acceptability 
will be measured at end of wk 6 and 12 using a 15-item Acceptability Questionnaire (Appendix B1) using a 
numeric scale (1 to 6: 6 = agrees strongly) with higher scores indicating greater acceptability of the exercise 
program. The Questionnaire has a Flesch-Kinkaid 6th grade reading level and was successfully used in our R21 
RCT and allows participants to rate how well barriers and facilitators to exercise are addressed. Open-ended 
questions provide further input.23,24 Efficacy will be measured using the same study variables and measures 
analyzed in Aim 1 (Table 3) for wks 7-12. 

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Section 8.0 Drug Formulation and Procurement 
Not applicable. This study is not a pharmaceutical trial. 
 
 
 
Section 9.0 Toxicity and Adverse Event Reporting Guidelines 
Study Monitoring 
 
The Principal Investigator of the study will monitor for all potential unanticipated problems that may involve risk 
to participants and will report adverse events (unanticipated problems), including serious adverse events in 
accordance to institutional policy. Continuous, close monitoring will occur in several ways. First, adverse 
events identified during implementation of the intervention are monitored through the nurse who assesses the 
participant on a weekly basis either by home and/or phone visit utilizing the Daily Diary. The nurse documents 
any adverse event reported by the participant and immediately reports the occurrence to the Principal 
Investigator. In addition, the Principal Investigator will monitor participants’ Daily Diaries for adverse events 
and specifically, as it relates to Section 9.0 of this application, any and all adverse events will be reviewed, 
evaluated, and documented. Using a consultative approach, Dr. Hoffman, the Principal Investigator, will ensure 
reporting of results from the data and safety review to the transdisciplinary team of Co-Investigators and Key 
Consultants occurring two times a year and more frequently when deemed necessary for the health and safety 
of participants. 
 
Note: All 72 two-arm R21 RCT participants used the Daily Diary to record their daily study-related physical 
activity including number of steps recorded (pedometer).23,137-140 used successfully in the R21 RCT without 
participant complaint about burden. Note: In the R21 RCT, no adverse events were reported; participants had 
a mean age of 67 with a mean of 8 comorbid conditions. The Daily Diary is structured with an area for 
participants to report experiences related to problems or symptoms during or after exercising. This format of 
reporting adverse events is supported in the literature and discussed in the Study Protocol in the Research 
Design Section (Section 5.0) and Study Parameters Section (Section 7.0).139 The nurse will review the Daily 
Diary once a week with the participant and more if necessary to evaluate for potential adverse events. 
Providing the participant with a means to record problems/symptoms (possible adverse events) will help the 
participant to develop skills to recognize CRF and other symptoms and effectively develop skills to interpret 
changes in symptoms and physical functioning.67 Likewise, as the participant records the solution to the 
problems or symptoms (possible adverse events), the participant is building a personal database of health 
problems and solutions to draw from in the future which enhances their PSE for CRF self-management.67 
DeNijs and colleagues138 reported in a systematic review of the general cancer population that persons with 
CRF did not adhere to an exercise regimen since they no longer felt certain about their bodies and needed 
support in order to self-manage fatigue. Thus, the nurse can enhance PSE to self-manage CRF through 
means of monitoring and interpreting symptoms using the diary to problem solve to make decisions regarding 
the effect of exercise on CRF and other outcomes. In addition, the Daily Diary outlines the safety procedures 
for the participant to follow before each exercise session. Moreover, the participant will have phone access 
seven days a week to contact the nurse should the participant identify or need support in managing problems 
or symptoms during or after exercising. 

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Auditing 
Auditing is a systematic and independent examination of trial-related activities and documents to determine: 
• whether the evaluated trial-related activities were conducted 
• the data were recorded, analyzed, and accurately reported, according to the protocol, to the 
sponsor's SOPs, GCP, and applicable regulatory requirement(s). 
 
Auditing is a Quality Assurance, one point snapshot of one subject. 
 
This study will undergo audit on at least a quarterly basis by the UNMC Fred & Pamela Buffett Cancer Center 
Audit Committee. 
 
Detailed policy and procedures for this section may be reviewed at: 
https://www.unmc.edu/cancercenter/clinical/prms.html 
 
FRED & PAMELA BUFFETT CANCER CENTER DATA AND SAFETY MONITORING COMMITTEE (DSMC) 
REPORTING 
 
In its initial review, the DSMC will make a recommendation for the frequency of DSMC monitoring based on an 
assessment of risk associated with study-associated therapy, per the DSMC policy. 
 
All adverse events grade three or higher (expected or unexpected, regardless of attribution) will be reported to 
the University of Nebraska Medical Center, Fred & Pamela Buffett Cancer Center DSMC in accordance with 
DSMC guidelines. 
 
An adverse event (AE) is defined as any untoward medical occurrence in a subject or clinical investigation 
subject participating in a clinical trial, which does not necessarily have a causal relationship with protocol 
specified therapy. An adverse event can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of any investigational 
therapy/device or intervention, whether or not the event is considered causally related to the use of the 
product. 
 
Any worsening of a pre-existing condition or illness is considered an adverse event. Laboratory abnormalities 
and changes in vital signs are considered to be adverse events if they result in discontinuation from the study, 
necessitate therapeutic medical intervention, meet protocol specific criteria and/or if the investigator considers 
them to be adverse events. In general, if a laboratory abnormality or change in vital sign is associated with a 
specific diagnosis that is being reported concurrently as an adverse event the findings that support the 
diagnosis do not need to be reported as separate adverse events unless the investigator feels it is appropriate. 
 
Treatment-emergent Adverse Event: Treatment-emergent adverse event is defined as any adverse event with 
onset or worsening from the time of trial intervention until 30 days after the final protocol specified intervention. 
 
Serious Adverse Event: A serious adverse event is one that at any dose (including overdose) and regardless of 
causality that: 
• Results in death 
• Is life-threatening 1 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 2 
• Is a congenital anomaly or birth defect 
• Is an important medical event 3 

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1. “Life-threatening” means that the subject was at immediate risk of death at the time of the serious adverse 
event; it does not refer to a serious adverse event that hypothetically might have caused death if it were more 
severe. 2. “Persistent or significant disability or incapacity” means that there is a substantial disruption of a 
person’s ability to carry out normal life functions. 3. Medical and scientific judgment should be exercised in 
deciding whether expedited reporting is appropriate in situations where none of the outcomes listed above 
occurred. 
 
Important medical events that may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the patient or may require intervention to prevent one of the other outcomes listed in the 
definition above should also usually be considered serious. 
 
Attribution of AE/SAE: The investigator will determine the likelihood of relationship of the AE to the study based 
on the following definitions: 
 
Not related: The subject was not exposed to the study treatment or another cause is obvious. 
Probably not related: The AE is most likely explained by another cause, and the time of occurrence of the AE 
is not reasonably related to the study. 
Possibly related: Study treatment administration and AE occurrence reasonably related in time, and the AE is 
explained equally well by causes other than study treatment, or treatment administration and AE occurrence 
are not reasonably related in time, but the AE is not obviously a result of other causes. 
Probably related: Study treatment administration and AE occurrence are reasonably related in time, and the 
AE is more likely explained by study treatment than by other mechanisms. 
Definitely related: The occurrence and timing of the AE are clearly attributable to the study treatment. 
 
AEs will be collected from the time the subject signs the consent form until 30 days after the final protocol 
specified intervention. All AEs will be followed until resolution or a cause is identified. AEs judged by the 
investigator as not related or probably not related to the treatment will NOT be followed beyond the end of the 
study. 
 
Section 10.0 Statistical Considerations 
 
Statistical Analysis. All tests of hypotheses will be two-tailed at alpha=0.05. We compare groups at baseline 
using parametric and non-parametric tests to assess equivalence of confounding physiological and contextual 
patient characteristics, and pre-surgical outcome variables. If substantive differences exist, they will be 
controlled for in subsequent analyses by regression techniques, guided by the degree of dissimilarity rather 
than strict statistical significance.144 
 
Primary analysis (Aim 1) is the comparison among study groups of the primary outcome CRF severity and 
fatigability assessed at approximately 6 wks post-surgery. Analysis is based on a regression model for both 
CRF scores with the following variables in the regression equation: baseline CRF, study group, age, and (if 
appropriate) plausible interaction between these variables. We test association of study group with outcomes. 
 
In Aim 2 our hypothesis comparing outcomes in IIG and WCG by age group will be addressed in the context of 
a longitudinal analysis. There are 6 time-ordered differences between IIG and WCG. We use generalized linear 
(mixed) models to allow flexible correlation structures in the repeated measures.145,146 Our regression equation 
has in addition to the aforementioned variables: time (week) of assessment, and critically, study group with 
time interactions. The model allows us to test if group effects are changing over time – referred to as a 
“parallel” profile analysis.147 If the hypothesis is supported, we test whether that average profiles (over time) in 

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the two groups are the same. Aim 3 concerns three binary responses in the IIG group at 6 wks: extension, 
retention, and adherence. Logistic regression models will be used to assess the influence of explanatory 
variables on the likelihood of outcome.147-149 
 
Secondary Outcomes: An analogous strategy is applicable to continuous outcomes assessed at 12 wks. We 
will use linear models with the caveat that models are conditional on electing to extend participation. Statistical 
analysis will include intent-to-treat (ITT) analysis and per protocol analysis.150,151 ITT principle calls for making 
inference on the whole sample, with patients as randomized to their study group.152 To address missingness in 
our response data we will explore strategies for imputation.153 The techniques described above allow missing 
at random (MAR). Inverse-probability weighting154 will be investigated to accommodate missing data patterns 
that are not MAR. Assurance of analysis robustness and minimization of bias: We use a range of outcome 
measures based on the patient-centered principle to ensure the relevance of the study both biologically and 
practically. To enhance reproducibility, we will ensure protocol fidelity and follow our analytic plans, including 
addressing missing data in outcomes. To minimize analysis bias, we will adjust for factors such as potential 
between group unbalance and examine the robustness of our conclusions under deviations of model 
assumptions. 
 
Note: Determination of Sample Size is discussed under the Research Design (Section 5, specifically, 
Section 5B) 
 
TIMELINE. The research timeline is shown in Table 4. 
 
POTENTIAL PROBLEMS AND ALTERNATIVE STRATEGIES. We acknowledge that NSCLC patients after 
surgery may be subject to complications requiring a break from the intervention. Should participants report 
unmanaged symptoms or clinical problems, they will be referred to their health care provider per protocol. 
Should the participant become ill, causing them to miss three consecutive exercise interventions, the 
participant will be instructed to call their nurse, who will reevaluate and adjust the exercise prescription per 
protocol. Should the primary nurse intervener become ill or unable to meet with participant, a pre-assigned 
secondary nurse intervener will step in. There could be diffusion of treatment effects between IIG, WCG, and 
ACG as well as confounding effects if a disproportionate number of physically active participants are assigned 
to the IIG, WCG, or ACG. We will assess functional capacity levels and use block randomization to minimize 
these effects. 
 
 
 
 
 

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Page 29 of 39 
 
Section 11.0 Records to be Kept 
 
The records described in “Table 3. Main Concepts, Variable, Measures, Collection Schedule, and 
Measurement Objective” will be kept. Likewise, data from the forms will be entered electronically into a study 
database and secured according to Institutional Review Board standards at the University of Nebraska Medical 
Center. 
 
 
Section 12.0 Patient Consent 
The consent form adheres to the guidelines established by the Institutional Review Board of the University of 
Nebraska Medical Center and is pending for IRB Review. 
 
 
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Section 14.0 Data Collection Forms 
Submitted as a separate document. 
Revision: 5/19/2019: 
The following three forms are submitted as the added Data Collection Forms. These forms are added to the 
Appendices Cover Page: 
 
1) Appendix B14: Sleep Related Impairment – Short Form 8a 
2) Appendix 15: Brief Pain Inventory 
3) Appendix B16: Perceived Self-Efficacy for Pain Self-Management Instrument