Exercise Therapy in Radiation Therapy (EXERT)
Phase: NA
Conditions: Metastatic Cancer
Sponsor: Milton S. Hershey Medical Center

Page 1 of 29  
                                                                                        
 
HRP-591 - Protocol for  
Human Subject Research 
 
Protocol Title: 
Exercise in Radiation Therapy (EXERT) 
 
Principal Investigator: 
Nicholas G Zaorsky, MD 
Department of Radiation Oncology 
Penn State Cancer Institute 
500 University Drive 
Hershey, PA 17033 
USA. Tel: +1-717-531-8024 
Fax: +1-717-531-0446 
E-mail: nzaorsky@pennstatehealth.psu.edu 
 
Version Date: 
 1/3/2018 
 
Clinicaltrials.gov Registration #: 
N/A 
 
If you need help… 
University Park and other campuses: 
Office for Research Protections Human Research 
Protection Program 
The 330 Building, Suite 205 
University Park, PA 16802-7014 
Phone: 814-865-1775 
Fax: 814-863-8699 
Email: irb-orp@psu.edu 
College of Medicine and Hershey Medical Center: 
Human Subjects Protection Office 
90 Hope Drive, Mail Code A115, P.O. Box 855 
Hershey, PA 17033 
(Physical Office Location: Academic Support Building Room 
1140) 
Phone: 717-531-5687 
Fax number: 717-531-3937 
Email: irb-hspo@psu.edu 
 
 
 

Page 2 of 29  
Table of Contents 
1.0 
Objectives 
2.0 
Background 
3.0 
Inclusion and Exclusion Criteria 
4.0 
Recruitment Methods 
5.0 
Consent Process and Documentation 
6.0 
HIPAA Research Authorization and/or Waiver or Alteration of Authorization 
7.0 
Study Design and Procedures 
8.0 
Subject Numbers and Statistical Plan 
9.0 
Confidentiality, Privacy and Data Management 
10.0 
Data and Safety Monitoring Plan 
11.0 
Risks 
12.0 
Potential Benefits to Subjects and Others 
13.0 
Sharing Results with Subjects 
14.0 
Subject Stipend (Compensation) and/or Travel Reimbursements 
15.0 
Economic Burden to Subjects 
16.0 
Resources Available 
17.0 
Other Approvals 
18.0 
Multi-Site Research 
19.0 
Adverse Event Reporting 
20.0 
Study Monitoring, Auditing and Inspecting 
21.0 
Future Undetermined Research: Data and Specimen Banking 
22.0 
References 
 
 

Page 3 of 29  
Figure 1. Summary of central hypothesis. As treatment intensity
increases (with RT), so do the tumor control probability and normal
tissue complication probability. Complications vary per disease site.  ET 
may increase the therapeutic window by shifting the complication
1.0 
Objectives 
 
1.1 
Study Objectives and Endpoints 
Aim 1. To determine the acceptability, feasibility, and safety of an exercise intervention among cancer 
patients receiving radiation therapy. We anticipate that >25% of approached patients will consent to the 
protocol; >33% of eligible radiation therapy patients who consent will perform the exercise prescribed 
(based on the response rate from EnACT); and <25% of participants will experience a musculoskeletal 
impairment (without treatment alterations) and <5% will experience a musculoskeletal injury with 
symptoms lasting ≥ week or requiring medical attention.  Our approach will be to include patients 
receiving definitive RT; excluding patients at high risk for side effects from combination therapy, 
including fracture or cardiovascular events.   
Aim 2. To discern the clinical outcomes of patients receiving RT+ET. The hypothesis is that adding ET to 
RT will improve patient reported outcomes and physical functioning. Our approach will be to use 
standardized questionnaires and assessment tools: patient reported outcomes will be assessed using 
Common Terminology Criteria for Adverse Events – Patient Reported Outcomes (CTCAE-PROs), loaded 
onto tablets that patients use in the clinic. Questions will assess global PROs relevant to the ability to 
tolerate RT, including fatigue, pain, nausea, vomiting; and disease-site-specific PROs, including 
genitourinary/sexual symptoms for patients receiving pelvic RT. RT dose alterations will be documented. 
Scores will be compared pre- vs post- RT. We will also use standardized measures already used in EnACT, 
including grip strength, 30-second chair stand, timed up-and-go, and 4-stage balance. Scores will be 
compared pre- vs post- RT. 
 
2.0 
Background  
 
2.1 
Scientific Background and Gaps 
In 2018, an estimated 1,735,350 new cases of cancer will be diagnosed in the US. The principal 
treatment options for cancer include surgery, systemic therapy, and radiation therapy (RT). All treatment 
options cause toxicity and reductions in quality of life (QOL). International oncologic guidelines recommend 
exercise therapy (ET) to improve QOL and toxicity associated with the disease and treatment, and to receive the 
full dose of therapy. To date, most clinical studies of the effect of ET are limited to patients receiving 
chemotherapy or survivors. Few studies have examined the effect of ET for patients receiving RT. The rationale 
for the current Exercise Therapy and Radiation Therapy 
(EXERT) study is that 60% of cancer patients receive RT, 
and in cancers with a high incidence (e.g. breast, prostate, 
lung), RT is frequently part of the definitive therapy 
paradigm. Thus, it is critical to understand if ET may 
improve patient reported outcomes, including toxicity and 
quality of life. Our long-term goal is to identify potential 
synergistic effects of RT and ET on treatment outcomes 
and short and long-term side effects of cancer patients and 
identify subgroups of patients likely to gain the most 
benefit from the combination. The central hypothesis is 
that the addition of ET to RT improves treatment 
tolerance, patient reported outcomes and physical 
function for certain cancers, thereby improving the therapeutic window (Figure 1).  
Preliminary data from a sister protocol running at Penn State Cancer Institute, Exercise in All 
ChemoTherapy (EnACT), demonstrates the infrastructure and support to implement our goals. Of the 139 
eligible patients, 108 consented; of these 108, 93 began the study; of these 93, 41 completed, and 37 are still in 
the study.  Thus, acceptability is 67% (108/139), goal >50%; feasibility is 87% (33/38); and dropout rate is 6%. No 
patients have experienced ET-related injury (goal < 5%). There has been no significant difference in the timed up 

Page 4 of 29  
and go (11.6 seconds, SD 10.7 pre-therapy vs 10.4 seconds, SD 1.6 post therapy, p=0.15). There has been an 
improvement in the 30-second chair stand (mean 13 iterations, SD 3.84 pre-therapy vs 14, SD 3.98 post-therapy, 
p=0.05). For EXERT, we will enroll 50 patients to a single-arm, prospective study of ET among those receiving RT. 
Patients will be >18 years of age, with any type of cancer, receiving 3-9 weeks of RT. Certified exercise oncology 
specialists will personalize, prescribe, and guide ET, including twice weekly resistance training (5 exercises, 
progressing resistance), and walking exercise (building weekly time as tolerated), performed at home, with 
supervised training at the Exercise Medicine Unit in the cancer institute. 
 
 
Methods to improve quality of life in cancer patients 
 
Cancer patients experience a decline in their quality of life (QOL) from their disease and from therapy. Several 
methods have been attempted at improving QOL, including altering the use of a type of chemotherapy or surgery,1,2 
using granulocyte colony stimulating factor support, 3 introducing religion and spirituality,4 and using cognitive 
behavioral therapy.5 These interventions have generally been limited because they either focus on altering the 
prescription of the therapy to treat the cancer (e.g. surgery, chemotherapy), or they likely have no impact on the 
physiology of the disease and the patient to provide an improvement in outcomes or toxicities (e.g. religion). Exercise 
therapy (ET) is a complementary treatment that improves QOL, other patient reported outcomes, and surrogates of 
longevity of cancer patients.6-9 Psychologically, moderate ET has been shown to improve fatigue, anxiety, and self-
esteem. Moreover, ET has physiologic benefits in that it improves vascular stability, muscle strength, and muscle mass. 
Thus, ET may be an excellent tool to improve patients’ abilities to tolerate treatment by widening the therapeutic 
window (Figure 1 above). Several national and international agencies recommend ET for all persons following a cancer 
diagnosis.10-13 
Guidelines for exercise therapy among cancer survivors 
 
However, despite guidance on implementing ET recommendations for cancer patients,14 ET counseling is still not 
standard of care in cancer centers across the US, and it is not mentioned in most cancer treatment guidelines for those 
receiving therapy. Instead, ET has generally been listed as an option for certain cancer survivors, because it has mostly 
been studies among patients previously treated with systemic therapy (e.g., chemotherapy, hormone therapy) for 
prostate and breast cancer.15,16  
Exercise therapy among cancer patients receiving radiation therapy 
 
About 60% of cancer patients will receive radiation therapy (RT) at some point in their disease course. However, 
as of 2018, there are no recommendations from the American Society for 
Radiation Oncology (ASTRO), the European Society for Radiation Oncology 
(ESTRO), or the National Comprehensive Cancer Network (NCCN) regarding 
the integration of ET in the treatment regimen for cancer patients receiving 
RT. The lack of integration into the paradigm of RT for cancer patients is due 
to several factors: (1) there is limited clinical evidence supporting concurrent 
RT+ET, and clinicians are concerned that introduction of ET will not be 
feasible in a clinic; (2) combination therapy may introduce toxicity; (3) clinics 
lack a dedicated ET unit with supervised support; and (4) combination ET+RT 
has generally only been attempted across single disease sites (e.g. prostate 
alone, breast alone). The lack of integration of RT+ET is problematic because 
clinical and preclinical data suggest that there is synergy between these 
therapies that improves patient outcomes and toxicities (Figure 2). In the 
current work, we will show that integration of RT+ET across a diverse range 
of tumors (Aim 1) is safe, feasible, and has limited toxicity; improves clinical 
patient reported outcomes (Aim 2). 
 
Clinical evidence supporting radiation therapy + exercise 
therapy 
 
In the clinical setting, there have been only main disease sites where investigators have studied the interaction 
of RT and ET: breast and prostate cancer (pink and blue in the figure).  In the realm of breast cancer, Lipsett et al15 
performed a systematic review and meta-analysis of trials concurrent RT+ET. Among 9 studies,17-25 ET reduced the 
development of fatigue vs standard care (standardized mean difference, -0.46, 95% confidence interval, -0.79 to 0.14). 
Similarly, Taaffe et al16 performed a randomized controlled trial of prostate cancer patients receiving androgen 
Figure 2. Outcomes statistically significantly improved vs 
not improved among RT+ET studies (Zaorsky et al, 
unpublished systematic review). The colors correspond to 
the disease sites where RT+ET have been tested 
concurrently. 

Page 5 of 29  
deprivation therapy, randomized to 6 months of supervised exercise followed by a 6 month home-based maintenance 
program, or to printed physical activity educational material. Those in the supervised exercise arm had improved muscle 
performance and body composition, including lean and fat mass, and appendicular skeletal muscle.  These studies 
suggest that RT+ET is acceptable and feasible for both male and female patients; a study for many cancer patients 
receiving RT is warranted.  
 
Although these clinical data are encouraging, there are several unknown factors about ET+RT. For example, 
patient acceptability and feasibility have not been characterized outside of prostate and breast cancer. Further, ET+RT 
may be better tolerated by patients in certain disease sites compared to others; the impact of ET+RT to reduce toxicities 
may be more pronounced in disease sites that where treatments have a relatively narrow therapeutic window. 
Additionally, the exercise intervention type may play a role in acceptability and patient reported outcomes.  
Preclinical evidence supporting radiation therapy + exercise therapy 
 
The improvement in the therapeutic window is likely secondary to a left-shift of the tumor control probability 
curve (i.e. making RT more effective in killing cancer cells), or secondary to a right-shift of the normal tissue 
complication probability curve (i.e. making patients less likely to experience toxicity from therapy). The shift in either 
curve is secondary to a physiologic mechanism, and understanding this mechanism will advance our understanding of 
cancer therapy.  
 
In the preclinical setting, combination RT+ET is  postulated to improve outcomes and toxicities for many cancer 
patients, as they affect the endocrine system, myokine release, autonomic function, immune function, the extracellular 
tumoral microenvironment, and neurocognitive function. For example, with respect to the endocrine system, ET causes 
systemic epinephrine production, interleukin (IL)-6 secretion, and mobilization of cytotoxic immune cells that may 
infiltrate the tumor.26 Similarly, ET stimulates epinephrine-dependent Hippo YAP signaling, decreasing cancer cell 
seeding and formation of metastases.27,28 Thus, combination of ET and RT may be beneficial for patients who have 
metastatic disease. After several weeks of ET, there is a decrease in pro-inflammatory markers (e.g., C-reactive protein 
[CRP], tumor necrosis factor [TNF]-α, IL-6),29-32 which are associated with chronic toxicity (e.g., fibrosis) from RT. ET 
improves and treats certain comorbidities (e.g., diabetes), which increase toxicity of RT;33 thus, a study combining RT 
and ET may also decrease toxicities in patients. 
 
ET reduces systemic adiposity, thereby decreasing systemic estrogen, which is a growth stimulus for certain 
cancers expressing the estrogen receptor (e.g., breast).34 Further, over weeks, ET increases systemic muscle mass.35,36  
Maintenance of muscle mass is most important in (1) patients with swallowing dysfunction, including those with 
pancreatic cancer, esophageal cancer, stomach cancer, head and neck cancer; (2) cancers creating muscle-wasting 
hormones (parathyroid hormone-related protein [PTHrP]37 and myostatin38), as seen in colon and lung cancer; and (3) 
patients receiving systemic treatments that cause sarcopenia, including androgen deprivation and chemotherapy.39-42 
Prevention of sarcopenia decreases the risk of perioperative complications with neoadjuvant RT.43 Thus, there is 
potential synergy of RT and ET to improve tolerance of patients receiving combined modality therapy.   
 
ET increases autonomic stimulation, pulse, and blood pressure, and causes mild hyperthermia.44-47 Subsequently, 
there is an increase in natural killer (NK) cell and cytotoxic T-cell trafficking, which are important in cancer cell killing 
after RT. Further, RT and hyperthermia act synergistically: RT causes DNA damage, while hyperthermia causes damage 
to proteins. ET has also been shown to increase blood vessel diameter and reduce hypoxia.44,48-51 DNA damage caused by 
RT is contingent on oxygenation, and an improvement in tumoral oxygenation would be expected to increase cancer 
killing.52  Taken together, these data suggest that combination RT and ET would be synergistic in treatment of cancer of 
the pancreas, endometrium, cervix, soft tissue (sarcomas), and brain, which are all hypoxic and are sometimes also 
treated with hyperthermia. 
 
With respect to the immune system, ET and RT both independently increase myokines, including IL-6, IL-7, and 
IL-5.53-57 These myokines cause NK and T-cell proliferation, differentiation, maturation, infiltration of tumor.26,53,58-63  ET 
and RT also independently increase peritumoral release of TNF-α,64 65 which induces macrophage activation towards a 
pro-inflammatory or classically-activated (M1) phenotype and enhances myeloid cell recruitment, causing increased 
anti-tumoral response and decreased chronic tissue injury.  Similarly, ET and RT independently cause an increase in IL-
1β,66-69 70 which subsequently causes CD8+ T-cell accumulation, and accumulation of monocytes and M1 macrophages. 
ET also causes conversion of M1 macrophages to M2 macrophages, which may have increased activity against various 
cancers.71,72 Additionally, ET decreases immunosuppressive factors, including lactate73 and lactate dehydrogenase.74 
Taken together, these results suggest that RT and ET would have synergistic anti-tumoral effects in tumors that are 
immunogenic, including melanoma, renal cell carcinoma, hepatocellular carcinoma, non-small cell lung cancer, 

Page 6 of 29  
gastroesophageal carcinoma, cervical carcinoma, Hodgkin lymphoma, and colorectal carcinoma. Notably, patients with 
these cancers have typically been excluded from trials evaluating RT + ET.   
 
With respect to neurocognitive function, ET improves short term memory and processing.75-77  Preservation of 
neurocognitive function may be most important to those receiving RT to the brain.78-80  Demonstration of a positive 
impact of ET would be important given the relative failure of other neuroprotective treatments available for these 
patients: (1) the use of RT + memantine has not been shown to preserve neurocognitive function; and (2) the use of 
hippocampal-sparing RT is still investigational. Thus, combination RT and ET could serve as a new therapy to preserve 
neurocognitive function for patients with cancers of the central nervous system among all cancer patients. 
 
As of 2018, there have been no studies focusing on combination of exercise therapy and RT for all cancer 
patients.  Herein, we capitalize on the ability of our center to assess the synergy of RT and exercise therapy. In my 
analysis of the Surveillance, Epidemiology, and End Results database, I showed that patients with cancers of the liver, 
ovary, gallbladder, pancreas, esophagus, cervix, head and neck, lung, and nervous system have had limited 
improvement in outcomes from the 1970s to the 2010s.81 These patients are in dire need of novel treatment 
approaches, and combination RT + exercise therapy may be the ideal low-cost strategy. The long-term goal is to identify 
potential synergistic effects of RT and exercise therapy on the outcomes of cancer patients to design better 
interventions and identify subgroups of patients likely to gain the most benefit from the combination. The central 
hypothesis is that the combination of radiation therapy and exercise therapy is an acceptable, feasible and safe 
treatment approach for cancer patients that decreases toxicity and improves survival, thereby increasing the 
therapeutic ratio. Exercise therapy will become a standard co-treatment that is integrated in the guidelines set forth by 
ASTRO, ESTRO, and the NCCN. 

Page 7 of 29  
Table 1. Interaction between exercise therapy and radiation therapy on various body systems and cancers 
Effect 
Physiologic effects of 
exercise therapy 
(approximate time after 
event) 
Physiologic effects of RT 
Biologic effects of combined therapy Cancers or normal tissue most 
affected 
Long-course, low 
dose RT (1.8-2 Gy/  
fraction) 
Short-course, high 
dose RT (>6-8 Gy/ 
fraction) 
Systemic endocrine 
Acute systemic epinephrine 
production, IL-6 secretion, 
mobilization of cytotoxic 
immune cells 
Increased in minutes 26 Negligible / 
unknown 
Negligible / 
unknown 
NK and T-cell proliferation, 
differentiation, maturation, 
infiltration of tumor 
Multiple cancers 
Epinephrine-dependent Hippo 
YAP signaling, decreased 
cancer cell seeding and 
formation of metastases 
Decreasing in 
minutes27,28 
Negligible / 
unknown 
Negligible / 
unknown 
Possible interaction through abscopal 
response 
Metastatic cancers, particularly 
those where local RT may be 
effective in metastatic disease82 
Long-term changes in pro-
inflammatory markers (e.g. 
CRP, TNF-α, IL-6) 
Decreased in weeks  29-32 Typically negligible Typically negligible Decreased toxicities in normal 
tissues. Decreased formation of 
second caner. 
Multiple cancers. Metastatic 
cancers. 
Comorbid conditions (e.g. 
diabetes) 
Improved in weeks 
Negligible; 
however, worse RT 
toxicity with 
comorbidities 33 
Negligible; 
however, worse RT 
toxicity with 
comorbidities 33 
Decreased toxicities in normal 
tissues. 
Normal tissue  
Estrogen 
Decreased from lower 
adiposity 34 
Negligible / 
unknown 
Negligible / 
unknown 
Decreased growth stimulus for 
cancer cells, synergistic with tumoral 
RT effects 
Breast cancer 
Testosterone 
Decreased with fitness 
83 
Negligible / 
unknown 
Negligible / 
unknown 
Decreased growth stimulus for 
cancer cells, synergistic with tumoral 
RT effects 
Prostate cancer 
Fat mass 
Decreased in weeks 84 
Negligible direct. 
However, weight 
gain after therapy 
in certain cancers 
(prostate, breast) 
85 
Negligible direct. 
However, weight 
gain after therapy 
in certain cancers 
(prostate, breast)  
85 
Decreased growth stimulus for 
cancer cells. Decreased ability of 
cancer cells to repair DNA.  Effects 
synergistic with tumoral RT effects.84 
Decreased systemic low-grade 
inflammation, insulin production 
Multiple cancers (especially 
prostate, breast); normal tissue 
Insulin, IGF1 production 
Increased in body within 
minutes; concurrent 
reductions in circulating 
levels 34,36,86,87 
Negligible / 
unknown 
Negligible / 
unknown 
Decreased growth stimulus for 
cancer cells. Decreased ability of 
cancer cells to repair DNA.  Effects 
synergistic with tumoral RT effects 
Multiple cancers 
Leptin  
Decreased in weeks36,84 Negligible / 
unknown. 
Increased in 
patients who gain 
weight. 
Negligible / 
unknown.  
Increased in 
patients who gain 
weight. 
Decreased growth stimulus for 
cancer cells. Decreased ability of 
cancer cells to repair DNA.  Effects 
synergistic with tumoral RT effects 
Multiple cancers (especially 
prostate, breast); normal tissue 
Muscle / myokines 
Muscle mass 
Increased in weeks 35,36 Negligible / 
unknown direct 
effect. However, 
decreased with 
certain treatments 
(e.g. chemo-RT, 
ADT) 
Negligible / 
unknown direct 
effect. However, 
decreased with 
certain treatments 
(e.g. chemo-RT, 
ADT) 
Prevention of sarcopenia/cachexia, 
which has high incidence in certain 
cancers. 
Decreased risk of perioperative 
complications43 
Important in (1) patients with 
swallowing dysfunction: pancreatic 
cancer, esophageal cancer, stomach 
cancer, head and neck cancer; (2) 
cancers creating muscle-wasting 
hormone (PTHrP37, myostatin38): 
colon, lung; (3) treatment causing 
sarcopenia: ADT, chemo39-42 
Muscle tissue.  
IL-6, IL-7, IL-15 
Increased in minutes 53-
56  
Increased 57 
Increased 57 
NK and T-cell proliferation, 
differentiation, maturation, 
infiltration of tumor.53,58,59  Increase 
immune response 
Antagonize TGF-β and Wnt signaling 
Multiple cancers (especially 
melanoma). 
Oncostatin M 
Increased88 
Decreases cancer cell viability 
SPARC 
Increased89 
Decreases tumorigenesis 
Bone 
Bone mineral density 
Increased in weeks 
Negligible / 
unknown; loss of 
density in 
irradiated area 
Negligible / 
unknown; loss of 
density in 
irradiated area 
Possible prevention of loss of 
function 
Multiple cancers (especially 
prostate, breast); normal tissue 
(prevention of fracture) 

Page 8 of 29  
Neuro-cognitive 
Depression, worse cognition 
Improved cognition 75-77 Decreased with 
brain RT. 78 79 
Increased risk of 
suicide among all. 
80 
Decreased with 
brain RT. 78 79  
Increased risk of 
suicide among all. 
80 
Prevention of cognitive decline, 
depression, suicide 
Multiple cancers (especially 
those of brain) 
Extracellular tumoral 
microenvironment 
TNF release 
Increased in minutes; 
concurrent reductions in 
circulating levels 64 
Increased in 
minutes 65 
Induce macrophage activation 
towards a pro-inflammatory (M1) 
phenotype and enhance myeloid cell 
recruitment. Increased anti-tumoral 
response; decreased chronic tissue 
injury 
Multiple cancers 
IL-1β release 
Increased in minutes 66 
67,68 
Increased in 
minutes 69 70    
CD8+ T-cell accumulation; 
accumulation of monocytes and 
macrophages with M1 phenotype 
(classically activated) 
Multiple cancers 
CCL2 
Increased in minutes66 
CD8+ T-cell accumulation; 
accumulation of monocytes and 
macrophages with M1 phenotype 
(classically activated) 
Multiple cancers 
M1 macrophage conversion to 
M2 macrophages 
Increased in minutes71 72 
Intratumoral  
Multiple cancers 
Parasympathetic stimulation, 
elevation in pulse and blood 
pressure, mild hyperthermia 
Increased 44-47 
Increased perfusion of tumor, 
synergy between RT and 
hyperthermia. Hyperthermia 
increases NK cell infiltration, 
cytotoxic T-cell trafficking.  
Multiple cancers 
Blood vessel diameter size, 
improved tumor perfusion, 
reduction in hypoxia 
Increased 44,48-51 
Improved efficacy of RT via OER 
Multiple cancers 
Vascular normalization 
Increased 44,48-51 
Minutes  52 
Increased oxygenation, infiltration of 
tumor by immune cells 
Multiple cancers 
T-cell infiltration 
Increased in minutes 
26,63,90 61,62,91 
Increased in 
minutes - days  
Increased in 
minutes - days 52,92 
Immune recognition of cancer cells 
Multiple cancers 
Overall secretion of 
immunosuppressive factors 
Decreased in minutes 93 
Decreased immunosuppressive 
metabolites, increased 
immunogenicity in tumors 
Multiple cancers (esp. 
melanoma) 
Lactate 
Decreased 73 
Decreased immunosuppressive 
metabolites, increased 
immunogenicity in tumors 
Multiple cancers (esp. 
melanoma) 
LDH 
Decreased74 
Decreased immunosuppressive 
metabolites, increased 
immunogenicity in tumors 
Multiple cancers (esp. 
melanoma) 
NK cell infiltration 
Increased in minutes26,60-
62 63 
NK cells mobilized within minutes; 
max levels can be maintained up to 
3h by continues training. 
Immune recognition 
Multiple cancers 
Intracellular tumoral 
microenvironment 
Tumor growth kinetics 
Decreased melanoma, 
lung, colon, breast, HCC, 
head and neck 94-96 
Decreased, 
short/long-term 
Decreased, 
short/long-term 
Multiple cancers 
Cellular energy stress 
Induces stress, higher 
susceptibility to fasting, 
caloric restriction, RT in 
minutes 87,97,98 84 
Increased 
Increased 
Higher susceptibility to damage 
Multiple cancers 
Peptide pools and mTOR 
activation 
Decreased in minutes 
54,98 
Decreased in 
seconds-minutes    
52 
Decreased cell growth 
Increased IL-15 production, NK cell 
production, tumor cell recognition; 
synergistic effects with stress 
Multiple cancers 
AMPK 
Increased in organs and 
tumors 99 
Activated in 
seconds 100 
Activated in 
seconds 100 
Improvement in normal tissue repair. 
Initiates DNA damage repair. 
Activates ATM. Inhibits mTOR to 
inhibit protein translation. 
Multiple tumors and normal 
tissues 
Fas production 
Increased in 
minutes, lasting 
weeks     52 
Increased in 
minutes, lasting 
weeks     52 92 
Promotion of tumor death pathways Multiple cancers 
MHC-1 
Up-regulation  in 
Up-regulation in 
Increased immune recognition 
Multiple cancers 

Page 9 of 29  
 
 
 
2.1.4 Premise for current trial 
 
As of 2018, there are no studies evaluating the impact of exercise therapy and radiation therapy 
among all patients with cancer.  Thus, we plan a single group, pre-post intervention study to capture the 
effects of an exercise intervention on the average radiation therapy patient. 
 
2.2 
Previous Data 
 
International 
 
Previously published work on exercise interventions among all cancer patients revealed few 
injuries, no adverse effects of exercise during radiation therapy on relative dose intensity, and 
improvements in fatigue, pain, fitness, physical function, symptom scales, quality of life, depression, and 
anxiety.103,104  However, these studies generally recruited fewer than 15% of the patient pool originally 
targeted for recruitment.  Further, comparison of patient characteristics of those who entered these 
studies reveals that study participants tend to be younger, healthier, and have lower stage cancer, to be 
better educated, and to reflect less distress from their diagnosis.  As such, it may not be surprising to 
note that it has been challenging to translate these results into clinical practice.  The overarching goal of 
this protocol is to gather the necessary data to undertake a program of research in the area of 
dissemination and implementation science to translate the RCT evidence base on exercise during 
radiation therapy into clinical practice. 
 
Penn State Cancer Institute 
 
Table 2 details the patients treated at Penn State Cancer Institute in FY 2016.  Each month, 80 
patients (standard deviation, 9) start a course of definitive radiation therapy in the Department of 
Radiation Oncology.  Each day, there is an average of 52 patients on treatment (SD, 4).  Roughly half of 
these patients have an ECOG status of 0-2 and would be eligible for the current protocol.  Thus, we 
estimate that roughly 20-40 patients could be eligible for EXERT per month. 
  
Table 2.  Patients receiving treatment in the Department of Radiation Oncology at Penn State Cancer Institute. 
Month 
High dose rate 
brachytherapy 
procedures 
LINAC Based Treatment Procedures 
New Starts Total body 
irradiation Stereotactic Intensity 
modulated 
Standard 
Total  
 
Average 
Daily 
Patient 
Load 
July 
19 
72 
8 
23 
481 
616 
1120 
38 
August 
0 
61 
1 
13 
334 
575 
922 
34 
September 
0 
72 
6 
23 
277 
753 
1053 
42 
seconds-minutes    
52 
seconds-minutes     
52 
CD4+ and CD8+ cell 
production 
Minutes 56 
Continued increase 
over days    52,70 
Continued increase 
over days    52,92,101 
Cancer cell death, production of anti-
tumoral immune response 
Multiple cancers 
Chemokine release from CD8+ 
cells; Activation and expansion 
of tumor-specific CD4+, CD8+ 
T cells 
Minutes 56 
Continued increase 
over days    52 70 
Continued increase 
over days    52,101 
Cancer cell death, production of anti-
tumoral immune response 
Multiple cancers 
Reactive oxygen species 
production in tumor 
Increased blood 
circulation, O2 delivery 
49 48,51 
Increased in 
seconds-minutes    
52 
Increased in 
seconds-minutes     
52 
Improved killing by RT 
Multiple cancers 
Cancer cell necrosis, 
necroptosis 
Seconds-minutes     
52,101 
Cancer cell death, production of anti-
tumoral immune response 
Multiple cancers 
HMGB1 production 
Minutes 102 
Seconds-minutes     
101 
Increased tumor sensitivity to 
therapy, decreased normal tissue 
inflammation 
Multiple cancers 
Novel peptide production; 
TAA expression / release (e.g.  
gp70 and p53) 
Minutes 
Seconds-minutes   
52 
Days-weeks 52,92,101 Increased immune recognition 
Multiple cancers 

Page 10 of 29  
October 
10 
70 
0 
8 
294 
852 
1154 
53 
November 
4 
75 
0 
26 
308 
759 
1093 
66 
December 
11 
100 
0 
20 
344 
831 
1195 
68 
January 
5 
53 
1 
22 
374 
571 
968 
58 
February 
11 
79 
0 
24 
313 
603 
940 
48 
March 
8 
68 
0 
12 
402 
840 
1254 
76 
April 
0 
67 
1 
25 
406 
621 
1052 
52 
May 
0 
59 
1 
19 
399 
630 
1160 
53 
June 
1 
66 
0 
47 
307 
753 
1107 
64 
69 
842 
18 
262 
4239 
8404 
13018 
54 
 
 
2.3 
Study Rationale 
The slow maturation process from exercise research to clinically integrated cancer programming is 
similar to that experienced in cardiac rehabilitation. Challenges to knowledge translation in this field of 
exercise oncology persist and require strategic approaches to ensure that exercise programming is 
approached in a manner that is widely acceptable to patients and their clinicians.105 Therefore, we seek 
to conduct a safety and feasibility study to assess patient interest in exercise, adherence to exercise 
during radiation therapy, and logistics of operating an exercise intervention program in the department.  
We hope to gather data that will lead to externally funded dissemination and implementation research 
grants on the benefits of exercise during radiation therapy.   A new exercise facility has been built within 
the 2nd floor in the Penn State Cancer Institute in anticipation of this protocol. 
3.0 
Inclusion and Exclusion Criteria 
3.1 
Inclusion Criteria for cancer patients 
 
Males and females ≥18 years of age 
 
Fluent in written and spoken English 
 
Must be able to provide and understand informed consent 
 
Must have an ECOG PS of ≤ 2 
 
Diagnosed with a malignancy 
0
20
40
60
80
100
120
140
Breast
Bronchus & Lung
Thyroid Gland
Prostate Gland
Brain
Hematopoietic &…
Skin
Kidney
Spinal Cord & Other CNS
Corpus Uteri
Esophagus
Meninges
Rectum
Lymph Nodes
Bladder
Pancreas
Connective & Other Soft…
Cervix Uteri
Larynx
Stomach
Colon
Liver & Intrahepatic Bile Duc
Tonsil
Unknown Primary Site
Anus & Anal Canal
Base of Tongue
Other Tongue
Retroperitoneum &…
Bones & Cartilage of Other
Nasal Cavity & Middle Ear
Nasopharynx
Oropharynx
Other Endocrine Glands
Other Parts of Biliary Tract
Palate
Trachea
Uterus Nos
Vulva
Adrenal Gland
Bones & Cartilage of Limbs
Eye & Adnexa
Heart/Mediastinum/Pleura
Other Urinary Organs
Parotid Gland
Peripheral & Autonomic…
Renal Pelvis
Small Intestine
Testis
Thymus
Ureter
Vagina
number treated in 2015 

Page 11 of 29  
 
Cancer patients (stage 1-4) 
 
Treatment to primary site or metastatic disease 
 
Scheduled to receive radiation therapy at Penn State Cancer Institute 
 
Absence of absolute contraindications for exercise according to the American Heart Association (see 
below) 
 
Primary attending oncologist approval 
 
Receiving treatment as an outpatient 
 
3.2 
Exclusion Criteria for cancer patients 
 
Receiving radiation therapy at a location other than Penn State Cancer Institute 
 
Not fluent in written and spoken English 
 
Evidence in the medical record of an absolute contraindication for exercise  
 
Cardiac exclusion criteria: 
o Class II, III or IV heart failure as defined by the New York Heart Association (NYHA) 
functional classification system 
o History of acute coronary syndromes (including myocardial infarction and unstable 
angina), coronary angioplasty or stenting within the past 6 months prior to the start of 
radiation therapy 
o Uncontrolled arrhythmias; patients with rate controlled atrial fibrillation for >1 month 
prior to start of radiation therapy may be eligible 
o syncope 
o acute myocarditis, pericarditis, or endocarditis 
o acute pulmonary embolus or pulmonary infarction 
o thrombosis of lower extremities 
o suspected dissecting aneurysm 
o pulmonary edema 
o respiratory failure 
o acute non-cardiopulmonary disorder that may affect exercise performance or be 
aggravated by exercise 
o mental impairment leading to inability to cooperate 
 
Pregnant women 
 
In-patient receiving radiation therapy for a radiation emergency (e.g. cord compression, SVC 
syndrome, brain metastases) 
 
High risk of fracture or spine instability (Mirels score ≥7, SINS ≥7) 
 
Children (the protocol will only include individuals 18 and older) 
 
 
3.3 Early Withdrawal of Subjects 
 
3.3.1. Criteria for removal from study 
Subject consent withdrawal for any reason; consent process will ensure that patients 
understand this does not mean radiation therapy would stop. 
Development of contraindication(s) to exercise training. 
Worsening physical condition that indicates medical requirement of stopping exercise (as 
determined by treating oncologist). 
 
3.3.2. Follow-up for withdrawn subjects 
No follow up for withdrawn subjects. The patients will continue with their usual follow-up 
recommendations per standard of care. 
 

Page 12 of 29  
4.0 
Recruitment Methods 
 
4.1 
Identification of subjects 
 
4.1.1. Cancer patients 
Research staff members will pre-screen electronic medical records weekly for: new patients scheduled 
to receive radiation therapy at the Penn State Cancer Institute, and are diagnosed with cancer. 
Following identification of these patients, research staff will email the patient’s radiation oncologist via 
secure email for approval to approach the patient for the study and for medical clearance.  
 
 
4.2 
Recruitment process 
4.2.1. Cancer Patients 
If the radiation oncologist gives clearance, research staff will approach the patient either by phone 
following oncologist clearance (see script), or at their first fraction for presentation of the study. 
Meeting and consenting the patient earlier in their treatment would allow them to digest the 
information being discussed and start the study earlier in their treatment.   
 
 
4.3 
Recruitment materials 
4.3.1. Cancer Patients  
See attached script for staff member presentation of study. 
 
 
4.4 
Eligibility/screening of subjects 
4.4.1. Cancer Patients  
After initial presentation of the study to the patient, research staff will confirm eligibility utilizing the 
eligibility checklist. If the patient is deemed ineligible during this time, we will inform the patient that 
deidentified information/data will be kept and the purpose of keeping this information.  
 
5.0 
Consent Process and Documentation  
5.1 
Consent Process  
  
5.1.1 
Obtaining Informed Consent 
5.1.1.1 Timing and Location of Consent 
5.1.1.1.1. Cancer Patients 
If the patient remains interested in the study at the end of the study 
presentation we will confirm eligibility via the eligibility checklist. We will then 
walk through the consent form and answer any remaining questions. We will 
then obtain written informed consent. 
 
 
5.1.1.2 Coercion or Undue Influence during Consent 
5.1.1.1.1. Cancer patients. 
While exercise is recommended during cancer treatment, patients will be 
reminded that self-directed physical activity is also an available alternative for 
them.  Further, because faculty, staff, and students of Penn State University will 
not be excluded, we will include specific language to clarify that the patient 
relationship with their clinicians at Penn State will not be altered if they choose 
not to consent or choose to withdraw later. 

Page 13 of 29  
 
 
5.1.2 
Waiver or alteration of the informed consent requirement 
Requested for screening of medical records for recruitment purposes only. We also request that 
we are able to keep de-identified pre-screening data for those ineligible or not interested in the study.  
 
5.2 
Consent Documentation 
5.2.1 
Written Documentation of Consent 
Written informed consent document will be obtained from all patient participants prior to 
participation in any study activities. 
 
5.2.2 
Waiver of Documentation of Consent (Implied consent, Verbal consent, etc.) 
N/A 
 
 
5.3 
Consent – Other Considerations  
 
5.3.1 
Non-English Speaking Subjects 
Study staff are not fluent in languages other than English.  
 
5.3.2 
Cognitively Impaired Adults 
n/a 
 
5.3.2.1 Capability of Providing Consent 
This will be determined by the radiation oncologist in cancer patient clearance for 
the study and is assumed for the radiation oncology clinician participants. 
 
5.3.2.2 Adults Unable To Consent 
A contraindication to exercise training/counseling, and thus an ineligibility criteria 
is mental impairment leading to inability to cooperate. 
It is assumed that this will not be an issue for the radiation oncology clinicians. 
5.3.2.3 Assent of Adults Unable to Consent 
n/a 
 
5.3.3 
Subjects who are not yet adults (infants, children, teenagers)  
 
5.3.3.1 Parental Permission 
 
 
n/a 
 
5.3.3.2 Assent of subjects who are not yet adults 
n/a 
 
6.0 
HIPAA Research Authorization and/or Waiver or Alteration of Authorization 
6.1 
Authorization and/or Waiver or Alteration of Authorization for the Uses and Disclosures of PHI 
 
Check all that apply: 
 
Not applicable, no identifiable protected health information (PHI) is accessed, used or 
disclosed in this study. [Mark all parts of sections 6.2 and 6.3 as not applicable] 
 
 
Authorization will be obtained and documented as part of the consent process. [If this is the 
only box checked, mark sections 6.2 and 6.3 as not applicable] 

Page 14 of 29  
 
 
Partial waiver is requested for recruitment purposes only (Check this box if patients’ medical 
records will be accessed to determine eligibility before consent/authorization has been 
obtained). [Complete all parts of sections 6.2 and 6.3] 
 
 
Full waiver is requested for entire research study (e.g., medical record review studies). 
[Complete all parts of sections 6.2 and 6.3] 
 
 
Alteration is requested to waive requirement for written documentation of authorization 
(verbal authorization will be obtained). [Complete all parts of sections 6.2 and 6.3] 
 
6.2 
Waiver or Alteration of Authorization for the Uses and Disclosures of PHI 
 
6.2.1 
Access, use or disclosure of PHI representing no more than a minimal 
risk to the privacy of the individual 
 
6.2.1.1 Plan to protect PHI from improper use or disclosure 
Information is included in the “Confidentiality, Privacy and Data Management” 
section of this protocol. 
 
6.2.1.2 Plan to destroy identifiers or a justification for retaining identifiers  
We will identify eligible patients through electronic medical records prior to their 
consent in the study (pre-screen eligibility criteria).  Information from the pre-
screening will be collected and retained (not to include PHI) in order to track trends 
of those being screened, deemed ineligible, etc. 
 
6.2.2 
Explanation for why the research could not practicably be conducted 
without access to and use of PHI 
As we will be conducting the exercise intervention in the Exercise Medicine Unit located in the 
Penn State Cancer Institute we will be reviewing electronic patient records for this location. 
Further, this location also conducts infusions for MS patients, transplant patients, and 
rheumatoid arthritis patients. Therefore, screening patients at this location is necessary for 
identification of eligible patients.  
 
6.2.3 
Explanation for why the research could not practicably be conducted 
without the waiver or alteration of authorization 
Pre-screening individuals through electronic medical records allows for the timing of physician 
approval and approach of the patient. This study flow is being utilized to minimize clinician 
burden for clearing patients for eligibility, and to maximize our ability to determine the 
denominator of patients who could have participated in the study, which is required for the 
primary outcomes of safety, feasibility, and acceptability. In order to lessen the burden on the 
patient by extending a current visit or asking for additional visits to the institution, we will seek 
verbal consent authorization over the phone. 
 
6.3 
Waiver or alteration of authorization statements of agreement 
 
Protected health information obtained as part of this research will not be reused or disclosed to any 
other person or entity, except as required by law, for authorized oversight of the research study, or for 
other permitted uses and disclosures according to federal regulations.  
 

Page 15 of 29  
The research team will collect only information essential to the study and in accord with the ‘Minimum 
Necessary’ standard (information reasonably necessary to accomplish the objectives of the research) 
per federal regulations.  
 
Access to the information will be limited, to the greatest extent possible, within the research team. All 
disclosures or releases of identifiable information granted under this waiver will be accounted for and 
documented. 
 
7.0 
Study Design and Procedures 
 
7.1 
Study Design 
Pre/post single group (non-controlled) feasibility intervention trial. The study schema is outlined in 
Figure 3.  
 
Figure 3. Study schema.  In Part I, a patient is seen in consultation, consented, and simulated for 
radiation therapy.  Prior to initiation.  In Part II, radiation therapy is delivered, once per day, five days 
per week, for 1-8 weeks.  A weekly exercise therapy session is performed, and the patient is counseled 
on home exercise.  Part III is the first follow up of the patient. 
 
7.2 
Study Procedures 
7.2.1.1 Clinical covariates:  
Detailed clinical covariates will be obtained from a Health Behaviors Questionnaire (HBQ Exert) 
and medical record review including demographics (age, gender, race), cardiovascular history 
and risk factors (hypertension, arrhythmia, hyperlipidemia, tobacco use, family history of cardiac 
disease), clinical variables (blood pressure, weight), cancer factors (stage, histology, location), 
cancer treatment regimen (radiation dose, chemo use), and medication use.  These factors will 
be assessed in examining the patient acceptability of the study. 
 
7.2.1.2 Safety assessment 
Our team has developed a standardized survey (Injury History Questionnaire) for assessing 
injuries as well as discomfort from exercise.  This survey will be administered at the end of 
radiation therapy.  We will evaluate the number of injuries over the length of each patient’s 
chemo regimen and adjust the number by the number of weeks of radiation therapy. In 
addition, the exercise professional delivering the intervention will ask about any new injuries or 
discomfort at each encounter (radiation fraction) and record any issues that require a 
modification to exercises.  
 
7.2.1.3. Quality of life surveys: 

Page 16 of 29  
Godin Physical Activity Questionnaire,  Barriers to Exercise RM 5-FM, , Work Productivity and 
Activity Impairment Questionnaire, Scored Patient-Generated Subjective Global Assessment 
(PG-SGA), EORTC Quality of life questionnaire, ECHO EXERT and Health Belief Scale and adverse 
effects of treatment (CTCAE-PRO), as per Table 3. These will be administered during the first and 
last scheduled counseling session through REDCap 
 
The CTCAE-PRO will be analyzed descriptively for future studies. 
Table 3. CTCAE-PRO questions to be used, depending on cancer disease site. 
Question 
number 
Statistical 
plan 
Head/Neck 
Pelvis male 
(prostate, rectal, 
anal) 
Pelvis female 
(endometrial, 
cervix, rectal, 
anal) 
Breast 
Thorax (lung, 
esophagus, 
select 
lymphomas) 
Brain (glioma, 
meningioma) 
Upper abdomen 
(pancreas, liver, 
stomach, 
retroperitoneal 
sarcoma) 
Extremity 
(sarcoma) 
1 
Evaluate 
individual 
core 
questions 
before 
and after 
ET+RT 
Anxious 
Anxious 
Anxious 
Anxious 
Anxious 
Anxious 
Anxious 
Anxious 
2 
Discouraged 
Discouraged 
Discouraged 
Discouraged 
Discouraged 
Discouraged 
Discouraged 
Discouraged 
3 
Sad 
Sad 
Sad 
Sad 
Sad 
Sad 
Sad 
Sad 
4 
Insomnia 
Insomnia 
Insomnia 
Insomnia 
Insomnia 
Insomnia 
Insomnia 
Insomnia 
5 
Fatigue 
Fatigue 
Fatigue 
Fatigue 
Fatigue 
Fatigue 
Fatigue 
Fatigue 
6 
General Pain 
General Pain 
General Pain 
General Pain 
General Pain 
General Pain 
General Pain 
General Pain 
7 
Headache 
Headache 
Headache 
Headache 
Headache 
Headache 
Headache 
Headache 
8 
Concentration 
Concentration 
Concentration Concentration 
Concentration Concentration 
Concentration Concentration 
9 
Memory 
Memory 
Memory 
Memory 
Memory 
Memory 
Memory 
Memory 
10 
These 
questions 
will be 
averaged 
across 
entire 
disease 
site, then 
evaluated 
before 
and after 
ET+RT 
Dry mouth 
Diarrhea 
Diarrhea 
Rash 
Difficulty 
swallowing 
Dry mouth 
Diarrhea 
Rash 
11 
Difficulty 
swallowing 
Abdominal pain 
Abdominal 
pain 
Skin dryness 
Hoarseness 
Difficulty 
swallowing 
Nausea 
Skin dryness 
12 
Mouth/throat 
sores 
Fecal incontinence 
Fecal 
incontinence 
Itching 
Decreased 
appetite 
Skin dryness 
Vomiting 
Hair loss 
13 
Cheilosis 
Painful urination 
Painful 
urination 
Radiation skin 
reaction 
Nausea 
Mouth/throat 
sores 
Heartburn 
Itching 
14 
Voice changes 
Urinary urgency 
Urinary 
urgency 
Breast swelling and 
tenderness 
Vomiting 
Numbness/tingling Abdominal pain 
Radiation skin 
reaction 
15 
Hoarseness 
Urinary frequency 
Urinary 
frequency 
Hot flashes 
Heartburn 
Dizziness 
Gas 
Numbness and 
tingling 
16 
Taste changes 
Urinary 
incontinence 
Urinary 
incontinence 
Skin darkening 
Abdominal 
pain 
Radiation skin 
reaction 
Taste changes 
Bruising 
17 
Nausea 
Achieve/ maintain 
erection 
Vaginal 
discharge 
Bruising 
Shortness of 
breath 
Blurred vision 
Hiccups 
Swelling 
18 
Vomiting 
Ejaculation 
Vaginal dryness Decreased appetite 
Cough 
Flashing lights 
Shortness of 
breath 
Skin darkening 
19 
Rash 
Decreased libido 
Decreased 
libido 
Chills 
Heart 
palpitations 
Ringing in ears 
Fecal 
incontinence 
Stretch marks 
20 
Radiation skin 
reaction 
Pain w intercourse 
Pain w 
intercourse 
Increased sweating 
Chills 
Hair loss 
Decreased 
appetite 
Bed/pressure 
sores 
 
7.2.1.4 Exercise intervention: 
The exercise intervention will utilize the “Moving Through Cancer: A Guide to Exercise for 
Cancer Survivors” framework. A certified cancer exercise physiologist will work through this 
guide at radiation therapy visits, with at least 1 visit per week, per the study schema. The cancer 
exercise physiologist will teach participants proper: warm ups, use of equipment, exercise form, 
modes of activity, intensity of exercise, flexibility exercises, and cool down. The cancer exercise 
physiologist will tailor the instruction to convey special considerations for exercise based on 
treatment and cancer type. The patient will perform supervised exercise in the Exercise 
Medicine Unit under the guidance of the cancer exercise specialist. The exercise done will be 
educational in nature (i.e. learning about proper walking form, proper intensity for a 
warmup/cool down, proper techniques for resistance exercises). 
 
In addition, patients will be instructed to exercise on their own, at home, according to the 
instructions from the cancer exercise specialist.   Each patient will be provided a specific exercise 
prescription to follow at home, in between radiation therapy fractions and will be asked to 

Page 17 of 29  
record what they do in between daily radiation fraction visits. The exercise intervention is 
tailored to each patient; exercises as performed between 1 and 7 times per week, depending on 
the patient’s tolerance to the treatment. 
The cancer exercise physiologist will review the records at each radiation fraction visit and will 
provide guidance to revise the program as symptoms change and fitness level shifts.  Questions 
on nutrition will result in a referral to a Registered Dietitian.   
 
 
 
7.2.1.5. Physical functioning testing: 
Participants will be tested for balance and strength using the following assessments:  
Grip Strength Dynamometer 
30-second Chair Stand* 
Timed Up and Go* 
4-Stage Balance* 
 
*part of the CDC STEADI program to assess fall risk. 
Protocols and source docs are provided in attachments. 
 
 
7.3 
Duration of Participation 
 
Cancer Patients 
Estimated time to enroll all subjects = <12 months  
Length of a participant's participation = 3-8 weeks, depending on the length of their radiation therapy 
 
8.0 
Subject Numbers and Statistical Plan 
 
8.1 
Number of Subjects 
50 total participants planned to accept the study. 
 
8.2 
Sample size determination 
Cancer Patients 
Our primary aim is to establish safety and feasibility.   Our sample size is based on review of the volume 
of patients seen at the cancer institute for radiation therapy.  We hope to recruit over 25% of radiation 
therapy patients into this intervention trial, as described in the section on “Feasibility of recruiting the 
required number of subjects.”  
 
Patients will have the opportunity to decline enrollment but all attempts to recruit all patients will be 
done. Records will reflect the number of patients for determining the proportion that agree to exercise 
counseling and a brief set of measures. Therefore, our sample size is based on expected # of patients, 
rather than the ability to power a specific statistical test. 
 
 
8.3 
Statistical methods 
Our primary outcomes are descriptive. We will compare pre- and post- values for all of our secondary 
outcomes, within patients.  A two-sided significance level of 0.05 will be used for all statistical tests.  
 
Acceptability is defined as: (number of patients agreeing to perform RT+ET)/(number approached); 
feasibility is defined as: (number of patients who completed RT+ET)/(number agreeing to perform 
RT+ET); safety is defined as freedom from any Common Terminology Criteria for Adverse Events (CTCAE) 
grade 3 or higher event. 
 

Page 18 of 29  
These values do not have associated statistical tests of 95% confidence intervals, but are vital to 
establishing that it is possible to do the intervention in a manner that will support future research and 
translation into clinical practice.  Dr. Schmitz’ laboratory has used this same approach in multiple prior 
studies.108    
 
Other outcomes in our study include timed up and go, grip strength, and quality of life surveys.  Our goal 
with this pilot and feasibility study is to demonstrate the effect size that might be expected in future 
studies.  As such, statistical tests are not appropriate at this stage of inquiry. 
 
Finally, we will also be abstracting data from the medical record regarding the progress of the patient 
through radiation therapy (e.g. recording dose alterations and delays and adverse effects of treatment).  
We will compare the results to published values for these outcomes.  This comparison will not include 
any statistical testing; it will be done for the purpose of determining the effect size that might be 
expected in future research. 
9.0 
Confidentiality, Privacy and Data Management  
See the Research Data Plan Review Form  
10.0 Data and Safety Monitoring Plan 
10.1 
Periodic evaluation of data 
As part of the exercise session the cancer exercise physiologist will review any new health issues.  
Further, prior to every session, the study staff will review the medical record to identify any changes in 
status that might influence exercise capacity.  It is fully expected that exercise capacity will vary 
throughout radiation therapy and exercise counseling will reflect personalized response to these 
fluctuations in functional capacity. 
 
10.2 
Data that are reviewed 
Laboratory reports and clinician progress notes. 
 
10.3 
Method of collection of safety information 
The cancer exercise physiologist will document any adverse events in participants.   
 
10.4 
Frequency of data collection 
At each counselling session. 
 
10.5 
Individuals reviewing the data 
Kathryn Schmitz (Kinesiology; Physical Medicine and Rehabilitation), Diane Hershock (Medical 
Oncology), Nicholas Zaorsky (Radiation Oncology), Jessica Moyer (project manager), and a masters 
trained exercise physiologist.   
 
10.6 
Frequency of review of cumulative data 
We will review cumulative data quarterly.  
 
10.7 
Statistical tests 
Fisher’s exact tests and χ2-tests will be used to examine pre-post differences in all secondary outcomes 
(e.g.; symptoms, function). 
 
10.8 
Suspension of research 
 
There is some level of injury expected from strength training.  The injury rate observed in the general 
population in those who report involvement in strength training over the past 30 days is 3-4%.9,103  The 

Page 19 of 29  
principal investigator will review adverse event rates at 6 months into the intervention.  Any training 
injury rate over 24% in 6 months will be reported to the safety officer and the Penn State IRB.   
 
For patients with breast cancer, we will use the PAL trial results as guide to know whether to stop the 
intervention.  For patients who enter the study with lymphedema, we expect 15% of them to experience 
at least 1 ‘flare-up’ or exacerbation of lymphedema over 12 months.  If the proportion of lymphedema 
flare-ups exceeds this rate, we will stop the intervention for patients with lymphedema.  Similarly, we 
expect the onset rate of lymphedema to be about 4%.  If the proportion of participants who experience 
lymphedema onset exceeds 4% we will stop the intervention.  
 
11.0 Risks  
Cardiovascular 
There is some level of injury expected from aerobic exercise training which rises to the level of medical 
treatment.  The injury rate observed in the general population in those who report involvement in 
aerobic exercise training over the past 30 days was 1.8%, with injuries defined as symptoms that last a 
week or longer and/or require the attention of a medical professional.  Over a 12 month period we 
might expect 12 times that rate or 21.6%. The principal investigator will review adverse event rates at 6 
months into the intervention.  Any training injury rate over 10.8% in 6 months will be reported to the 
safety officer and the Penn State IRB. 
 
The risk of an exercise training induced CV event is 2 nonfatal CV events in 375,000 subject hrs of 
exercise, or about 1 event per 1.7 million walk/jogging miles, based on a large Dallas, TX physical activity 
center study. There is some level of injury expected from exercise which rises to the level of medical 
treatment.  The injury rate observed in the general population in those who report involvement in 
aerobic exercise training over the past 30 days was 1.8% 109, with injuries defined as symptoms that last 
a week or longer and/or require the attention of a medical professional.  The injury rate observed in the 
general population in those who report involvement in strength training over the past 30 days is 3-4%.  
In 242 breast cancer patients randomized to an aerobic or resistance training intervention during 
radiation therapy, the researchers observed an injury rate of 4.4%.  
Fracture 
There is a risk of fracture in patients with a cancer that involves a long bone or the vertebral column.    
There are two scoring systems commonly used to estimate the risk of fracture in these scenarios.  The 
Mirels score106 is a scoring system used by radiation oncologists to estimate risk of fracture with 
metastasis in long bones.  This study will exclude patients with a score of ≥7.  A score of <7 corresponds 
to a 0% fracture risk. The spinal instability neoplastic score (SINS)107 estimates risk of fracture for spine 
metastases; a SINS score < 5 also corresponds to a 0% fracture risk.  All of the patients on EXERT will 
have scores < 7 or not applicable. 
 
 
 
SINS variable 
0 
1 
2 
3 
4 
Location 
Rigid (S2-S5) 
Semirigid (T3-T10) Mobile (C3-C6, 
L2-L4) 
Junctional (Occiput-
C2, C7-T2, T11-L1, L5- - 
Mirels score 
n 
fracture rate, % 
<7 
11 
0 
7 
19 
5 
8 
12 
33 
9 
7 
57 
10-12 
18 
100 
Points for Mirels score 
1 
2 
3 
site 
upper 
extremity  
Lower 
extremity 
peritrochanteric 
pain 
mild 
moderate mechanical 
radiograph 
blastic 
mixed 
lytic 
% of shaft 
<33% 
34-67% 
>68% 

Page 20 of 29  
S1) 
Pain 
None 
Occasional 
- 
Yes 
- 
Bone lesion 
Blastic 
Mixed 
Lytic 
- 
- 
Radiographic 
alignment 
Normal 
- 
De novo 
kyphosis/ 
scoliosis 
- 
Subluxation/ 
translation 
Vertebral body 
collapse 
None, <50% 
vertebral body 
involved 
None, >50% 
vertebral body 
involved 
<50% 
>50% 
- 
Posterior 
involvement 
None 
Unilateral 
- 
Bilateral 
- 
 
Other risks 
There are no medical risks associated with filling out surveys, however a patient may become uncomfortable 
providing personal information. Any questions that make a patient uncomfortable can be skipped. This will be 
clarified during the consent process. 
 
There are no reported risks for hand dynamometer testing. Performance of the chair stands, timed up and go, 
and balance tests can result in muscle injury or falls.  This risk will be minimized by having trained staff perform 
the tests and monitor participants closely.  If it becomes apparent that the activity cannot be continued without 
injury, the staff will stop the evaluation activity. 
There is a risk of loss of confidentiality if medical information or identity is obtained by someone other than the 
investigators, but precautions will be taken to prevent this from happening. 
12.0 Potential Benefits to Subjects and Others 
 
12.1 
Potential Benefits to Subjects 
Cancer Patients: Participants may decrease their risk for chronic diseases and may decrease their cancer 
related fatigue, dose limiting toxicities, improve quality of life, and complete radiation therapy with 
better function than if they do not exercise.  Participants will also receive exercise training without cost.   
 
 
12.2 
Potential Benefits to Others 
The information obtained from this research study may benefit future cancer patients by demonstrating 
safety and efficacy of exercise counseling in cancer care.  
13.0 Sharing Results with Subjects 
Patients will be offered a report of the changes in their functional testing from baseline to post-radiation 
therapy. 
14.0 Subject Stipend (Compensation) and/or Travel Reimbursements 
None 
15.0 Economic Burden to Subjects 
 
15.1 
Costs  
None 
 

Page 21 of 29  
15.2 
Compensation for research-related injury 
It is the policy of the institution to provide neither financial compensation nor free medical treatment 
for research-related injury. In the event of injury resulting from this research, medical treatment is 
available but will be provided at the usual charge. Costs for the treatment of research-related injuries 
will be charged to subjects or their insurance carriers.  
16.0 Resources Available 
16.1 
Facilities and locations 
All recruitment and testing will be conducted at the Penn State Hershey Medical Center, in the 
dedicated Exercise Therapy Unit. 
 
16.2 
Feasibility of recruiting the required number of subjects 
Cancer patients:  We aim to recruit 50 eligible patients (i.e. 50 people who consent to the study when 
initially approached) undergoing radiation therapy at the Milton S. Hershey Medical Center.   
 
The Department of Radiation Oncology starts approximately 71 patients on radiation therapy on a LINAC 
per month (Table 2).  There are about 17 GammaKnife Radiosurgery procedures per month; 
approximately 4 patients receiving SBRT per month; approximately 9 starting definitive intensity 
modulated radiation therapy per month; and over 30 patients receiving 2D or 3D- conformal radiation 
therapy per month.  The average daily load is about 54 patients receiving some form of radiation 
therapy.  We hope to recruit over 25% of radiation therapy patients into this intervention trial.  With a 
conservative recruitment of only 10% performing the intervention, we would still be able to enroll 96 
patients per year. 
 
 
 
 
16.3 
PI Time devoted to conducting the research 
The PI (Nicholas G Zaorsky, MD) has assembled a research team composed of clinicians, researchers, and 
exercise physiologists whom will carry out and oversee the study.  While this is an unfunded study, the 
PI has 40% protected time for this work associated with his recruitment package. 
 
16.4 
Availability of medical or psychological resources 
All necessary equipment to take part in this study is provided (surveys, testing on site). If medical or 
psychological needs arise, subjects will be directed to the Emergency Department for follow-up. 
 
16.5 
Process for informing Study Team 
All study team members have been involved in the development of the study and have approved study 
protocols. 
 

Page 22 of 29  
17.0 
Other Approvals 
17.1 
Other Approvals from External Entities 
 
 
n/a 
 
17.2 
Internal PSU Committee Approvals 
 
Check all that apply: 
  Anatomic Pathology – Hershey only – Research involves the collection of tissues or use of pathologic 
specimens. Upload a copy of HRP-902 - Human Tissue For Research Form on the “Supporting 
Documents” page in CATS IRB. This form is available in the CATS IRB Library.   
 
  Animal Care and Use – All campuses – Human research involves animals and humans or the use of 
human tissues in animals 
 
  Biosafety – All campuses – Research involves biohazardous materials (human biological specimens 
in a PSU research lab, biological toxins, carcinogens, infectious agents, recombinant viruses or DNA 
or gene therapy). 
 
  Clinical Laboratories – Hershey only – Collection, processing and/or storage of extra tubes of body 
fluid specimens for research purposes by the Clinical Laboratories; and/or use of body fluids that 
had been collected for clinical purposes, but are no longer needed for clinical use. Upload a copy of 
HRP-901 - Human Body Fluids for Research Form on the “Supporting Documents” page in CATS IRB. 
This form is available in the CATS IRB Library.  
 
  Clinical Research Center (CRC) Advisory Committee – All campuses – Research involves the use of 
CRC services in any way. 
 
  Conflict of Interest Review – All campuses – Research has one or more of study team members 
indicated as having a financial interest. 
 
  Radiation Safety – Hershey only – Research involves research-related radiation procedures. All 
research involving radiation procedures (standard of care and/or research-related) must upload a 
copy of HRP-903 - Radiation Review Form on the “Supporting Documents” page in CATS IRB. This 
form is available in the CATS IRB Library. 
 
  IND/IDE Audit – All campuses – Research in which the PSU researcher holds the IND or IDE or 
intends to hold the IND or IDE. 
 
  Scientific Review – Hershey only – All investigator-written research studies requiring review by the 
convened IRB must provide documentation of scientific review with the IRB submission. The 
scientific review requirement may be fulfilled by one of the following: (1) external peer-review 
process; (2) department/institute scientific review committee; or (3) scientific review by the Clinical 
Research Center Advisory committee.  NOTE: Review by the Penn State Hershey Cancer Institute 
Scientific Review Committee is required if the study involves cancer prevention studies or cancer 
patients, records and/or tissues. For more information about this requirement see the IRB website 
at: http://www.pennstatehershey.org/web/irb/home/resources/investigator  
 
18.0 
Multi-Site Research 
 

Page 23 of 29  
18.1 
Communication Plans 
n/a 
 
18.2 
Data Submission and Security Plan 
n/a 
 
18.3 
Subject Enrollment 
n/a 
 
18.4 
Reporting of Adverse Events and New Information 
n/a 
 
18.5 
Audit and Monitoring Plans 
n/a 
 
19.0 
Adverse Event Reporting 
 
19.1 
Reporting Adverse Reactions and Unanticipated Problems to the Responsible IRB  
 
In accordance with applicable policies of The Pennsylvania State University Institutional Review Board 
(IRB), the investigator will report, to the IRB, any observed or reported harm (adverse event) 
experienced by a subject or other individual, which in the opinion of the investigator is determined to be 
(1) unexpected; and (2) probably related to the research procedures. Harms (adverse events) will be 
submitted to the IRB in accordance with the IRB policies and procedures. 
 
20.0 
Study Monitoring, Auditing and Inspecting 
 
20.1 
Auditing and Inspecting  
 
The investigator will permit study-related monitoring, audits, and inspections by the Penn State quality 
assurance program office(s), IRB, the sponsor, and government regulatory bodies, of all study related 
documents (e.g., source documents, regulatory documents, data collection instruments, study data 
etc.).  The investigator will ensure the capability for inspections of applicable study-related facilities 
(e.g., pharmacy, diagnostic laboratory, etc.). 
 
21.0 
Future Undetermined Research: Data and Specimen Banking 
 
21.1 
Data and/or specimens being stored 
 
 
No data or specimens will be stored for research not related to this protocol.  
 
21.2 
Location of storage 
 
 
n/a 
 
21.3 
Duration of storage 
n/a 
 
21.4 
Access to data and/or specimens 
n/a 
 

Page 24 of 29  
21.5 
Procedures to release data or specimens 
n/a 
 
21.6 
Process for returning results 
n/a 
 
 
 

Page 25 of 29  
22.0 
References 
 
 
1. 
Bunn PA, Jr., Kelly K. New chemotherapeutic agents prolong survival and improve quality of life in non-small cell lung 
cancer: a review of the literature and future directions. Clin. Cancer Res. May 1998;4(5):1087-1100. 
2. 
Coates A, Gebski V, Bishop JF, et al. Improving the quality of life during chemotherapy for advanced breast cancer. A 
comparison of intermittent and continuous treatment strategies. N. Engl. J. Med. Dec 10 1987;317(24):1490-1495. 
3. 
Thatcher N, Girling DJ, Hopwood P, Sambrook RJ, Qian W, Stephens RJ. Improving survival without reducing quality of life in 
small-cell lung cancer patients by increasing the dose-intensity of chemotherapy with granulocyte colony-stimulating factor 
support: results of a British Medical Research Council Multicenter Randomized Trial. Medical Research Council Lung Cancer 
Working Party. J. Clin. Oncol. Jan 2000;18(2):395-404. 
4. 
Balboni TA, Vanderwerker LC, Block SD, et al. Religiousness and spiritual support among advanced cancer patients and 
associations with end-of-life treatment preferences and quality of life. J. Clin. Oncol. Feb 10 2007;25(5):555-560. 
5. 
Osborn RL, Demoncada AC, Feuerstein M. Psychosocial interventions for depression, anxiety, and quality of life in cancer 
survivors: meta-analyses. Int. J. Psychiatry Med. 2006;36(1):13-34. 
6. 
Galvao DA, Newton RU. Review of exercise intervention studies in cancer patients. J. Clin. Oncol. Feb 01 2005;23(4):899-
909. 
7. 
Courneya KS, Segal RJ, McKenzie DC, et al. Effects of exercise during adjuvant chemotherapy on breast cancer outcomes. 
Med. Sci. Sports Exerc. Sep 2014;46(9):1744-1751. 
8. 
Segal RJ, Reid RD, Courneya KS, et al. Randomized controlled trial of resistance or aerobic exercise in men receiving 
radiation therapy for prostate cancer. J. Clin. Oncol. Jan 20 2009;27(3):344-351. 
9. 
Schmitz KH, Holtzman J, Courneya KS, Masse LC, Duval S, Kane R. Controlled physical activity trials in cancer survivors: a 
systematic review and meta-analysis. Cancer Epidemiol. Biomarkers Prev. Jul 2005;14(7):1588-1595. 
10. 
Schmitz KH, Courneya KS, Matthews C, et al. American College of Sports Medicine roundtable on exercise guidelines for 
cancer survivors. Med Sci Sports Exerc. Jul 2010;42(7):1409-1426. 
11. 
Hayes SC, Spence RR, Galvao DA, Newton RU. Australian Association for Exercise and Sport Science position stand: 
optimising cancer outcomes through exercise. J Sci Med Sport. Jul 2009;12(4):428-434. 
12. 
van den Berg JP, Velthuis MJ, Gijsen BC, Lindeman E, van der Pol MA, Hillen HF. [Guideline "Cancer rehabilitation"]. Ned 
Tijdschr Geneeskd. 2011;155(51):A4104. 
13. 
Rock CL, Doyle C, Demark-Wahnefried W, et al. Nutrition and physical activity guidelines for cancer survivors. CA Cancer J 
Clin. Jul-Aug 2012;62(4):243-274. 
14. 
Wolin KY, Schwartz AL, Matthews CE, Courneya KS, Schmitz KH. Implementing the exercise guidelines for cancer survivors. 
The journal of supportive oncology. Sep-Oct 2012;10(5):171-177. 
15. 
Lipsett A, Barrett S, Haruna F, Mustian K, O'Donovan A. The impact of exercise during adjuvant radiotherapy for breast 
cancer on fatigue and quality of life: A systematic review and meta-analysis. Breast. Apr 2017;32:144-155. 
16. 
Taaffe DR, Buffart LM, Newton RU, et al. Time on androgen deprivation therapy and adaptations to exercise: secondary 
analysis from a 12-month randomized controlled trial in men with prostate cancer. BJU Int. Sep 05 2017. 
17. 
Chandwani KD, Perkins G, Nagendra HR, et al. Randomized, controlled trial of yoga in women with breast cancer 
undergoing radiotherapy. J. Clin. Oncol. Apr 01 2014;32(10):1058-1065. 
18. 
Chandwani KD, Thornton B, Perkins GH, et al. Yoga improves quality of life and benefit finding in women undergoing 
radiotherapy for breast cancer. J. Soc. Integr. Oncol. Spring 2010;8(2):43-55. 
19. 
Chen Z, Meng Z, Milbury K, et al. Qigong improves quality of life in women undergoing radiotherapy for breast cancer: 
results of a randomized controlled trial. Cancer. May 01 2013;119(9):1690-1698. 
20. 
Campbell A, Mutrie N, White F, McGuire F, Kearney N. A pilot study of a supervised group exercise programme as a 
rehabilitation treatment for women with breast cancer receiving adjuvant treatment. European journal of oncology nursing 
: the official journal of European Oncology Nursing Society. Mar 2005;9(1):56-63. 
21. 
Mutrie N, Campbell AM, Whyte F, et al. Benefits of supervised group exercise programme for women being treated for 
early stage breast cancer: pragmatic randomised controlled trial. BMJ. Mar 10 2007;334(7592):517. 
22. 
Hwang JH, Chang HJ, Shim YH, et al. Effects of supervised exercise therapy in patients receiving radiotherapy for breast 
cancer. Yonsei Med. J. Jun 30 2008;49(3):443-450. 
23. 
Steindorf K, Schmidt ME, Klassen O, et al. Randomized, controlled trial of resistance training in breast cancer patients 
receiving adjuvant radiotherapy: results on cancer-related fatigue and quality of life. Ann. Oncol. Nov 2014;25(11):2237-
2243. 
24. 
Reis D, Walsh ME, Young-McCaughan S, Jones T. Effects of Nia exercise in women receiving radiation therapy for breast 
cancer. Oncol. Nurs. Forum. Sep 2013;40(5):E374-381. 
25. 
Drouin JS, Young TJ, Beeler J, et al. Random control clinical trial on the effects of aerobic exercise training on erythrocyte 
levels during radiation treatment for breast cancer. Cancer. Nov 15 2006;107(10):2490-2495. 

Page 26 of 29  
26. 
Pedersen L, Idorn M, Olofsson GH, et al. Voluntary Running Suppresses Tumor Growth through Epinephrine- and IL-6-
Dependent NK Cell Mobilization and Redistribution. Cell Metab. Mar 08 2016;23(3):554-562. 
27. 
Gabriel BM, Hamilton DL, Tremblay AM, Wackerhage H. The Hippo signal transduction network for exercise physiologists. J 
Appl Physiol (1985). May 15 2016;120(10):1105-1117. 
28. 
Yu FX, Zhao B, Panupinthu N, et al. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell. Aug 
17 2012;150(4):780-791. 
29. 
Friedenreich CM, O'Reilly R, Shaw E, et al. Inflammatory Marker Changes in Postmenopausal Women after a Year-long 
Exercise Intervention Comparing High Versus Moderate Volumes. Cancer Prev Res (Phila). Feb 2016;9(2):196-203. 
30. 
Jones SB, Thomas GA, Hesselsweet SD, Alvarez-Reeves M, Yu H, Irwin ML. Effect of exercise on markers of inflammation in 
breast cancer survivors: the Yale exercise and survivorship study. Cancer Prev Res (Phila). Feb 2013;6(2):109-118. 
31. 
Imayama I, Ulrich CM, Alfano CM, et al. Effects of a caloric restriction weight loss diet and exercise on inflammatory 
biomarkers in overweight/obese postmenopausal women: a randomized controlled trial. Cancer Res. May 01 
2012;72(9):2314-2326. 
32. 
Ballard-Barbash R, Friedenreich CM, Courneya KS, Siddiqi SM, McTiernan A, Alfano CM. Physical activity, biomarkers, and 
disease outcomes in cancer survivors: a systematic review. J. Natl. Cancer Inst. Jun 06 2012;104(11):815-840. 
33. 
Zaorsky NG, Shaikh T, Ruth K, et al. Prostate Cancer Patients With Unmanaged Diabetes or Receiving Insulin Experience 
Inferior Outcomes and Toxicities After Treatment With Radiation Therapy. Clin. Genitourin. Cancer. Apr 2017;15(2):326-335 
e323. 
34. 
McTiernan A. Mechanisms linking physical activity with cancer. Nat. Rev. Cancer. Mar 2008;8(3):205-211. 
35. 
Christensen JF, Jones LW, Andersen JL, Daugaard G, Rorth M, Hojman P. Muscle dysfunction in cancer patients. Ann. Oncol. 
May 2014;25(5):947-958. 
36. 
Pollack MN. Insulin, insulin-like growth factors, insulin resistance, and neoplasia. Am J Clin Nutr. Sep 2007;86(3):s820-822. 
37. 
Kir S, Komaba H, Garcia AP, et al. PTH/PTHrP Receptor Mediates Cachexia in Models of Kidney Failure and Cancer. Cell 
Metab. Feb 09 2016;23(2):315-323. 
38. 
Gallot YS, Durieux AC, Castells J, et al. Myostatin gene inactivation prevents skeletal muscle wasting in cancer. Cancer Res. 
Dec 15 2014;74(24):7344-7356. 
39. 
Hojman P, Fjelbye J, Zerahn B, et al. Voluntary exercise prevents cisplatin-induced muscle wasting during chemotherapy in 
mice. PLoS ONE. 2014;9(9):e109030. 
40. 
Casla S, Hojman P, Cubedo R, Calvo I, Sampedro J, Barakat R. Integrative exercise and lifestyle intervention increases 
leisure-time activity in breast cancer patients. Integr. Cancer Ther. Nov 2014;13(6):493-501. 
41. 
Christensen JF, Jones LW, Tolver A, et al. Safety and efficacy of resistance training in germ cell cancer patients undergoing 
chemotherapy: a randomized controlled trial. Br. J. Cancer. Jul 08 2014;111(1):8-16. 
42. 
Nguyen PL, Alibhai SM, Basaria S, et al. Adverse effects of androgen deprivation therapy and strategies to mitigate them. 
Eur. Urol. May 2015;67(5):825-836. 
43. 
Fearon K, Arends J, Baracos V. Understanding the mechanisms and treatment options in cancer cachexia. Nat. Rev. Clin. 
Oncol. Feb 2013;10(2):90-99. 
44. 
Evans SS, Repasky EA, Fisher DT. Fever and the thermal regulation of immunity: the immune system feels the heat. Nat. 
Rev. Immunol. Jun 2015;15(6):335-349. 
45. 
Evans ES, Hackney AC, McMurray RG, et al. Impact of Acute Intermittent Exercise on Natural Killer Cells in Breast Cancer 
Survivors. Integr. Cancer Ther. Sep 2015;14(5):436-445. 
46. 
Chen Q, Fisher DT, Clancy KA, et al. Fever-range thermal stress promotes lymphocyte trafficking across high endothelial 
venules via an interleukin 6 trans-signaling mechanism. Nat. Immunol. Dec 2006;7(12):1299-1308. 
47. 
Fisher DT, Chen Q, Skitzki JJ, et al. IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for 
trafficking of cytotoxic T cells. J. Clin. Invest. Oct 2011;121(10):3846-3859. 
48. 
Garcia E, Becker VG, McCullough DJ, et al. Blood flow responses to mild-intensity exercise in ectopic vs. orthotopic prostate 
tumors; dependence upon host tissue hemodynamics and vascular reactivity. J Appl Physiol (1985). Jul 01 2016;121(1):15-
24. 
49. 
Betof AS, Lascola CD, Weitzel D, et al. Modulation of murine breast tumor vascularity, hypoxia and chemotherapeutic 
response by exercise. J. Natl. Cancer Inst. May 2015;107(5). 
50. 
McCullough DJ, Stabley JN, Siemann DW, Behnke BJ. Modulation of blood flow, hypoxia, and vascular function in orthotopic 
prostate tumors during exercise. J. Natl. Cancer Inst. Apr 2014;106(4):dju036. 
51. 
McCullough DJ, Nguyen LM, Siemann DW, Behnke BJ. Effects of exercise training on tumor hypoxia and vascular function in 
the rodent preclinical orthotopic prostate cancer model. J Appl Physiol (1985). Dec 2013;115(12):1846-1854. 
52. 
Kwilas AR, Donahue RN, Bernstein MB, Hodge JW. In the field: exploiting the untapped potential of immunogenic 
modulation by radiation in combination with immunotherapy for the treatment of cancer. Frontiers in oncology. 
2012;2:104. 

Page 27 of 29  
53. 
Satoh-Takayama N, Lesjean-Pottier S, Vieira P, et al. IL-7 and IL-15 independently program the differentiation of intestinal 
CD3-NKp46+ cell subsets from Id2-dependent precursors. J. Exp. Med. Feb 15 2010;207(2):273-280. 
54. 
Marcais A, Cherfils-Vicini J, Viant C, et al. The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the 
development and activation of NK cells. Nat. Immunol. Aug 2014;15(8):749-757. 
55. 
Henningsen J, Rigbolt KT, Blagoev B, Pedersen BK, Kratchmarova I. Dynamics of the skeletal muscle secretome during 
myoblast differentiation. Mol. Cell. Proteomics. Nov 2010;9(11):2482-2496. 
56. 
Conlon KC, Lugli E, Welles HC, et al. Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and 
cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. J. Clin. 
Oncol. Jan 01 2015;33(1):74-82. 
57. 
Calveley VL, Khan MA, Yeung IW, Vandyk J, Hill RP. Partial volume rat lung irradiation: temporal fluctuations of in-field and 
out-of-field DNA damage and inflammatory cytokines following irradiation. Int. J. Radiat. Biol. Dec 2005;81(12):887-899. 
58. 
Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol. Rev. Oct 
2008;88(4):1379-1406. 
59. 
Pedersen BK, Febbraio MA. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat. Rev. Endocrinol. Apr 03 
2012;8(8):457-465. 
60. 
Timmons BW, Cieslak T. Human natural killer cell subsets and acute exercise: a brief review. Exerc. Immunol. Rev. 
2008;14:8-23. 
61. 
Ferrone C, Dranoff G. Dual roles for immunity in gastrointestinal cancers. J. Clin. Oncol. Sep 10 2010;28(26):4045-4051. 
62. 
Pages F, Galon J, Dieu-Nosjean MC, Tartour E, Sautes-Fridman C, Fridman WH. Immune infiltration in human tumors: a 
prognostic factor that should not be ignored. Oncogene. Feb 25 2010;29(8):1093-1102. 
63. 
Idorn M, Hojman P. Exercise-Dependent Regulation of NK Cells in Cancer Protection. Trends Mol. Med. Jul 2016;22(7):565-
577. 
64. 
Sloan RP, Shapiro PA, Demeersman RE, et al. Aerobic exercise attenuates inducible TNF production in humans. J Appl 
Physiol (1985). Sep 2007;103(3):1007-1011. 
65. 
Hallahan DE, Spriggs DR, Beckett MA, Kufe DW, Weichselbaum RR. Increased tumor necrosis factor alpha mRNA after 
cellular exposure to ionizing radiation. Proc. Natl. Acad. Sci. U. S. A. Dec 1989;86(24):10104-10107. 
66. 
Fielding RA, Manfredi TJ, Ding W, Fiatarone MA, Evans WJ, Cannon JG. Acute phase response in exercise. III. Neutrophil and 
IL-1 beta accumulation in skeletal muscle. Am. J. Physiol. Jul 1993;265(1 Pt 2):R166-172. 
67. 
Peake JM, Neubauer O, Walsh NP, Simpson RJ. Recovery of the immune system after exercise. J Appl Physiol (1985). May 01 
2017;122(5):1077-1087. 
68. 
Peake J, Peiffer JJ, Abbiss CR, et al. Body temperature and its effect on leukocyte mobilization, cytokines and markers of 
neutrophil activation during and after exercise. Eur. J. Appl. Physiol. Mar 2008;102(4):391-401. 
69. 
Ishihara H, Tsuneoka K, Dimchev AB, Shikita M. Induction of the expression of the interleukin-1 beta gene in mouse spleen 
by ionizing radiation. Radiat. Res. Mar 1993;133(3):321-326. 
70. 
Hong JH, Chiang CS, Tsao CY, Lin PY, McBride WH, Wu CJ. Rapid induction of cytokine gene expression in the lung after 
single and fractionated doses of radiation. Int. J. Radiat. Biol. Nov 1999;75(11):1421-1427. 
71. 
Kizaki T, Takemasa T, Sakurai T, et al. Adaptation of macrophages to exercise training improves innate immunity. Biochem. 
Biophys. Res. Commun. Jul 18 2008;372(1):152-156. 
72. 
Sugiura H, Nishida H, Sugiura H, Mirbod SM. Immunomodulatory action of chronic exercise on macrophage and lymphocyte 
cytokine production in mice. Acta Physiol. Scand. Mar 2002;174(3):247-256. 
73. 
Aveseh M, Nikooie R, Aminaie M. Exercise-induced changes in tumour LDH-B and MCT1 expression are modulated by 
oestrogen-related receptor alpha in breast cancer-bearing BALB/c mice. J. Physiol. Jun 15 2015;593(12):2635-2648. 
74. 
Hersey P, Watts RN, Zhang XD, Hackett J. Metabolic approaches to treatment of melanoma. Clin. Cancer Res. Nov 01 
2009;15(21):6490-6494. 
75. 
Cooney GM, Dwan K, Greig CA, et al. Exercise for depression. Cochrane Database Syst. Rev. Sep 12 2013(9):CD004366. 
76. 
Mishra SI, Scherer RW, Snyder C, Geigle PM, Berlanstein DR, Topaloglu O. Exercise interventions on health-related quality of 
life for people with cancer during active treatment. Cochrane Database Syst. Rev. Aug 15 2012(8):CD008465. 
77. 
Mishra SI, Scherer RW, Geigle PM, et al. Exercise interventions on health-related quality of life for cancer survivors. 
Cochrane Database Syst. Rev. Aug 15 2012(8):CD007566. 
78. 
Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or 
radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. Nov 2009;10(11):1037-1044. 
79. 
Tsao M, Xu W, Sahgal A. A meta-analysis evaluating stereotactic radiosurgery, whole-brain radiotherapy, or both for 
patients presenting with a limited number of brain metastases. Cancer. May 01 2012;118(9):2486-2493. 
80. 
Misono S, Weiss NS, Fann JR, Redman M, Yueh B. Incidence of suicide in persons with cancer. J. Clin. Oncol. Oct 10 
2008;26(29):4731-4738. 
81. 
Zaorsky NG, Churilla TM, Egleston BL, et al. Causes of death among cancer patients. Ann. Oncol. Nov 09 2016. 

Page 28 of 29  
82. 
Rusthoven CG, Jones BL, Flaig TW, et al. Improved Survival With Prostate Radiation in Addition to Androgen Deprivation 
Therapy for Men With Newly Diagnosed Metastatic Prostate Cancer. J. Clin. Oncol. Aug 20 2016;34(24):2835-2842. 
83. 
Hawkins VN, Foster-Schubert K, Chubak J, et al. Effect of exercise on serum sex hormones in men: a 12-month randomized 
clinical trial. Med. Sci. Sports Exerc. Feb 2008;40(2):223-233. 
84. 
Lu YP, Lou YR, Nolan B, et al. Stimulatory effect of voluntary exercise or fat removal (partial lipectomy) on apoptosis in the 
skin of UVB light-irradiated mice. Proc. Natl. Acad. Sci. U. S. A. Oct 31 2006;103(44):16301-16306. 
85. 
Demark-Wahnefried W, Campbell KL, Hayes SC. Weight management and its role in breast cancer rehabilitation. Cancer. 
Apr 15 2012;118(8 Suppl):2277-2287. 
86. 
Thompson HJ, Wolfe P, McTiernan A, Jiang W, Zhu Z. Wheel running-induced changes in plasma biomarkers and 
carcinogenic response in the 1-methyl-1-nitrosourea-induced rat model for breast cancer. Cancer Prev Res (Phila). Nov 
2010;3(11):1484-1492. 
87. 
Lee C, Safdie FM, Raffaghello L, et al. Reduced levels of IGF-I mediate differential protection of normal and cancer cells in 
response to fasting and improve chemotherapeutic index. Cancer Res. Feb 15 2010;70(4):1564-1572. 
88. 
Gannon NP, Vaughan RA, Garcia-Smith R, Bisoffi M, Trujillo KA. Effects of the exercise-inducible myokine irisin on malignant 
and non-malignant breast epithelial cell behavior in vitro. Int. J. Cancer. Feb 15 2015;136(4):E197-202. 
89. 
Aoi W, Naito Y, Takagi T, et al. A novel myokine, secreted protein acidic and rich in cysteine (SPARC), suppresses colon 
tumorigenesis via regular exercise. Gut. Jun 2013;62(6):882-889. 
90. 
Idorn M, Thor Straten P. Exercise and cancer: from "healthy" to "therapeutic"? Cancer Immunol. Immunother. May 
2017;66(5):667-671. 
91. 
Nelson BH. The impact of T-cell immunity on ovarian cancer outcomes. Immunol. Rev. Apr 2008;222:101-116. 
92. 
Chakraborty M, Abrams SI, Coleman CN, Camphausen K, Schlom J, Hodge JW. External beam radiation of tumors alters 
phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing. Cancer Res. Jun 15 
2004;64(12):4328-4337. 
93. 
Hojman P, Gehl J, Christensen JF, Pedersen BK. Molecular Mechanisms Linking Exercise to Cancer Prevention and 
Treatment. Cell Metab. Oct 17 2017. 
94. 
Pedersen BK, Saltin B. Exercise as medicine - evidence for prescribing exercise as therapy in 26 different chronic diseases. 
Scand. J. Med. Sci. Sports. Dec 2015;25 Suppl 3:1-72. 
95. 
Pedersen L, Christensen JF, Hojman P. Effects of exercise on tumor physiology and metabolism. Cancer J. Mar-Apr 
2015;21(2):111-116. 
96. 
Dethlefsen C, Lillelund C, Midtgaard J, et al. Exercise regulates breast cancer cell viability: systemic training adaptations 
versus acute exercise responses. Breast Cancer Res. Treat. Oct 2016;159(3):469-479. 
97. 
Higgins KA, Park D, Lee GY, Curran WJ, Deng X. Exercise-induced lung cancer regression: mechanistic findings from a mouse 
model. Cancer. Nov 01 2014;120(21):3302-3310. 
98. 
Jiang W, Zhu Z, Thompson HJ. Effects of limiting energy availability via diet and physical activity on mammalian target of 
rapamycin-related signaling in rat mammary carcinomas. Carcinogenesis. Feb 2013;34(2):378-387. 
99. 
Atherton PJ, Babraj J, Smith K, Singh J, Rennie MJ, Wackerhage H. Selective activation of AMPK-PGC-1alpha or PKB-TSC2-
mTOR signaling can explain specific adaptive responses to endurance or resistance training-like electrical muscle 
stimulation. FASEB J. May 2005;19(7):786-788. 
100. 
Sanli T, Steinberg GR, Singh G, Tsakiridis T. AMP-activated protein kinase (AMPK) beyond metabolism: a novel genomic 
stress sensor participating in the DNA damage response pathway. Cancer Biol Ther. Feb 2014;15(2):156-169. 
101. 
Meng MB, Wang HH, Cui YL, et al. Necroptosis in tumorigenesis, activation of anti-tumor immunity, and cancer therapy. 
Oncotarget. Aug 30 2016;7(35):57391-57413. 
102. 
Giallauria F, Gentile M, Chiodini P, et al. Exercise training reduces high mobility group box-1 protein levels in women with 
breast cancer: findings from the DIANA-5 study. Monaldi Arch. Chest Dis. Jun 2014;82(2):61-67. 
103. 
Speck RM, Courneya KS, Masse LC, Duval S, Schmitz KH. An update of controlled physical activity trials in cancer survivors: a 
systematic review and meta-analysis. Journal of cancer survivorship : research and practice. Jun 2010;4(2):87-100. 
104. 
Brown JC, Huedo-Medina TB, Pescatello LS, Pescatello SM, Ferrer RA, Johnson BT. Efficacy of exercise interventions in 
modulating cancer-related fatigue among adult cancer survivors: a meta-analysis. Cancer Epidemiol Biomarkers Prev. Jan 
2011;20(1):123-133. 
105. 
Santa Mina D, Alibhai SM, Matthew AG, et al. Exercise in clinical cancer care: a call to action and program development 
description. Current oncology. Jun 2012;19(3):e136-144. 
106. 
Mirels H. Metastatic disease in long bones. A proposed scoring system for diagnosing impending pathologic fractures. Clin. 
Orthop. Relat. Res. Dec 1989(249):256-264. 
107. 
Sahgal A, Atenafu EG, Chao S, et al. Vertebral compression fracture after spine stereotactic body radiotherapy: a multi-
institutional analysis with a focus on radiation dose and the spinal instability neoplastic score. J. Clin. Oncol. Sep 20 
2013;31(27):3426-3431. 

Page 29 of 29  
108. 
Beidas RS, Paciotti B, Barg F, et al. A hybrid effectiveness-implementation trial of an evidence-based exercise intervention 
for breast cancer survivors. Journal of the National Cancer Institute. Monographs. Nov 2014;2014(50):338-345. 
109. 
Powell KE, Heath GW, Kresnow MJ, Sacks JJ, Branche CM. Injury rates from walking, gardening, weightlifting, outdoor 
bicycling, and aerobics. Med Sci Sports Exerc. Aug 1998;30(8):1246-1249.