Resiliency Among Older Adults Receiving Lung Cancer Treatment (ROAR-LCT): Physical Therapy and Progressive Muscle Relaxation in Improving Physical Performance and Mood in Older Patients With Stage IIIA-B or IV Lung Cancer Undergoing Treatment
Phase: NA
Conditions: Advanced Lung Carcinoma, Extensive Stage Lung Small Cell Carcinoma, Stage IIIA Lung Cancer AJCC v8, Stage IIIB Lung Cancer AJCC v8, Stage IV Lung Cancer AJCC v8, Stage IVA Lung Cancer AJCC v8, Stage IVB Lung Cancer AJCC v8, Unresectable Lung Carcinoma, Unresectable Lung Non-Small Cell Carcinoma
Sponsor: Ohio State University Comprehensive Cancer Center

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Resiliency among Older Adults Receiving Lung Cancer Treatment (ROAR-LCT) 
Principle Investigator:  
Carolyn Presley, MD, MHS 
Co-Investigators: 
Ashley Rosko, MD 
Erin Bertino, MD 
Dwight Owen, MD 
Greg Otterson, MD 
David Carbone, MD PhD 
Kai He, MD PhD 
Peter Shields, MD 
Barbara Anderson, PhD 
Karen Hock, PT, MS, CLT-LANA 
Amy Compston, PT, DPT, CLT-LANA 
Madison Grogan 
Nicole Arrato 
Stephen Lo 
Brittany Knauss 
Elyse Redder 
Nyelia Williams 
Sarah Janse, PhD 
Christin Burd, PhD & Dan Spakowicz, PhD 
Jason Benedict, MS 
Key Personnel: 
External Collaborators:  
 Scientific Leads: 
Statisticians:   
Protocol/Version/Date:
NCT #: 
Original/ V7 Mar 2021
 NCT04229381

 
 
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Table of Contents 
 
1.0 HYPOTHESIS AND OBJECTIVES…………………………………………….4 
1.1 Primary Objective…………………………………………………………..4 
        
1.2 Hypothesis……………………………………………………………….....4 
2.0 BACKGROUND………………………………………………………………….4 
 
2.1 Lung Cancer in Older Adults…………………………………..............…..4 
 
2.2 Functional Decline + Resiliency …...……………………………………...4 
 
2.3 PT/Relaxation Interventions…………………………………………….….5              
3.0 METHODS………………………………………………………………………...5 
 
3.1 Study Overview …………………………………………………………....5 
 
3.2 Patient selection…………………………………………………...………..5 
 
3.3 Inclusion Criteria...........................................................................................5 
 
 
3.4 Exclusion Criteria………………………………………………………..…6 
 
 
3.5 Informed Consent…………………………………………………………..6 
 
 
3.6 Inclusion of Women and Minorities……………………………………..…6     
4.0 STUDY DESIGN……………………………………………………………….…6 
 
 
4.1 Overview of study design………………………………………………..…6           
 
4.2 Physical Therapy Intervention…….………………………………………..7 
 
 
4.3 Progressive Muscle Relaxation..……………………………….…………...9 
 
 
4.4 Short Physical Performance Battery ………………………….……………9 
 
 
4.5 6 Minute Walk Test………………………………………………….…;....10  
 
4.6 Functional Status Assessments………………………………...………;….10  
 
4.7 PROMIS-10…………………………………………………………….….11  
 
4.8 GAD-7……...……………………………………………………………...11  
 
4.9 PHQ-9…. ……………………………………………………………….…11 
 
4.10 EORTC QLQ-C30 and EORTC QLQ-LC 13………………………….  .11  
4.11 POMS….……….………………………………………………………...12  
4.12 Biomarkers……..………………………………………………………...12 
 
4.13 Toxicities……….………………………………………………………...13  
 
4.14 Disease Response………………………………………………………...14 
 
 
4.15 Virtual Teleahealth …….………………………………………………...14  
 
4.16 Actigraph………….……………………………………………………...16  
 
4.17 Study Compensation ………………………………………………….....16 
 
 
4.18 Potential Risks……………………………………………………..…….16 
 
4.19 Semi-Structured Interviews……………………………………………....17 
 
 
5.0 DATA COLLECTION AND MANAGEMENT……………………………….17 
 
 
5.1 Registration Process ……………………………………………………....17  

 
 
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5.2 Electronic Data Capture…………………………………………………...17 
 
 
 
5.2.1 IPad Survey Administration…………………………………….….17  
 
 
5.2.2 Survey Software and Data Management…………………….…..18  
 
 
5.2.3 Data and Safety Monitoring Plan…………………………….….18  
 
5.3 Baseline Demographic Questionnaire…………………………………….19 
 
5.4 Clinical Data.……………………………………………………………...19 
6.0 STATISTICAL ANALYSIS…………………………………………………….19 
 
 
6.1 Primary Endpoint ………………………………………………………....20 
 
 
6.2 Secondary Endpoint……………………………………………………….20 
 
 
 
6.2.1 Power Calculations……………………………………...……....20 
7.0 CORRELATIVE ANALYSIS…………………………………………...……....21  
 
7.1 Overview ………………………………………………………..….…..…21 
 
7.2 Correlative Analysis Procedures………………………………..………....21 
 
7.3 Statistical Considerations …………………………………...………..…...22 
 
7.4 Obtaining Samples ……………………………………………………......22 
 
7.5 Sample processing ……………………………………………………......22 
8.0 STUDY CALENDAR…………………………………………………….….......24 
9.0 REFERENCES…………………………………………………………………..25 
10.0 APPENDICES (attached) 
 
10.1 
Appendix A: Non-enrollment Survey 
 
 
 
 
 
 
10.2  Appendix B: Exercise Log 
 
 
 
 
 
 
 
 
10.3 
Appendix C: PMR Instructions 
 
 
 
 
 
 
 
10.4 
Appendix D: PMR Log 
 
 
 
 
 
 
 
 
10.5    Appendix E: Short Physical Performance Battery 
 
 
 
 
 
10.6    Appendix F: 2-6 Minute Walk Test 
 
 
 
 
 
 
 
10.7    Appendix G: Functional Status Assessment  
 
 
 
 
 
10.8    Appendix H: EQ-5D-5L 
 
 
 
 
 
 
 
 
10.9    Appendix I: PROMIS-10 
 
 
 
 
 
 
 
 
10.10  Appendix J: GAD-7 
 
 
 
 
 
 
 
 
 
10.11  Appendix K: PHQ-9  
 
 
 
 
 
 
 
 
10.12  Appendix L: Stool Sample Collection Instructions 
 
 
 
 
 
10.12  Appendix M: MyChart Patient Instructions  
 
 
 
 
 
10.13  Appendix N: Survey Email Link 
 
 
 
 
 
 
 
10.14  Appendix O: Captured Data Points 
 
 
 
 
 
 
 
            10.15  Appendix P: EORTC QLQ-30 
10.16  Appendix Q: EORTC LC-13 
10.17  Appendix R: POMS-Revised 
             
 

 
 
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HYPOTHESIS AND OBJECTIVES 
1.1 Primary Objective 
To assess the feasibility of a novel, weekly supervised virtual health-assisted physical therapy 
plus relaxation intervention delivered to older adults with advanced thoracic malignancy (N=20). 
The overall goal is to be able to pilot this intervention targeting modifiable risk factors for 
worsening functional status: physical performance and negative mood.  
1.2 Hypothesis 
We hypothesize that we will be able to accrue 20 older adults (≥ 60 years) with a thoracic 
malignancy and implement a 12-week virtual health-assisted physical activity + relaxation 
intervention program with biospecimen collection. We hope to achieve 70% adherence to all 
sessions and a total patient retention rate of 60% at the end of the 12 – week intervention 
program.  
2.0 BACKGROUND AND RATIONALE 
2.1 Lung Cancer in Older Adults  
Lung cancer is a disease that disproportionally affects older adults as the median age of diagnosis 
is 70 years.1 This is important because older adults are the fastest growing demographic in not 
only the United States but worldwide.2 However, this population is significantly under-
represented in clinical trials that examine outcomes of new lung cancer drugs.3 This is 
particularly relevant due to the approval of novel cancer drugs called immune checkpoint 
inhibitors (Immunotherapy: IO; e.g. pembrolizumab, atezolizumab). The new standard of care 
for first-line treatment for either advanced non-small cell lung cancer (NSCLC) or small cell 
lung cancer (SCLC) includes combination of chemotherapy plus IOs, 4,5 affecting 2/3rds of 
patients with advanced disease. The effect on older adult’s functional status and their ability to 
complete basic activities of daily living (ADLs) while on these new treatment plans is still 
widely unknown. This lack of information on how these new treatments may affect older adult’s 
functional status maintains feelings of uncertainty regarding treatment plans.  
2.2 Functional Decline + Resiliency 
Functional status and resiliency are patient-centered outcomes that should be prioritized in 
research among older adults with cancer.6 Functional status refers to the behaviors needed for an 
individual to maintain an independent lifestyle. It is defined as an individual’s ability to perform 
basic activities of daily living,7 instrumental activities of daily living8, and mobility9. The 
majority of older adults with a chronic disease, including cancer, prioritize remaining 
functionally independent over survival.10 Even so, functional status is not a primary endpoint in 
oncology research.11 Resiliency among patients with cancer can be defined as the ability to 
recover one’s functional status after an intervening health care event, e.g. treatment, toxicity, 
disease progression.12 Resiliency is important because it demonstrates one’s ability to “bounce 

 
 
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back” from a stressor or intervening event.  Resiliency is incompletely understood among 
patients with lung cancer.   
2.3 Targeted Interventions 
Poor physical performance and negative mood are two risk factors for a decline in functional 
status.9 Targeted interventions to address these two risk factors with the goal of improving 
functional status and resiliency are urgently needed. Physical therapy13,14 and relaxation 
interventions15 (i.e. progressive muscle relaxation) are two such interventions that can improve 
symptoms and quality of life for patients with cancer.  
3.0 METHODS 
3.1 Study Overview 
This is a prospective, longitudinal study of 20 adults ≥ 60 years of age with advanced thoracic 
malignancy (NSCLC or SCLC) who plan to receive either immunotherapy and or chemotherapy 
treatment from the OSUCCC Thoracic Oncology clinic. This cohort is a 12-week pilot 
intervention consisting of a physical therapy and progressive muscle relaxation program 
delivered to older adults with advanced lung cancer. Functional trajectories and resiliency will be 
characterized in this cohort. Enrolled patients will participate in in-person physical therapy and 
progressive muscle relaxation sessions that are incorporated into routine treatment visits as well 
as performed via virtual health on the non-treatment weeks. Patients’ functional status will be 
assessed every 3 weeks and clinical outcomes will be evaluated every 6 weeks. Correlative 
biomarkers will also be assessed through blood and stool sample collection. Patient follow up 
will continue through 24 months post enrollment for 1 year and 2 year overall survival.  
3.2 Patient Selection 
Patients diagnosed with a thoracic malignancy age ≥ 60 will be recruited from the OSUCCC 
Thoracic Oncology Clinic. Patients who plan to receive either immunotherapy and/or 
chemotherapy treatment at the James OSUCCC Thoracic Oncology Clinic will receive 
information regarding the study via physician’s referral. Those individuals agreeing to participate 
will sign the study consent which includes the HIPAA authorization. Patients who sign the 
informed consent will be assigned a unique study ID.  
Failed screening will be captured as a part of feasibility analysis. Reasons for patient decline will 
be noted and tracked without the use of patient identifiers.  
3.3 Inclusion Criteria 
• Age ≥ 60 
• Diagnosed with advanced lung cancer: unresectable stage IIIA, IIIB, or stage IV NSCLC 
or extensive stage SCLC  
• Intent to receive treatment from the OSUCCC Thoracic Oncology Clinic 
• Patients are eligible at any time point during their treatment here at OSU. Rationale for 
this timeframe is due to the overwhelming nature of the first few visits and uncertainty 

 
 
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around an eventual treatment plan. Patients at any stage of their treatment can participate 
and benefit from a physical therapy and psychosocial intervention. Patients will be 
approached at their initial visit but we can also offer enrollment at any one of the patients 
regularly scheduled clinic visits. . 
• Ability to understand and willingness to sign an informed consent document (or indicate 
approval or disapproval by another means). 
 
3.4 Patient Exclusion Criteria 
• Prisoners are excluded from participation 
• There is NO exclusion criteria pertaining to ECOG performance status, laboratory values, 
prior cancer diagnoses, presence of comorbidities or brain metastases. 
3.5 Informed Consent 
Discussions between the study coordinators and/or treating physician and study participants will 
occur in the regular Thoracic Oncology Clinic setting. The study coordinators will address all 
questions regarding the study outline and that participation is voluntary and the participant can 
withdraw from the study at any time. If eligible patients are interested, study compensation 
including the virtual health equipment will then be explained to ensure no unethical coercion led 
to the patient enrollment. If eligible patients decide to participate in the study they will sign the 
consent form, be assessed for eligibility and, when applicable, register as detailed below.  
In the case of natural disasters or pandemic reasons there will be the option for the informed 
consent to be performed through the telephone. The research coordinators will follow a script 
[APPENDIX T]. If the patient is interested in the study the ICF will be sent through REDCap to 
the patients email. REDCap allows for electronic signature. The research coordinator will walk 
through the consent form with the patient at this time.  
3.6 Inclusion of Women and Minorities 
Both men and women and members of all races and ethnic groups are eligible for this study.  
 
4.0 STUDY DESIGN 
4.1 Overview of Study Design 
  
This is a prospective longitudinal study of 20 adults older than 60 years who have been 
diagnosed with a thoracic malignancy who intend to receive treatment at the Ohio State 
University. Eligible participants will undergo the informed consent process. With IRB and 
participant permission, demographic information will be collected on potential participants who 
decline enrollment in the study by use of a non-enrollment survey [Appendix A]. 
Participants will undergo treatment prescribed by the treating physician as per standard of care. 
In addition, patients will undergo an in-person and virtual health physical therapy program. The 

 
 
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in-person program will include a 10-minute cardiovascular warm up on a portable exercise 
peddler, using either their upper or lower extremities depending on patient abilities. The warm up 
will be followed by a resistance training module using exercise resistance bands. This is 
designed to strengthen the core and upper/lower extremities.  The workout will end with full 
body stretches that are held for 30 seconds each. The virtual health visits will include the exact 
same regimen and equipment as the in-person visits. The portable peddler and resistance bands 
will be given to the patients either in clinic or mailed to their home based on patient preference.  
In addition to the physical therapy program, participants will undergo progressive muscle 
relaxation (PMR) performed by research graduate students (MA and PhD level) in clinical 
psychology. The patient is taught to systematically tense and release 16 different muscle groups. 
Patients will be seen during their regularly scheduled clinic visits and with virtual health “check-
ins” in the off-treatment weeks. 
Patients enrolled in this study will complete baseline assessments consisting of demographic 
information, disease assessment, functional status assessments, depression/anxiety screenings, a 
quality of life measure, toxicity assessment, as well as a physical performance and an endurance 
test. A study coordinator will assess functional status every 3 weeks either in person, by phone, 
or virtual health monitoring. Participants’ clinical outcomes will be collected every 6 weeks 
during their regularly scheduled clinic visits (baseline, 6 weeks, 12 weeks, and 24 week time 
points). Triggered assessments will be collected on patients with any presence of disease 
progression, a new toxicity grade, fall, or healthcare utilization such as emergency department 
visit, inpatient admission, or worsening functional status on either survey. The study intervention 
will last approximately 12 weeks (3 months). If a patient cancels due to scheduling conflicts or 
treatment fatigue they will be given the option to reschedule their visit. At the end of the 12 
weeks if a patient is still benefiting from PT then those missed visits can be scheduled out. Study 
assessments will still take place at 12 weeks in an effort to control for time-varying confounders. 
In the case a patient does make up any visits beyond the study 12 week time period there will be 
an additional study visit that takes place. This will be an “end of treatment” visit rather than a 12 
week visit. The same study assessments performed at baseline will be completed at this time. 
The patients will be followed until 24 months post-enrollment for 1-year and 2-year overall 
survival. An additional qualitative assessment will be conducted on those patients that are 
agreeable and consent to being either video or voice recorded. Patients will participate in a semi-
structured interview to assess overall study acceptability. This assessment will help capture the 
“joy” our novel supportive care intervention brings to the patient, patient’s family, and clinic 
team.  

 
 
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Figure 1. Study Schema 
 
 
 
 
 
 
 
4.2 Physical Therapy Intervention 
The Physical Therapy Intervention will include a total of 12 weeks with one PT visit per week 
virtually or in-person depending on in-person clinic limitations due to pandemic or natural 
disasters. Week1 assessment will be during an in-person visit with physician team within the 
OSU Brain and Spine Hospital The other weekly visits will occur through virtual health 
monitoring at the best availability of the patient and Physical Therapist. There will be a final visit 
during week 13 where participants undergo the same assessments as the baseline visit as a 
routine usual care physical therapy discharge visit.  The VH visits will be billed as research or as 
standard-of-care depending on insurance reimbursement changes for VH visits.  
The exercise intervention will begin with a 10 minute warm-up using a portable exercise 
peddlers either using the patient’s feet or arms, depending on their mobility and pain status.  For 
example, if the patient is non-ambulatory and does not have the use of their legs, they will be 
instructed in peddler use with their arms. The Core exercises will include; seated posterior pelvic 
tilts and seated without back support seated marches. The resistance training exercises will 
include shoulder press, tricep extension, bicep curls, upper extremity side raises, chest press, calf 
raises, marches, standing side leg lifts, leg extension in standing, seated knee extension and 
clamshells. These will be done in 2 sets of 10 reps using resistance bands appropriate for 
patient’s level of fitness. The cool-down portion will include stretches targeting upper 
extremities (chest, shoulders, and triceps), lower extremities (calves, quadriceps, and hamstrings) 
and trunk. Each stretch will be held for 30 seconds each. At week 1 visit patient will receive 
exercise packet including handouts for above therapeutic exercises three resistance bands 
(yellow, red and green) in order to progress resistance at home based on patient feedback.  The 
physical therapist will educate and demonstrate appropriate use of the equipment during virtual 
visits or in-clinic visits depending on encounter type.  In order to evaluate how hard the 
participant is working  during the virtual health visits; the relative perceived effort (RPE)16 will 

 
 
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be used with a target goal of 12-14 on the Borg Rating Scale.17 This indicates a moderate level of 
intensity. 
An exercise log in the patient’s electronic medical record will be filled out after each workout to 
keep track of patient progress. The patient will first be prescribed weekly sessions, then it will 
increase to twice weekly, then three times weekly based on patient behavior and activity 
tolerance.  One session per week will be supervised virtually or in-person by the physical 
therapist. Additional sessions will be done by the patient on their own per standard-of care 
physical therapy practice. During the virtual health sessions, the physical therapist will assess 
barriers to doing their physical therapy and will problem solve with the patients on how to 
improve adherence. Please see [Appendix B] for a detailed description of the study exercise log. 
 
Physical Therapy Safety Procedures 
Upon the initial in-person visit the physician team or physical therapist will perform a standard-
of-care safety screening of pulse oximetry assessment, heart rate and blood pressure monitoring, 
asking if patient has cardiac or pulmonary history.  This screening will take into account if the 
patient is on oxygen, wears glasses or hearing aids.  The in-person visit will also determine the 
location of the VH physical therapy, their emergency contact, and will verify their home address. 
It will be recommended that the patient perform their physical therapy in the same location each 
time.   The physical therapist will perform a VH safety checklist at the beginning of each session.  
This checklist may include but not limited to the following questions: 
-Where are you currently located? 
-Is anyone else home with you? 
-Is your cell phone charged and located near you?  
-Have you had any new or different chest pain in the last week? 
-Have you had any new or different shortness of breath in the last week? 
During the VH visits, similar to an in-person visit, if the patient experiences any sudden chest 
pain or shortness of breath, they will be instructed to stop the activity, sit-down, and call their 
emergency contact within the home.  If they are unable to call for help or are home alone, the 
physical therapist will call 911 and will notify the treating physician.  
4.3 Progressive Muscle Relaxation 

 
 
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In addition to the exercise intervention, patients will participate in progressive muscle relaxation 
training at week 1 visit and will undergo “check-ins” each week following either during their 
regularly scheduled clinic visits (whether in-person or virtually) or through virtual-health study 
visits. During the training, one of the study psychology graduate students will meet with the 
patient for approximately 20 minutes. Following the training, the trainer will provide a brief 
summary of PMR and its efficacy for cancer symptoms. Using the standardized procedures of 
Bernstein and Borkovec,18 
tension/release procedures 
for 16 muscle groups are 
described and 
demonstrated: right hand 
and forearm; right bicep; 
left hand and forearm; left 
bicep; forehead; upper 
cheeks and nose; lower 
cheeks and jaw; neck and 
throat; chest, shoulders, 
and upper back; stomach; 
right thigh; right calf; right 
foot; left thigh; left calf; 
and left foot. The trainer will solicit feedback from the patient and all questions will be 
answered. 
PMR is most effective when practiced regularly. To facilitate at-home practice and 
standardization, patients will also be provided with a PMR CD with standardized shortened 
versions of PMR and instructions [APPENDIX C] for shortening the 16-muscle-group program 
to 8 and 4 muscle groups. Additionally, patients will be given a written description of PMR with 
directions for tensing and releasing each muscle group, following the same sequence of the CD. 
Individuals are encouraged to practice at home at least 3-5 times per week, and to record the 
frequency and duration of home practice in a log sheet provided [APPENDIX D].  
4.4 Short Physical Performance Battery (SPPB)  
Every six weeks (regularly scheduled clinic visits) patients will undergo the short physical 
performance battery [APPENDIX E]. This will result in a total of four SPPB measurements. This 
test will be administered by the Clinical Research Coordinator (CRC) in-person or the physical 
therapist virtually and scores will be captured. The SPPB 19 is a validated tool used to assess 
lower extremity functioning. It is comprised of three objective measures testing for standing 
balance, normal gait speed, and strength performance by use of a timed sit-to-stand. The 
participants are asked to stand with their feet side by side, semi tandem, and tandem for 10 
seconds each to assess balance. Normal gait speed is tested by asking participants to walk 8 feet 
at his or her normal speed. Strength performance is tested by asking participants to complete five 
timed chair sit to stands without the use of hands. These three measures are scored individually 
from 0 to 4 with an aggregate score ranging from 0 to 12, with higher scores correlating with a 
ROAR-LCT Study Assessments (Baseline, Weeks 7, 13, and 24) 
Assessment/Test 
What it measures 
Short Physical Performance Battery (SPPB) 
Physical performance 
2-6 minute walk test 
Endurance 
EQ-5D-5L & 16 item Functional activity scale 
Functional status surveys 
GAD-7  
Anxiety Screening 
PHQ-9 
Depression Screening 
PROMIS-10 
Quality of Life  
Blood & stool sample 
Microbiome 
Common Toxicity Criteria for Adverse Event (CTCAE v5)  Toxicity 
RECIST 1.1 criteria  
Disease response 
EORTC QLQ C-30 + LC-13 
Symptom monitoring 
POMS 
Symptom monitoring 
EQ-5D-5L performed every 3 weeks  Not assessed at baseline 

 
 
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greater functional status. The scores are then classified into 4 categories; very low physical 
function (0-3); low physical function (4-6); moderate physical function (7-9); and high physical 
function (10-12). This tool can be administered in under 10 minutes and has been found to 
accurately predict falls, disability, and nursing home admissions among older adults.19 It also has 
been found to be a prognostic biomarker among older adult cancer survivors20 as well as serve as 
Quality of Life predictors.21 In order to support safety at home for patient while performing test, 
physical therapist will instruct patient to perform test near stable surface that patient can support 
themselves on in order to reduce fall risk.  If at any point during test patient demonstrates fall 
risk physical therapist will hold from advancing on to the next phase of the test.  
4.5 6 Minute Walk Test 
If patients are able to see PT in-person the 2 or 6 minute walk [APPENDIX F] test will be done 
as an additional physical function measure. This will be performed every 6 weeks. [APPENDIX 
F]. The 6MWT (6 Minute Walk test) is a validated tool used to assess endurance and overall 
functional exercise capacity.22 Patients are instructed to walk on a treadmill at their own pace for 
as long as they are able. At the end of the allotted 6 minutes patients are told to stop and the total 
distance covered is recorded. Participants walking less than 300 meters are considered to have 
low endurance while those walking over 300 meters are considered to have normal endurance.23 
The distance covered has been found to be strongly related to important clinical outcomes and is 
positively associated with peak exercise capacity and quality of life, and negatively associated 
with risk of disease exacerbation, number of hospitalizations, and mortality.24 If the patient is 
unable to perform the 6-minute walk test, they will be transitioned to the 2-minute walk test.  
4.6 Functional Status Assessments 
The Functional Status Assessment survey [APPENDIX G] will be assessed every 3 weeks by the 
CRC either in person, by phone, by email, or through virtual health monitoring. These surveys 
will be comprised of 16 activities including seven Activities of Daily Living (ADL) meausres7, 5 
Instrumental Activities of Daily Living (IADL) measures25, and 3 mobility activities.9 For each 
activity, disability is defined as the need for personal assistance or inability to perform the 
activity. Activities are scored as 0 being no help, 1 being with help, and 2 meaning unable to 
perform the activity. Higher scores indicate greater disability or a lower functional status. The 
ADL trajectories will include; eating, grooming, bathing, dressing, walking, toileting, and 
transferring, the IADL trajectories include; shopping, housework, meal preparation, taking 
medications, and managing finances, and the mobility measures will include; walking a quarter 
mile, climbing a flight of stairs, or lifting/carrying a 10lbs. The final mobility activity included is 
if the participant drove a car in the past month, where disability is defined as having not driven. 
In addition to these 16 measures, the patients will undergo the EQ-5D-5L [APPENDIX H]. The 
EQ-5D-5L26 is a brief 5 question assessment that captures disability in self-care, mobility, and 
usual activities. It uses a scoring scale from 3, meaning no disability to 15 points, indicating 
severe disability. This tool has been mapped to the EORTC-QLQ-C30,27specifially in patients 
with advanced NSCLC28. However, the EQ-5D-5L has been shown to be the preferred 
assessment due to its shortened length and its improved sensitivity and face validity.26 

 
 
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4.7 PROMIS-10 
The Patient-Reported Outcome Measurement Information System (PROMIS) Global Health 
Scale Short Form v1.1 HRQL [APPENDIX I] is the most widely used self-rated health item. It 
has been shown to be a useful tool in screening for disability and improving communication 
between patients and clinicians.29 This assessment consists of each domain of health with items 
representing physical health, pain, fatigue, mental health, social health, and overall health. Each 
of the 10 measures consist of five responses; Excellent, Very good, Good, Fair, and Poor.  The 
CRC will administer the PROMIS by use of IPads during the patient’s regularly scheduled visits 
or by phone approximately every 6 weeks.  
4.8 GAD-7 
The GAD-730 [APPENDIX J] is a reliable tool used to assess the prevalence and severity of 
Generalized Anxiety Disorder (GAD) in clinical settings. This assessment is a 7 item 
questionnaire that asks patients how often in the past 2 weeks, have they been bothered by each 
symptom. The responses are scored as 0 being “not at all,” 1 being “several days,” 2 being “more 
than half the days”, and 3 being “nearly every day,” for an aggregate score of 21. Higher scores 
indicate a higher prevalence of anxiety and are strongly associated with multiple domains of 
functional impairment and disability days.30  
4.9 PHQ-9 
The Patient Health Questionnaire is a self-administered assessment used for diagnostic purposes 
of common mental disorders.31 The PHQ-9 [APPENDIX K] is the 9-item depression segment 
which assesses the severity of depressive symptoms within the last two weeks. Patients will 
complete the PHQ-9 approximately every 6 weeks administered by the CRC. Items are scored 
from 0-3 with higher scores indicating greater levels of depression. If 5 or more of the 9 
symptoms have been present for “more than half the days,” then major depression is indicated. 
Other depression is indicated if 2, 3, or 4 of the symptoms have been present at least “more than 
half the days” in the past 2 weeks, and 1 of the symptoms is depressed mood or anhedonia.  
4.10 EORTC QLQ-C30 and EORTC QLQ-LC13 
The EORTC QLQ-C30 [APPENDIX P] is a widely used quality of life assessment for cancer 
patients.32 It is comprised of five functional scales, three symptom scales, a global health scale 
and one quality of life scale. This measure takes an average of 11 minutes to complete and is a 
reliable and valid measure to assess quality of life in cancer patients. The EORTC QLQ-LC13 
[APPENDIX Q] is a modular supplement to the EORTC QLQ C30. This is a 13 item lung 
cancer-specific questionnaire that assesses for symptoms such as coughing and dyspnea.33 It has 
been shown to be a valid assessment for monitoring symptoms in patients with a thoracic 
malignancy. Patients will complete both the EORTC QLQ C30 and the LC13 along with the 
other assessments during their regularly scheduled visits. 
4.11 POMS-Revised 

 
 
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The original POMS is 65 items. The POMS Short Form (POMS-SF) is 37 items and there are 
many studies that have shown its reliability and validity. The “POMS-12” {APPENDIX R] was 
created in the following way. 34 Factor analysis of the 37-item version identified 6 factors, which 
are identified as the subscales. For each subscale, the two items with the largest factor loading 
were selected and included in this abbreviated version. This method has been validated in 
previous research. 
4.12 Biomarkers 
Peripheral blood and stool samples will be collected at baseline prior to treatment and pre and 
post PT + PMR session. Thereafter, blood will be collected every 6 weeks pre and post PT + 
PMR session and at additional triggered time points for correlative biomarker studies. Each 
patient will have a minimum of 6 research blood draws performed (2 pre-treatment) and 4 total 
post-treatment. The post-PT +PMR blood sample will be drawn from the peripheral IV so an 
additional needle stick is not required. The blood will be processed into peripheral blood T 
lymphocytes (PBTLs), plasma, and serum for cellular senescence correlative analyses. The 
analysis consists of routine laboratory values including hematologic functions, renal function, 
hepatic function and calculated creatinine clearance, and markers of inflammation and 
coagulation, and potential molecular markers of aging (P16INK4a Expression, DNAge). The 
details of this biological assessment are below: 
Table 2: Biomarker Assessment 
Laboratory Values captured 
in Routine Practice 
Biologic Correlates* 
Hematologic 
functions:  
WBC 
Molecular 
markers of aging:  OSU_Senescence 
  
  
HGB 
  
DNAge 
  
  
Platelets 
  
Inflammatory Cytokines 
  
  
Absolute Neutrophil 
count 
  
Peripheral blood T Lymphocyte 
subtyping 
  
Absolute Lymphocyte 
count 
  
  
  
Absolute Lymphocyte 
count 
  
  
Renal 
Function:  
BUN 
  
  
  
Creatinine 
  
  
Hepatic 
function:  
AST 
  
  
  
ALT 
  
  
  
Total Bilirubin 
  
  
  
Alkaline Phosphatase 
  
  
  
Albumin 
  
  
    
 

 
 
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*patients who have already begun treatment prior to visit 1 will not partake in research blood 
samples in order to preserve the integrity of the data.  
Stool samples will be used for microbiome correlative analyses. At their clinic visit patients will 
be given a home microbiome collection kit that includes instructions for collecting a sample within 
24 hours of their next clinic visit. (Please see APPENDIX L for the instructions included in this 
box.) Briefly, a rigid plastic scaffold is placed over the toilet seat to collect stool in a plastic tub. 
Patients return the sample at their next clinic. Staff transfer the samples to the Spakowicz lab (IBC 
2018R00000115) where stool is transferred to cryo-vials and stored at -80C until processing in 
batch. 
DNA is purified using the QIAGEN PowerSoil kit and the 16S rDNA amplified using barcoded 
universal primers (V3-V4). Sequencing is performed on an Illumina MiSeq 2x300 for 16S to a 
depth of > 105k reads per sample. Demultiplexed fastq files are cleaned and paired using 
Spakowicz Lab resources in the Ohio Supercomputing Center and analyzed following the 
DADA23532 pipeline in R33. 
Sequences are processed to identify amplicon sequence variants (ASVs) and then to closest 
taxonomic identification using the SILVA34 and GreenGenes35 databases. Metabolic pathway 
composition is inferred using the PICrUST pipeline. Samples are clustered by ASV abundances 
using Non-Metric Multidimensional Scaling36, with the significance of clusters defined by the 
multi-response permutation procedure37, calculated in the vegan package in R38. The alpha 
diversity metric Simpson’s Index calculated to quantify the number of species and evenness of 
the stool microbiome samples. Taxon abundances, at each taxonomic rank, and pathway 
abundances are modeled using formulae appropriate for each hypothesis, most commonly using 
the DESEQ2 package in R to accommodate the negative binomial distribution of microbial 
abundances39.  
4.13 Toxicities 
The toxicity assessment and chemo drug & dose information will be collected by the CRC or a 
member of the clinical team at the beginning of every treatment cycle. Therapeutic toxicity will 
be collected using NIA Common Toxicity Criteria for Adverse Event v5 (CTCAE v5)40. During 
each scheduled doctor’s appointment or telephone encounter a research staff member or nurse will 
collect the therapy toxicities including grade and attribution to therapy. Additional toxicities may 
be collected from clinical encounters (scheduled or emergency visits) within the medical record. 
The clinical encounters include clinic notes, emergency room visits, and hospitalization. 
Furthermore, dose reductions, dose delays or discontinuation of the therapy course and the cause 
of each aforementioned event will be recorded. 
Serious Adverse Event (SAE) per the NIA Common Toxicity Criteria for Adverse Event v5 (CTCAE 
v5)40 is defined as any adverse event that results in one of the following: 1.) death; 2.) a life-
threatening event; 3.) inpatient hospitalization or prolongation of an existing hospitalization >24 
hours; 4.) persistent or significant incapacitation or substantial disruption to the participants ability 
to conduct normal life functions; 5.) congenital anomaly/birth defect;  6.) Important Medical 
Events (IME) that may not result in death, be life threatening, or require hospitalization but may 
be considered serious when, based upon medical judgement, the event may jeopardize the patient 

 
 
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and may require medical or surgical intervention to prevent one of the outcomes listed in the 
definition. The occurrence and incidence of SAE will be documented as part of toxicity assessment 
per CTCAE guidelines at each treatment visit.   
 
4.14 Disease Response 
Disease response will be routinely evaluated and will be classified using RECIST 1.1 criteria.41 
The current version of RECIST is the most widely used tumor response criteria used in clinical 
trials. RECIST categorizes disease as either measurable or non-measurable. The disease response 
is then classified into the following categories; complete response (CR), partial response (PR), 
non-CR/non-PR, and Progressive disease (PD).42 The study clinician will evaluate individual 
disease response for all 20 study participants. The CRC will be notified of any PD as this will 
require triggered study assessments.  
4.15 Virtual Telehealth  
Epic is a secure, electronic medical record platform that can utilize embedded technology from 
Vidyo to allow video encounters between patients and providers. Patients log in through the My 
Chart app and the physician logs in through Epic to kick off the video. Alternative virtual health 
options include doximitry, UpDox, or another OSU-approved virtual interface such as facetime, 
facebook messenger, zoom or a new preferred virtual health interface as dictated by OSU.  
Steps for virtual health visit: example using mychart. Instructions will be similar if using other 
interface. 
1. Eligible patients are identified by OSU staff. 
2. Device criteria is reviewed and if needed, a mobile or tablet device is provided to the 
patient. 
3. OSU staff provides patient with “MyChart Video Visit Instructions for Patients” 
document. Instructions are also provided within the appointment. [APPENDIX M] 
4. Video visit appointment is scheduled for patient.  
5. The patient signs up for MyChart if they have not done so already. 
6. Patient installs the MyChart app on a mobile or tablet device (preinstalled if OSU 
provides the device) 
7. Once the patient appointment is scheduled, it is accessible in MyChart. 
8. Before the appointment, patient can enter the appointment via the MyChart app, complete 
e-checkin and test their video.  Video testing is unavailable within 20 minutes of the 
appointment time 
9. At the time of the visit, patient can enter the appointment, complete e-check-in if not 
already completed, and then click “begin visit.” 
10. Provider enters the scheduled encounter in Epic and has option to pre-chart and then 
begin video visit at the appropriate time. 
11. They perform the video session 
12. Either side can click ‘disconnect’ to end the session as appropriate. 
 

 
 
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Video visits are encrypted and are not recorded. The patient and provider can only access the 
video visit by clicking on the appointment in MyChart and Epic respectively.  They can only 
access the appointment if they are logged into these systems using their individual credentials. 
4.16 Actigraph/ActivPal 
In addition to the physical therapy peddler, the participants will receive either an actigraph or an 
activpal. They will be instructed to wear the actigraph or activepal 24 hours a day for three 
weeks at the beginning of the intervention and three weeks post intervention, An actigraph is a 
small watch-like band worn on the non-dominant wrist and the active pal is a small adhesive 
monitor placed on the outer thigh. 
The actigraph will be used to measure gross motor activity and monitor sleep patterns. The 
activpal will be used to monitor physical activity habits such as time sedentary, standing, steps, 
and intensity of activities. This allows patients to go about their regular routines while 
simultaneously collecting important data regarding calories burned, wake-time activity, circadian 
rhythm sleep disorders, insomnia, energy expenditure, steps taken, and sleep efficiency.  
At the end of the PT intervention the participants will be asked to bring their actigraph or 
activpal back in to the research team. All of the data is saved on the watch or monitor until it is 
brought back in and then downloaded. Programs such as SAS or R have the capabilities to 
download and analyze the circadian rhythmicity. This data will be looked at in regards to clinical 
outcomes among our patient population. 
4.17 Study Compensation 
Participants who do not currently have one of our study compatible devices (iPhone, IPad, or 
Samsung phone or tablet) with internet access will be given one of our internet-compatible 
donated devices. We will confirm device functioning prior to the start of each patient program 
start. Patients that do require the use of a loner tablet will be asked to return the device at the 
completion of all 12 sessions or when coming off study. Meaning that if a patient schedules any 
missed visits beyond the 12 weeks they may hold on to the device in order to complete these 
visits. The CRC will follow up with the patient to serve as a reminder of when they should return 
their study materials.The enrolled participants will also be compensated with a $50 Visa gift card 
for study participation. Study compensation will be monitored and completed by the CRC. If a 
patient does schedule any missed or canceled visits beyond the 12-week study time period they 
will still be paid their visa giftcard at the 12 week time point.  
4.18 Potential Risks 
 Our study team anticipates that there will be minimal physical and psychological risks or 
discomforts for the study participants. Informed consent will be obtained from all participants 
prior to study enrollment to ensure all potential risks are understood by participant. There is a 
small risk that patients have some distress associated with the completion of the study 
questionnaires. However, if this occurs, questions are easily skipped and the study staff will 
speak to the participant about the distress that the surveys have caused and will offer referral to a 
mental health professional if necessary. There is also a small risk of injury due to the prescribed 
exercise intervention. Patients will be taught by a licensed Physical Therapist how to safely 

 
 
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perform these exercises and instructed to only perform each task to the level of his or her 
physical ability. A safety checklist will be performed as detailed above before every physical 
therapy session. In the case of an injury, the on-study Physical Therapists will assess the patient 
and his or her exercise intervention may be modified accordingly. 
4.19 Semi-Structured Interview 
Study participants will be asked to participate in a semi-structured interview conducted by the 
study CRC or another study team member. These questions will serve as proof of concept for our 
study emphasizing the importance of supportive care and targeted interventions among older 
adults with lung cancer [APPENDIX V]. Interviews will be conducted through either updox, 
teams, or zoom platforms. Patients are not required to turn on video capabilities but must consent 
to voice recording. The interviews will then be transcribed and coded by a study team member 
for analysis. Our primary rationale for this qualitative assessment is to be able to capture the joy 
this study has brought to our patients and clinic team. Our quantitative acceptability questions 
fail to do this in the same way qualitative interviews can. The interview recordings will be stored 
in a password-protected folder within our secure study folder in the shared T-drive. Only study 
personnel will have access to this folder. Upon analysis of interview transcripts, the recordings 
will be deleted and transcripts will be de-identified in order to protect patient private health 
information. Patients are not excluded from participation if they decline participation in this 
additional qualitative assessment.  
 
 
 

 
 
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5.0 DATA COLLECTION AND MANAGEMENT 
5.1 Registration Process 
• Potential patient identified 
• Patient signs informed consent and HIPAA form 
• Eligibility Screening  
• Register the patient on the study (Oncore) 
• Assign a patient study number 
• Pend blood work orders 
• Documentation of Consent in EPIC  
 
5.2 Electronic Data Capture 
5.2.1 IPad Survey Administration 
 
All of our study assessments are either self-administered or done by the CRC during regularly 
scheduled clinic visits whether in-person or virtual. In the case a patient does not have a monthly 
visit scheduled, the surveys will be administered over the phone or by use of a survey email link 
[APPENDIX N]. All assessments in survey form are completed via IPad and compatible pen 
with the exception that the CRC will administer the SPPB. Patients unable or unwilling to use 
the IPad will be offered a paper copy as an alternative to the electronic version.  
5.2.2 Survey Software and Data Management 
All data obtained via the IPad survey platform is supported by REDCap. The Ohio State 
University (OSU) Research Informatics Services (RIS) core utilizes REDCap as its primary 
Electronic Data Capture (EDC) support. The REDCap platform is a secure, web-based 
application flexible enough to be used for a variety of types of research, provides an intuitive 
interface for users to enter data, and enforces real time validation rules (with automated data type 
and range checks) at the time of entry.  
REDCap data collection projects rely on a study-specific data dictionary defined in an iterative 
self-documenting process. The project specific data dictionary is defined by the research team 
with assistance from RIS staff. As part of the data dictionary development process, individual 
fields can be denoted as identifiers.  When exporting a de-identified dataset, these variables are 
omitted.  Additionally, the data export tool allows for the shifting/removal of dates. REDCap 
supports electronic signatures by positively identifying the user through a unique username and 
password combination.  The provisioning of authorization (e.g. access to specific projects, user 
rights within the project, etc.) for all projects is managed by RIS staff in conjunction with the 
project Primary Investigator (PI). 
5.2.3 DATA AND SAFETY MONITORING PLAN 
Though this is not a clinical trial per the NIH definition, we have developed a Data and Safety Monitoring 
Plan for this project. The purpose of the data and safety monitoring plan is to ensure the safety of 
participants, the validity and integrity of data, and the appropriate termination of projects for which 
significant benefits or risks have been uncovered or when it appears that the project cannot be concluded 

 
 
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successfully. Risks associated with participation in research must be minimized to the extent practical, and 
the method and degree of monitoring should be commensurate with risk. The essential elements of the Data 
and Safety Monitoring Plan include: 
• 
Monitoring the progress of the project and the safety of participants; 
• 
Plans for assuring compliance with requirements regarding the reporting of adverse events (AE); 
• 
Plans for assuring that any action resulting in a temporary or permanent suspension of the project 
is reported to the appropriate agencies; and 
• 
Plans for assuring data accuracy and protocol compliance. Prior to the initiation of the project, staff 
will receive standardized training to ensure that the activities of the project are conducted in a 
uniform, safe, confidential and secure manner. A tracking system will be implemented to document 
data collection activities, and reports will be generated on a weekly and monthly basis to monitor 
the project activities.  Research project meetings will take place on a monthly basis to monitor the 
activities of the project and to continually reassess the progress of the project, including 
assessments of data quality, timeliness, participant recruitment, accrual, retention and monitoring 
of the risks versus benefits throughout the project period. In addition, face-to-face meetings with 
project staff will take place once per week to discuss the project activities. 
We will use REDCap (Research Electronic Data Capture) electronic data capture tools hosted by the Center 
for Clinical and Translational Science (CCTS) at OSU for data collection. REDCap provides a secure, web-
based, HIPAA compliant application that is housed behind the OSU Medical Center firewall. This platform 
provides an intuitive data manipulation interface, custom reporting capabilities, audit trail functionality, 
and real-time data monitoring/querying of participant records. REDCap has multiple data export options to 
common statistical packages (SPSS, SAS, Stata, R/S-Plus). 
 
To monitor data quality, the clinical research coordinator will conduct a 10% project eligibility verification.  
If a violation is noted, the clinical research coordinator will document the violation and inform the research 
project and the PI the matter. The appropriate action will be taken to rectify the violation and to determine 
what, or if any, corrective actions need to take place. All protocol violations will be documented and 
reported to the appropriate IRBs.  Also, any privacy violations will be reported to the IRBs and the 
institutional privacy offices. All privacy violations, AEs, and protocol violations will be reported to and 
reviewed by the PI and the research team, who will be responsible for reporting to the OSU Office of 
Responsible Research Practices/IRB. 
The clinical research coordinator will be responsible for submitting reports; annual reports will be sent to 
the OSU IRB, External Advisory Board, and, as required, to the OSUCCC Data and Safety Monitoring 
Board and the NIA project office. Information included in the reports will include the number of individuals 
enrolled in the project, dropout rates and any protocol deviations.  
 
Any unexpected SAE will be reported to the NIA, DSMC, and IRB within 48 hours of occurrence, while 
any other SAEs, protocol deviations, and anticipated problems will be made note to file and reported to the 
NIA, DSMC, and IRB within 72 hours. Any expected AE such as chemotherapy toxicity will not be reported 
but made note to file and documented within our REDCap database. The DSMC reviews safety reports 
every 6 months while all SAE reports are reviewed monthly. All submissions are made via OnCore. The PI 
will also submit a progress report (biannually for Phase II and quarterly for Phase I) that will be reviewed 
by the committee per the IRB of record as per the policies of the IRB.  
 
5.3 Baseline Demographic Questionnaire 

 
 
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Patient demographic information will be collected via a standard form [APPENDIX O] 
administered at baseline. The information with be pulled from the patient demographics section 
in IHIS.  
5.4 Clinical Data  
Clinical data regarding the specifics of the patients thoracic malignancy will be collected from 
IHIS including but not limited to, diagnosis, diagnosis date, stage, genetic mutation information, 
prognostic measures, treatment history, medications, hospitalizations, readmissions, hematologic 
and chemistry parameters (e.g. creatinine, BUN, albumin).  
6.0 STATISTICAL ANAYLYSIS 
6.1 Primary Endpoint  
In order to evaluate the feasibility of the pilot intervention we will determine, recruitment, 
adherence, and retention rates at 12-weeks of follow-up. Follow-up will continue through 24 
weeks post-enrollment. Recruitment rates will be defined as the proportion of screened older 
adults accrued relative to those approached in the OSUCCC Thoracic Oncology Clinic. 
Successful recruitment rates will be defined as ≥ 50% of older adults (≥ 60 years) approached 
agree to participate. Study adherence will be defined as the completion of ≥ 70% of the program 
sessions, repeated assessments, and collection of bio specimens either at the end of the study 
period or death, whichever occurs first. Retention rates will be defined as the percentage of 
participants not lost to follow-up at 6, 12, and 24 weeks post-enrollment. Death during active 
follow-up will not be considered as lost to follow-up. We are excluding those people who die 
because our population of interest is those who live long enough to benefit from this 
intervention.  We will enroll 30 participants to account for a conservative drop out of 30% for a 
projected sample size of 20 participants who survive a 6 – month period. Reasons for missing 
any scheduled collection dates will be documented, and the proportions of missing information at 
each time point will be calculated. 
6.2 Secondary Endpoints  
Functional trajectories and resiliency will be evaluated using generalized linear mixed models 
(GLMMS). This model allows for the estimation of intercept and slopes at both the individual 
and sample level. GLMMs can determine whether factors affect all patient trajectories in similar 
ways or whether they affect individual trajectories differently. To allow for possible changes in 
functional status over time (e.g., a change-point analysis) the ‘segmented’ package in R will be 
used.43,44 Participants’ functional status scores will be modeled using a segmented mixed model 
with random change points. Estimating the change point identifies the point in time that patients' 
functional status scores change during the 12-months post-diagnosis. We anticipate that the start 
of treatment will be a change point depending on treatment tolerability vs. toxicity. This model 
allows for random and fixed effects, permitting analysis of between-subject and within-subject 
variance in longitudinal observations.  
 

 
 
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Resiliency will be defined as the ability to maintain or regain at least 50% of baseline functional 
status at any point during the 12 months after diagnosis with specific emphasis at 3 and 6-months 
post- the start of treatment. The association between resiliency and clinical factors will be 
evaluated with appropriate statistical techniques for the specific measure (e.g. Chi-square tests 
will compare categorical variables between participants demonstrating resiliency vs. worsening 
functional status; a two-sample t-test or Wilcoxon Rank Sum test will compare continuous 
variables). We will characterize differences in resiliency within each of these pre-defined groups. 
GLMMs will test for differences in resiliency between these groups. Models will be adjusted for 
important clinical and demographic variables. The data obtained from the primary endpoint will 
be used to refine the timing and duration of the pilot intervention as described in our secondary 
endpoint. Using GLMMS we will compare functional status in the 24-week follow-up period 
using both functional status measurement strategies to inform the survey design of a larger 
intervention trial.  
6.2.1 Power Calculations 
A follow-up rate of study participation at 12 weeks of at least 60% (p1) would be desirable; a 
continuation rate below 40% (p0) would be unacceptable. With 20 eligible and recruited 
participants alive during a 24 week follow-up period, this study is powered to reject acceptability 
of these measures if the follow-up rate is less than 40% (10% one-sided type one error) and 
deemed feasible if the follow-up rate is 64% or more (80% power). If 13 of the 20 patients 
continue at 12 weeks, we will consider this method to have acceptable adherence for further 
study (follow-up rate >40%). We will also determine adherence and follow-up rates for both PT 
and PMR at 24 weeks of follow-up. 
7.0 CORRELATIVE ANALYSIS 
7.1 Overview 
Peripheral blood will be obtained for mRNA, DNA, and flow cytometry analyses.  While 
specific details of the processing, extraction, and analysis are included in this protocol, these 
details may change with innovations in laboratory techniques and hence are considered general 
guidelines only. 
 
7.2 Correlative Analysis Procedures 
Patients enrolled will have peripheral blood collected for analysis before therapy initiation. 
Patients who have started on chemotherapy (within 30 days) will not have correlative analysis 
performed.  Peripheral blood will be obtained and separated for serum and PBMC analysis. 
Peripheral blood will be obtained in EDTA coated tubes and CD3+ T-cells isolated using 
RosetteSep Reagents. We developed a custom Nanostring Codeset, OSU_Senescence, to 
comprehensively assess the phenotypes of human PBTLs.  The OSU_Senescence platform 
measures p16 and 70+ additional transcripts indicative of immunosenescence, cell cycle/cellular 
senescence, T-cell subtype, exhaustion and cytokine production.  Examples of OSU_Senescence 
detectors 
include 
T-cell 
subtypes 
(e.g.TBX21/TH1, 
GATA3/TH2, 
FOXP3/Treg), 
immunosenescence (e.g. CD27, CD28); exhaustion markers (e.g. PRDM1/Blimp-1, PDCD1/PD-

 
 
23 
Version 7, Mar 2021 
1, CD274/PDL-1) and standard housekeeping genes. The ability of OSU_Senescence to report 
dynamic changes in T-cell subtype is a major advantage over traditional real-time PCR-based 
methods to detect p16.  Moreover, OSU_Senescence is more cost effective, focused and 
analytically straightforward than RNA-seq.   To increase the power of our Codeset, we developed 
and tested a companion flow cytometry-based immunophenotyping assay, which can be used to 
isolate specific T-cell subtypes for downstream functional assays.  In addition, we have consulted 
with Zymo Research Corp. to concurrently analyze changes in the Horvarth45 epigenetic 
clock/DNAge of these cells and PBMCs providing further insight into the global, molecular 
changes that accompany p16 expression in PBTLs.  All of these studies can be completed from a 
single, 20 mL sample of human peripheral blood. DNAge and OSU_Senescence mRNA 
expression will be compared to an age-matched control database developed at OSU. 
Patients enrolled have peripheral blood collected for OSU_Senescence analysis serially at Visit 1 
(Baseline) and Visit 4 (End of Treatment). Peripheral blood will be obtained in EDTA coated tubes 
and 10 mL used to isolate CD3+ T-cells using RosetteSep Reagents. At the same time, PBMCs 
will be isolated from 10 mL of peripheral blood using standard density gradient centrifugation 
procedures. PBMCs will be cryopreserved in media containing 10% DMSO for future flow 
cytometric and/or senescence evaluation.  RNA and DNA will be extracted from purified PBTL 
or PBMCs using a column-based commercial nucleic acid kit.  Measurement of OSU_Senescence 
transcripts will then be performed in accordance with standard Nanostring protocols and may be 
validated by RNA reverse-transcription followed by quantitative real-time PCR. DNA from T-
cells and/or PBMCs will be sent to Zymo for DNAge analysis. Levels of OSU_Senescence mRNA 
expression or DNAge values will be compared to an age-matched control dataset.  
PBMCS will also be analyzed by flow cytometry to allow for simultaneous multiparametric 
analysis of cellular markers. Markers of cellular senescence, exhaustion and T-cell regulation will 
be analyzed. 
 
7.3 Statistical Considerations 
Pearson correlations and Spearman correlations will be used to explore  the strength of the 
relationship between p16, senescence transcripts, and quantitative prognostic factors (e.g., age).  
Two-sided hypothesis tests of the correlations will be used to determine if there is evidence of an 
association between variables. With such a small sample size, this is an exploratory aim. One-way 
ANOVA and the Tukey-Kramer multiple comparison procedure 46 will be used to compare levels 
OSU_Senescence transcripts across the levels of categorical prognostic variables (e.g. stage of 
disease).  
7.4 Obtaining Samples 
Peripheral blood will be obtained by clinic staff for mRNA, DNA, and flow cytometric studies.  
Samples will be obtained in clinical space (currently on HTC and 5th floor James, or inpatient 
settings as examples). Specifically, approximately 40ml of peripheral blood will be collected into 
phlebotomy tubes: up to 20ml in purple top EDTA tubes and 20ml in serum separator tubes. 
 
 
7.5 Sample processing  

 
 
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Sample pick up and processing will be performed in the Leukemia Tissue Bank using the following 
general procedure for cryopreservation of samples. 
Plasma: To obtain the plasma the blood collected in EDTA coated tubes will be transferred to 50 
ml sterile tube and centrifuged at 1800 rpm for 10min at room temperature. The supernatant 
(plasma) will be collected and stored at -80°C for further studies. The cellular pellet will be gently 
re-suspended in PBS to reach 2X the original volume (for 10ml of plasma 20ml PBS) and then 
stratified in 1X of Ficoll-Paque. This will be centrifuged at room temperature for 20 min at 2000 
rpm. The white ring containing monocytes, T- and B- lymphocytes will be removed and washed 
with FBS enriched culture media. The tube will be centrifuged at 1200 rpm at room temperature 
for 6 min. The cellular pellet will be resuspended in 90% FBS and 10% DMSO and placed in cryo-
tubes at -80°C and after 3 days will be placed in liquid nitrogen for long-term storage.  
Serum/PBMCs: For the serum collection the tubes will be centrifuged at 2,200-2,500 rpm for 15 
min and the serum will be stored at -80°C. PBMC: Blood samples will be diluted in an equal 
volume of phosphate buffered saline containing 2% fetal bovine serum (PBS/2%FBS).  Diluted 
samples will be gently mixed and then carefully layered on top of Histopaque 1077 density 
medium (Sigma-Aldrich #10771) in a conical tube.  The amount of density medium used will 
equal the original blood aliquot volume.  Tubes will then be centrifuged at 1200xg for 20 
minutes at room temperature with the centrifuge brake set to ‘off’.  Following separation, 
PBMCs will be removed from the gradient interface, placed into a fresh conical tube, washed in 
PBS/2%FBS solution, pelleted and then stored in cryopreservation medium. 
T-cells: Whole blood collected in a purple top EDTA tube will be divided into two equal volume 
portions, approximately 5mL each.  RosetteSep Human T Cell Enrichment Cocktail (Stem Cell 
Technologies # 15061) will be added to each tube at a ratio of 50uL per mL of whole blood.  Tubes 
will be mixed by inversion and incubated for 20 minutes at room temperature.  Next, samples will 
be diluted in an equal volume of phosphate buffered saline containing 2% fetal bovine serum 
(PBS/2%FBS).  Diluted samples will be gently mixed and then carefully layered on top of 
Histopaque 1077 density medium (Sigma-Aldrich #10771) in a 50mL conical tube.  The amount 
of density medium used will equal the original blood aliquot volume (~5mL).  Tubes will then be 
centrifuged at 1200xg for 20 minutes at room temperature with the centrifuge brake set to ‘off’.  
Following separation, enriched T-cells will be removed from the plasma interface using a pipette 
and placed into a fresh 15mL conical tube.  The cells will be washed by adding PBS/2%FBS to 
the tubes until they are filled to the top fill line. Tubes will then be centrifuged at 400 x g for 4 
minutes at room temperature with maximum brake.  The resulting supernatant will be removed 
with a pipette and transferred to a 1.5 mL microcentrifuge tube.  This sample will be centrifuged 
at 400 x g for 4 minutes at room temperature with maximum brake. The resulting supernatant will 
be carefully and completely removed using a pipette.  The remaining T-cell pellet will be stored 
in a -80 ° freezer until processing. 
DNA/RNA recovery and basic analyses: Under the supervision of Dr. Burd, harvested cell mRNA 
will be converted to cDNA using the Promega ImProm-II Reverse Transcription System (Promega 

 
 
25 
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#A3802) and random hexamer primers (Invitrogen #588875) as directed by the manufacturers.  
p16 levels will be measured using a Taqman-based quantitative RT-PCR methods essentially as 
described by Liu et al. (20). Validated Taqman-based controls for T-cell purity (CD3G, Applied 
Biosystems #4331182 Hs00962186), sample viability (p14ARF, Applied Biosystems #4351370 
HUMP14-ARF3) and RNA quantity (YWHAZ, Applied Biosystems #4331182 Hs03044281) are 
included in this analysis. Data clean up: Data will be filtered to exclude relatively invariant features 
(IQR = 0.5) and features below the detection threshold (defined for each sample by a cutoff 
corresponding to approximately twice standard deviation of negative control probes plus the mean 
of them) in at least half of the samples. Basic analysis Using R/Bioconductor and the filtered 
dataset, linear models for microarray data analysis47 will be employed with a contrast matrix for 
the comparisons. P values will be used to rank miRNAs and mRNA of interest, and correction for 
multiple comparisons will be done by the Benjamini-Hocheberg method.48  

 
 
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Assessment*:  
Screen  
Visit 1 
(Baseline) 
Every 
Treatment 
Visit 
Visit 2 
(4 weeks) 
Visit 3  
  (7 weeks) 
Visit 4 
(10 weeks) 
Visit 5 
(13 Weeks) 
End of 
intervention 
Visit 6 
(24 weeks) 
Follow up to 24 
months 
( 2 years) 
Signed Informed 
Consent 
x 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
x 
 
 
 
 
 
 
 
 
Medical & Cancer 
History 
x 
 
 
 
 
 
 
 
 
Sociodemographic 
 
x 
 
 
 
 
 
 
 
Disease Assessments 
 
x 
 
 
 
 
 
x 
 
Physical Exam 
 
x 
 
 
x 
 
x 
x 
 
Vital Signs 
 
x 
 
 
x 
 
x 
x 
 
SPPB 
 
x 
 
 
x 
 
x 
x 
 
2-6 MWT 
 
x 
 
 
x 
 
x 
x 
 
PROMIS-10 
 
x 
 
 
x 
 
x 
x 
 
Blood Chemistry 
 
x 
 
 
x 
 
x 
x 
 
Biomarker Testing 
(blood and stool) 
 
x 
 
 
x 
 
x 
x 
 
Functional Status 
Assessments 
 
x 
x 
x 
x 
x 
x 
x 
 
PROMIS-10 
 
x 
 
x 
x 
x 
x 
x 
 
GAD-7 
 
x 
 
x 
x 
x 
x 
x 
 
PHQ-9 
 
x 
 
x 
x 
x 
x 
x 
 
EORTCQLQ-30 
 
x 
 
x 
x 
x 
x 
x 
 
EORTC LC-13 
 
x 
 
x 
x 
x 
x 
x 
 
POMS-12 
 
x 
x 
x 
x 
x 
x 
x 
 

 
 
27 
Version 7, Mar 2021 
8.0 STUDY CALENDAR 
 
* all screening and study visits have the option of being virtual depending on clinic requirements due to pandemic status or natural disasters
Toxicities/ Disease 
Response 
 
x 
 
x 
x 
x 
x 
x 
 
Survival Status 
 
 
 
 
 
 
 
 
x 
Semi-structured 
interview 
 
 
 
 
 
 
x 
 
 

 
 
28 
Version 5, May 2020 
9.0 References 
1. 
Gajra A, Jatoi A. Non-small-cell lung cancer in elderly patients: a discussion of treatment options. 
J Clin Oncol. 2014;32(24):2562-2569. 
2. 
Mitka M. IOM report: Aging US population, rising costs, and complexity of cases add up to crisis 
in cancer care. JAMA. 2013;310(15):1549-1550. 
3. 
!!! INVALID CITATION !!! 3. 
4. 
Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in Metastatic 
Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(22):2078-2092. 
5. 
Horn L, Mansfield AS, Szczesna A, et al. First-Line Atezolizumab plus Chemotherapy in Extensive-
Stage Small-Cell Lung Cancer. N Engl J Med. 2018;379(23):2220-2229. 
6. 
Kuchel GA. Frailty and Resilience as Outcome Measures in Clinical Trials and Geriatric Care: Are 
We Getting Any Closer? J Am Geriatr Soc. 2018;66(8):1451-1454. 
7. 
Katz S, Downs TD, Cash HR, Grotz RC. Progress in development of the index of ADL. 
Gerontologist. 1970;10(1):20-30. 
8. 
Lawton MP. Assessment of Older People: Self-Maintaining and Instrumental Activities of Daily 
Living1. 1969. 
9. 
Presley CJ, Han L, Leo-Summers L, et al. Functional trajectories before and after a new cancer 
diagnosis among community-dwelling older adults. J Geriatr Oncol. 2018. 
10. 
Fried TR, Bradley EH, Towle VR, Allore H. Understanding the treatment preferences of seriously 
ill patients. N Engl J Med. 2002;346(14):1061-1066. 
11. 
!!! INVALID CITATION !!! 11. 
12. 
Hurria A, Soto-Perez-de-Celis E, Allred JB, et al. Functional Decline and Resilience in Older 
Women Receiving Adjuvant Chemotherapy for Breast Cancer. J Am Geriatr Soc. 2018. 
13. 
Morten Quist SWL, Mikael Rørth et al. “EXHALE”: exercise as a strategy for rehabilitation in 
advanced stage lung cancer patients: a randomized clinical trial comparing the effects of 12 
weeks supervised exercise intervention versus usual care for advanced stage lung cancer 
patients. BMC Cancer. 2013(13):477. 
14. 
Quist M, Adamsen L, Rorth M, Laursen JH, Christensen KB, Langer SW. The Impact of a 
Multidimensional Exercise Intervention on Physical and Functional Capacity, Anxiety, and 
Depression in Patients With Advanced-Stage Lung Cancer Undergoing Chemotherapy. Integr 
Cancer Ther. 2015;14(4):341-349. 
15. 
Pelekasis P, Matsouka I, Koumarianou A. Progressive muscle relaxation as a supportive 
intervention for cancer patients undergoing chemotherapy: A systematic review. Palliat Support 
Care. 2017;15(4):465-473. 
16. 
Rajarajeswaran P, Vishnupriya R. Exercise in cancer. Indian J Med Paediatr Oncol. 2009;30(2):61-
70. 
17. 
Borg GA. Psychophysical bases of perceived exertion. Medicine and science in sports and 
exercise. 1982;14(5):377-381. 
18. 
Bernstein DAB, T.D. Progressive relaxation training: A manual for the helping professions. 5 ed: 
University of Michigan: Research Press; 1973. 
19. 
Guralnik JM, Simonsick EM, Ferrucci L, et al. A Short Physical Performance Battery Assessing 
Lower-Extremity Function - Association with Self-Reported Disability and Prediction of Mortality 
and Nursing-Home Admission. Journals of Gerontology. 1994;49(2):M85-M94. 
20. 
Brown JC, Harhay MO, Harhay MN. Physical function as a prognostic biomarker among cancer 
survivors. Br J Cancer. 2015;112(1):194-198. 

 
 
29 
Version 5, May 2020 
21. 
Oh B, Cho B, Choi HC, et al. The influence of lower-extremity function in elderly individuals' 
quality of life (QOL): an analysis of the correlation between SPPB and EQ-5D. Arch Gerontol 
Geriatr. 2014;58(2):278-282. 
22. 
Gloeckl R, Teschler S, Jarosch I, Christle JW, Hitzl W, Kenn K. Comparison of two- and six-minute 
walk tests in detecting oxygen desaturation in patients with severe chronic obstructive 
pulmonary disease - A randomized crossover trial. Chron Respir Dis. 2016. 
23. 
Boxer R, Kleppinger A, Ahmad A, Annis K, Hager D, Kenny A. The 6-minute walk is associated 
with frailty and predicts mortality in older adults with heart failure. Congest Heart Fail. 
2010;16(5):208-213. 
24. 
Singh SJ, Puhan MA, Andrianopoulos V, et al. An official systematic review of the European 
Respiratory Society/American Thoracic Society: measurement properties of field walking tests in 
chronic respiratory disease. Eur Respir J. 2014;44(6):1447-1478. 
25. 
M. Powell Lawton P, 2 and Elaine M. Brody, ACSW3. Assessment of Older People: Self-
Maintaining and Instrumental Activities of Daily Living1. Gerontologist. 1969(9):179-186. 
26. 
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level 
version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727-1736. 
27. 
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and 
Treatment of Cancer QLQ-C30: A Quality-of-Life Instrument for Use in International Clinical 
Trials in Oncology. JNCI Journal of the National Cancer Institute. 1993;85(5):365-376. 
28. 
Khan I, Morris S, Pashayan N, Matata B, Bashir Z, Maguirre J. Comparing the mapping between 
EQ-5D-5L, EQ-5D-3L and the EORTC-QLQ-C30 in non-small cell lung cancer patients. Health Qual 
Life Outcomes. 2016;14:60. 
29. 
Hays RD, Bjorner JB, Revicki DA, Spritzer KL, Cella D. Development of physical and mental health 
summary scores from the patient-reported outcomes measurement information system 
(PROMIS) global items. Qual Life Res. 2009;18(7):873-880. 
30. 
Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure for assessing generalized anxiety 
disorder: the GAD-7. Arch Intern Med. 2006;166(10):1092-1097. 
31. 
Kroenke K, Spitzer RL, Williams JBW. The PHQ-9 - Validity of a brief depression severity measure. 
Journal of General Internal Medicine. 2001;16(9):606-613. 
32. 
!!! INVALID CITATION !!! . 
33. 
Team RC. R: A Language and Environment for Statistical Computing. Vienna, Austria: R 
Foundation for Statistical Computing; 2017. 
34. 
Quast C, Pruesse E, Yilmaz P, et al. The SILVA ribosomal RNA gene database project: improved 
data processing and web-based tools. Nucleic Acids Research. 2013;41(Database issue):D590-
D596. 
35. 
DeSantis TZ, Hugenholtz P, Larsen N, et al. Greengenes, a chimera-checked 16S rRNA gene 
database and workbench compatible with ARB. Applied and Environmental Microbiology. 
2006;72(7):5069-5072. 
36. 
Kruskal JB. Multidimensional scaling by optimizing goodness of fit to a nonmetric hypothesis. 
Psychometrika. 1964;29(1):1-27. 
37. 
Mielke Jr PW, Berry KJ, Johnson ES. Multi-response permutation procedures for a priori 
classifications. Communications in Statistics-Theory and Methods. 1976;5(14):1409-1424. 
38. 
Oksanen J, Blanchet FG, Friendly M, et al. vegan: Community Ecology Package. 2018. 
39. 
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq 
data with DESeq2. Genome Biology. 2014;15(12):550. 
40. 
Common Terminology Criteria for Adverse Events v4.0 (CTCAE). 2010;4. 

 
 
30 
Version 5, May 2020 
41. 
Mizuki Nishino M, MPH. Tumor Response Assessment for Precision Cancer Therapy: Response 
Evaluation on Criteria in Solid Tumors and Beyond. American Society of Clinical Oncology 
Educational Book. 2018;38:1019-1029. 
42. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 
43. 
Muggeo VM. Estimating regression models with unknown break-points. Stat Med. 
2003;22(19):3055-3071. 
44. 
Muggeo VM. Segmented: An R Package to Fit Regression Models With Broken-Line 
Relationships. R News. 2008;8(1):20-25. 
45. 
Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14(10). 
46. 
Hochberg YaT, A.C. (1987).  Multiple Comparison Procedures.   Wiley, New York. 
47. 
Smyth G, ed Limma: linear models for microarray data. New York: Springer; 2005. Gentleman 
RVC DS, Irizarry R, Huber W, ed. Bioinformatics and Computational Biology Solutions using R and 
Bioconductor. 
48. 
Benjamini Y, Hochberg Y. Controlling the False Discovery Rate: A Practical and Powerful 
Approach to Multiple Testing. Journal of the Royal Statistical Society Series B (Methodological). 
1995;57(1):289-300.