Improving Pulmonary Function Following Radiation Therapy
Phase: NA
Conditions: Non-Small Cell Lung Cancer
Sponsor: University of Wisconsin, Madison

Improving Pulmonary Function Following Radiation Therapy
NCT02843568
PI:  Carri K Glide-Hurst, PhD
Version Date: 6/9/2022

6/9/2022   
 
 Page 1 of 41 
UW16037 Improving Pulmonary Function Following Radiation Therapy 
 
Principal Investigator:  
Carri K. Glide-Hurst, PhD, DABR, FAAPM 
Director, Radiation Oncology Physics 
Department of Human Oncology 
University of Wisconsin Madison 
Office:  (608) 262-5319  
glidehurst@humonc.wisc.edu 
Co-Investigators: 
 
Andrew M. Baschnagel, MD 
Michael Bassetti, MD 
Bethany M. Anderson, MD 
Kristen Bradley, MD 
Paul M. Harari, MD 
Steven P. Howard, MD 
Mark Ritter, MD 
Randy Kimple, MD 
Greg Cooley, MD 
Jessica Schuster, MD 
Matthew Witek, MD 
 
 
Collaborator Albert van der Kogel, 
PhD 
Gary E. Christensen, PhD  
Joseph M. Reinhardt, Ph.D. 
 
 
 
Biostatistician: 
Rick Chappell, PhD 
Professor 
Depts. of Statistics and of Biostatistics & Medical Informatics 
  
Data Manager: 
Lisa Sanchez 
 
Clinical Coordinator 
Department of Human Oncology 
(608) 265-3281 
sanchez@humonc.wisc.edu 

 
 
6/9/2022   
 
i 
Improving Pulmonary Function Following Radiation Therapy 
 
SCHEMA  
All patients 
Pre-RT 4DCT scans 
All patients 
Pre-RT weight, labs, morbidity scores, and PFTs  
↓ 
 
Conventional Fractionation 
60* subjects 
(A total of 60-66 Gy, in daily fractions 
of 1.8-2.0 Gy/fx, nominally 5 
fx/week) 
 
Hypo-fractionation 
60* subjects 
Stereotactic body radiation therapy 
(40-60 Gy total, in 3-8 fx, using 
standard schemes at UWHCC) or 
12Gy x 4 fx, 10Gy x 5 fx, 5Gy x 8 fx, 
or 20Gy x 3 fx   
 
*To achieve primary objective,   
subjects must complete 3 month post 
RT assessments.  If this does not 
occur, the subject will be replaced. 
 
Arm 1: 
Create treatment plan that meets 
standard dose specifications  
 
Arm 2: 
Optimize treatment plan meet 
standard dose specifications and to 
minimize pulmonary function 
damage based on predictive model  
 
 
 
↓ 
 
All patients 
Receive full course of RT, as prescribed 
↓ 
All patients 
4DCTs @ 3, 6, & 12 months post-RT 
All patients 
PFTs @ 3, 6, & 12 months post-RT 
All patients 
Weight and RTOG Late morbidity scores @ 3, 6, 
& 12 months post-RT 
↓ 
S
T
R
A
T
I
F
Y 
R
A
N
D
O
M
I
Z
E 

 
 
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All patients 
 
 
 
Weight and RTOG Late morbidity scores every 
four months in year 2, then six months from year 3 
to 5 post-RT, then annually 
 
 

 
 
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iii 
TABLE OF CONTENTS 
 
PAGE 
SCHEMA ................................................................................................................................................. I 
1. OBJECTIVES ...................................................................................................................................1 
1.1. Primary Objective ......................................................................................................................1 
1.2. Secondary Objectives .................................................................................................................1 
2. BACKGROUND ...............................................................................................................................1 
2.1. Lung Cancer and Current Therapy ............................................................................................1 
2.2. Preliminary Study and Rationale ...............................................................................................2 
3. PATIENT SELECTION ..................................................................................................................5 
3.1. Eligibility Criteria ......................................................................................................................5 
3.2. Exclusion Criteria ......................................................................................................................5 
3.3. Inclusion of Women and Minorities ..........................................................................................6 
4. RANDOMIZATION PROCEDURES ............................................................................................6 
4.1. Information to be recorded .........................................................................................................6 
4.2. Randomization between Therapy Arms 1 & 2 ..........................................................................6 
5. PROCEDURES .................................................................................................................................7 
5.1. Baseline Standard of Care Assessments ....................................................................................7 
5.2. Baseline Research Assessments .................................................................................................7 
5.3. 4-Dimensional Computed Tomography (4DCT) Imaging ........................................................7 
5.4. Localization ................................................................................................................................8 
5.5. Radiation Therapy ......................................................................................................................8 
5.6. Chemotherapy ..........................................................................................................................10 
5.7. Study Procedures and Walkthrough .........................................................................................11 
5.8. General Concomitant Medication and Supportive Care Guidelines ........................................11 
5.9. Duration of Therapy .................................................................................................................11 
5.10. Duration of Follow Up .............................................................................................................11 
5.11. Adjuvant Therapy ....................................................................................................................12 
5.12. Assessments .............................................................................................................................12 
6. DOSING DELAYS/DOSE MODIFICATIONS ...........................................................................12 
7. ADVERSE EVENTS: .....................................................................................................................12 
7.1. Adverse Events Characteristics ................................................................................................13 
8. CORRELATIVE/SPECIAL STUDIES ........................................................................................17 
8.1. Correlative Objective ...............................................................................................................17 
8.2. Correlative lab study ................................................................................................................17 
9. STUDY CALENDAR .....................................................................................................................18 

 
 
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10. MEASUREMENT OF EFFECT ...................................................................................................19 
10.1. Primary endpoint ......................................................................................................................19 
10.2. Secondary endpoints ................................................................................................................19 
10.3. Data collection .........................................................................................................................20 
11. STATISTICAL CONSIDERATIONS ..........................................................................................20 
11.1. Study Design/Endpoints...........................................................................................................20 
REFERENCES ......................................................................................................................................22 
APPENDIX A: PERFORMANCE STATUS CRITERIA.................................................................26 
APPENDIX D: CTCAE V. 4.03 GRADING ......................................................................................30 
APPENDIX E: PATIENT SELF ASSESSMENT CRITERIA .........................................................31 
APPENDIX F: UWCCC DATA SAFETY MONITORING PLAN .................................................32 
 
 

 
1 
1. 
OBJECTIVES 
1.1. 
Primary Objective 
This clinical trial sets out to determine if subjects who have been treated with radiation 
therapy plans designed to spare high ventilation regions have superior preservation of 
pulmonary function compared to those treated with standard radiation dose distributions.  
Four dimensional computed tomographic imaging (4DCT) will be used to determine lung 
tissue elasticity, as required for ventilation. Lung tissue elasticity maps at 3 months after 
RT will be compared to those prior to RT, and used to quantify the change in the lung 
elasticity maps. Reduced lung tissue elasticity is defined in this study as a >6% reduction 
in expansion when compared to the baseline; the amount of lung tissue showing a >6% 
reduction is the metric for our primary endpoint, and will be tested for a significant 
difference between the two arms. 
1.2. 
Secondary Objectives 
1. Characterize and correlate temporal changes in lung tissue elasticity with delivered 
radiation doses to anatomical and functional regions within the thorax.  
2. Quantify global changes following radiation therapy (RT) for lung cancer, including 
those observed from Pulmonary Function Tests (PFTs) and inflammation markers in 
blood plasma for subjects who voluntary consent to provide their blood. These too 
will be correlated with the delivered radiation doses to anatomical and functional 
regions within the thorax, and with the maps of post-radiation therapy changes in lung 
tissue elasticity. 
3. Quantify the repeatability of 4DCT based measures of lung tissue elasticity to 
demonstrate the changes following radiation therapy are greater than the expected 
variation from the procedure itself and determine the expected variance in 
longitudinal studies. 
2. 
BACKGROUND 
2.1. 
Lung Cancer and Current Therapy 
In the year 2015, over 221,200 new cases of lung cancer were diagnosed and 158,040 
deaths were attributed to this disease.[1] Of these, approximately 13% are small cell lung 
cancers with the remainder being non-small cell lung cancer.[1] Treatment can involve 
combinations of surgery, chemotherapy, and radiation therapy (both conventional and 
hypo-fractionation).[2] 
Radiation therapy is typically used for small cell lung cancer and the total dose is 
typically between 45 and 70 Gy. This depends upon the extent of disease, the number of 
fractions, and the daily delivery technique (once daily versus twice daily). Small cell 
cancers, however, represent the minority of treatments for lung cancer and employ 
different treatment schema. 
Radiation therapy for non-small cell lung cancer is dependent upon operative status of the 
patient. Those patients treated primarily with surgery have radiation and chemotherapy 
post-operatively as determined by margin status and extent of disease pathologically.[2] 
Those with slightly more advanced disease are treated with neoadjuvant concomitant 
chemoradiotherapy. The pre-operative radiation dose is typically limited to 45-50 Gy, 
based on the hope that reduction of tumor burden will rend the patient operable. Patients 

 
2 
with more advanced non-small cell lung cancer are most commonly treated with 
definitive high dose combination chemotherapy and radiation, the radiation dose ranging 
from 60-70 Gy. Finally, an increasing number of patients may have limited disease but 
poor pulmonary function (limiting their operative status). These patients are being treated 
with stereotactic radiosurgery (generally 3-5 fractions and total dose from 36-60 Gy).  
This same approach is being used for a number of other patients with recurrent lung 
cancer or metastatic disease in the lung.  
In conclusion, a majority of patients receive radiation therapy as a component of their 
lung cancer management and the tolerance to this irradiation is limited by the detrimental 
impact of that treatment (or its potential) on lung function. While tolerance of lung to 
radiation is generally considered to be 20 Gy there is little data analyzing the anatomic 
heterogeneity of lung function in the subject prior to treatment so that the radiation may 
be tailored to minimize impact on function nor is there any significant data analyzing the 
impact of radiation therapy across lung function globally that takes into account the 
biomechanical principles that are critical for lung function. 
 
Radiation Side Effects 
Radiation to the tumor and nodal targets (commonly hilar and mediastinal) is complicated 
by respiratory motion. This requires a larger area of normal lung and mediastinal tissue to 
be treated to ensure that these targets are within the treatment beams used to deliver the 
dose. Additionally, lung tumors require radiation doses far in excess of the tolerance of 
normal lung tissue. Common toxicities include radiation pneumonitis, radiation fibrosis, 
and ultimately altered respiratory capacity. Dose escalation studies show a clear increase 
in tumor control with increasing radiation dose for primary lung tumors, but that toxicity 
also increased with dose. Quantification of lung function after radiotherapy has been 
limited although recognition of its significance is apparent. Spirometry indices as well as 
DLCO have been shown to be altered following radiotherapy.  
In particular, radiation pneumonitis has been loosely correlated to the fraction of the 
volume of lung irradiated[3] to doses of 10 – 50 Gy.[4-7] The volume of lung receiving 
20 Gy or more has a good correlation with radiation pneumonitis in some studies,[3, 5, 8] 
but not in others.[9, 10] The mean radiation dose to the lung has also provided conflicting 
results, showing good[3, 7, 11] and poor correlation between a mean dose > 20 Gy and 
radiation pneumonitis.[6, 12] All of these analyses ignore two factors we believe to be 
important: 1) the spatial distribution of pulmonary function within the lung is unlikely to 
be uniform, so the spatial location of the radiation dose matters, and 2) the changes in 
lung function may be caused by radiation dose both directly and indirectly, where 
changes occur in regions of the lung receiving what is currently believed to be “sub 
toxic” doses due to toxic doses in neighboring tissues. Fundamentally, we do not know 
the cause of this indirectly produced reduced lung function.  
2.2. 
Preliminary Study and Rationale 
The relationship between radiation dose and normal lung tissue toxicity has been 
thoroughly investigated since CT based planning became commonplace over a decade 
ago,[6] yet the clear indicators for toxicity remain elusive.[7, 13-20] It has been broadly 
accepted that radiation dose has a direct effect on treated lung tissue and the lung in the 
treatment field shows radiographic changes consistent with fibrosis.[21] It is largely 

 
3 
assumed that this is the predominant and in some cases only significant effecter of altered 
lung function despite known changes in inflammatory cells outside the treated area. All 
current avoidance methods for lung tissue depend on direct dose/volume relationships 
with treated lung.[6, 16, 22, 23] 
The present treatment-planning dosimetry constraints for the lung are based on studies 
that assume lung tissue is homogeneous in its response to toxicity, irrespective of its 
location or underlying function. Furthermore, it is well known lung function is not 
distributed uniformly, especially in diseased lungs.[24, 25] Because most patients with 
lung cancer have a history of smoking or other lung disease it is clear that a majority of 
patients will have other underlying lung issues such as chronic obstructive pulmonary 
disease. This will further exacerbate this anatomically relevant heterogeneity of lung 
function. 
No human studies have investigated the relationships between local lung function, spatial 
radiation dose distribution, and radiation induced lung function changes. However, rat 
studies are investigating changes in pulmonary function based on irradiation of different 
regions of rat lung. Luijk et al. showed structural changes in rat lung were only correlated 
with changes in breathing rate when irradiating lateral lung regions (shielding the 
mediastinum),[26] and then that greater lung damage was observed when irradiating the 
heart [27] while holding mean lung dose and volume of lung irradiated constant. They’ve 
also shown irradiation of larger volumes to smaller doses causes greater toxicity than 
treating smaller volumes to larger doses,[28] a result confirmed by others.[29] A common 
yet unspecified thread in the rat studies is radiation treatments including the mediastinum 
caused a greater change in pulmonary function. The reasons for these findings is 
mechanistically undefined. 
 
Our preliminary data is a 
retrospective analysis of 
in 
human 
subjects 
(University of Iowa IRB 
200805754 
from 
the 
University 
of 
Iowa). 
Using 4DCT and image 
registration, we examined 
the 
amount 
of 
lung 
expansion (function) in 
irradiated 
and 
non-
irradiated 
lung 
tissue. 
What began as a study to 
evaluate 
whether 
we 
might be able to avoid the 
most 
well-functioning 
lung 
tissue 
became 
something 
far 
more 
exciting once our first set 
of 
retrospective 
data 
analysis began. Figure 1 shows changes in pulmonary function correlating with 
calculated 3D radiation dose for a single patient. This patient had two 4DCT studies: the 
 
Figure 1. Planned radiation dose distribution (middle) and pulmonary 
function image before (left) and after (right) radiation therapy.  All 
images are for the same patient.  The top row is a transverse cut, the 
bottom row is a coronal cut.  The tumor is located in the left lung on the 
pre-treatment pulmonary function image and the computed dose 
distribution image, but absent in the post-treatment images.  Post 
treatment images show a reduction of pulmonary function in the 
treatment location, when compared to the pre-treatment image. 

 
4 
first was prior to RT for the tumor shown in the left lung, the second was 16 months post 
RT. The first row is an axial imaging and the second row is a coronal image. The middle 
image shows the radiation dose distribution (represented by colored lines) while the first 
and third image show pulmonary function images. The pulmonary function images are 
color-coded: green and blue indicate normally functioning (expanding) lung tissue with a 
value > 1.1, while orange and red regions show decreased lung function with a value < 
0.95.  
The right lung, which was un-treated, shows minimal changes in lung function, while the 
treated region in the left lung changes from significant expansion (green before RT) to 
little to no expansion (orange to red after RT). The functional changes observed in the 
lung appear to correlate well spatially with the delivered radiation dose distribution. A 
second example is shown in Figure 2, where the top three images show the computed 
dose distribution and the bottom images show the pulmonary function images. In this 
case the only pulmonary function images shown are after RT. An extremely interesting 
and unexpected finding is shown in Figure 2, where regions of decreased pulmonary 
function extend outside of the applied therapeutic radiation dose. In this case the 
therapeutic radiation dose is delivered to the tumor in the left lung, but also extends over 
the mediastinum just 1-2 cm beyond the vertebral bodies of the thoracic spine. Note in 
this case the change in pulmonary function extends all the way across both lungs even 
though the therapeutic radiation dose does not, unlike the first clinical case shown above. 
The numerical value of pulmonary function in a 2x2x2cm volume within the “streak” is 
0.96 ± 0.04, while the value in the normal lung is 1.25 ± 0.02. In a third patient (not 
shown) the pulmonary function values prior to RT were 1.29 ± 0.08 and 1.26 ± 0.01 in 
the lower lobe and 1.07 ± 0.01 and 1.05 ± 0.02 in the upper lobe of the right and left lung, 
respectively. These observed differences in un-irradiated areas of lung do not correlate 
with lower dose scatter patterns and cannot be explained by direct radiation dose effects.  
These preliminary results show that we are able to observe radiation induced changes in 
lung tissue function using 
4DCT 
and 
image 
registration. Surprisingly, 
we see that in the second 
case, 
lung 
function 
deficits 
extend 
well 
beyond 
the 
irradiated 
tissue. In this project, we 
will quantify the extent of 
radiation-induced 
functional 
change 
to 
irradiated 
and 
non-
irradiated 
lung, 
and 
correlate these changes 
with dose delivery plans. 
Standard 
indices 
for 
tracking 
pulmonary 
toxicity 
are 
highly 
subjective and, predicting 
RT-quantitative 
 
Figure 2. Planned radiation dose distribution (top) and pulmonary 
function image after radiation therapy (bottom).  Both rows of images 
display a transverse, sagital, and coronal cut.  The tumor is located in the 
left lung.  Post treatment lung function images show a reduction of 
pulmonary function in the treatment location, and an additional “streak” 
of function reduction across the right lung beyond the treated volume.  
This observation is consistent with non-spatial functional tests in the rat 
model and never before shown spatially in humans. 

 
5 
endpoints, as the most common approaches rely on subjective and ambiguous endpoints: 
shortness of breath, pulmonary function tests, blood gases, exercise capacity, and 
radiographic abnormalities. Functional imaging is being recognized as having the 
potential to provide biomarkers as objective endpoints. A nearly two decades of research 
in this area is based on single photon emission computed tomography (SPECT) perfusion 
scans to quantify functional lung by measuring blood content within the alveolar capillary 
network.[13, 25, 30-38] Other investigators are pursuing pulmonary function 
measurement using novel MRI techniques[38-40] including hyperpolarized helium-3 
detected MRI.[38, 40-45] These approaches are challenged by limited spatial resolution, 
motion correction, and accurate image registration with treatment planning CT scans. We 
have chosen to utilize CT based image-registration methods to compute local lung 
expansion from respiratory gated 4DCT, and have shown its correlation with 
ventilation.[46] Others have investigated 4DCT based pulmonary function assessment 
also finding favorable results.[47-54] CT has several practical advantages over SPECT 
and MRI as a tool to measure regional lung injury. CT is more readily available, more 
directly quantitative, has higher spatial and temporal resolution, is easier to perform with 
RT positioning devices, faster, and less expensive.  
Scores of investigators have worked to establish a relationship between radiation dose-
volume parameters and pneumonitis.[14, 36, 37, 48, 50-76]  The most substantial datasets 
used to establish the correlation of radiation dose with pulmonary toxicity are from 
Washington University in Saint Louis and RTOG trial 9311. The statistical model 
derived from the combined datasets identified greater risk for mean lung dose (MLD), 
and irradiation of the inferior lung. Unfortunately, two lessons from these results are 
unused in clinical practice: high doses to normal lung and the anatomic distribution of 
dose within the lung are relevant. Instead, the clinical RT paradigm for pulmonary 
toxicity modeling is driven by the dose-volume relationship of lung volume treated.  
This proposed clinical trial will elucidate the complex inter-relationship between RT 
treatment and the resultant changes in pulmonary function. While other groups have 
hypothesized the value of dose rearrangement to limit lung toxicity, we will carefully 
apply this information systematically in this prospective clinical trial to demonstrate its 
impact. 
3. 
PATIENT SELECTION 
3.1. 
Eligibility Criteria  
3.1.1. Histologic diagnosis of a non-small cell lung cancer or lung metastasis from a solid 
tumor. One biopsy site is adequate for multiple sites of thoracic disease. 
3.1.2. Treatment includes localized radiation therapy with or without chemotherapy 
3.1.3. Age ≥ 18 years 
3.1.4. Karnofsky ≥ 60% 
3.1.5. Not pregnant per radiation oncology standard procedures 
3.1.6. Ability to understand and the willingness to sign a written informed consent 
document 
3.2. 
Exclusion Criteria 
3.2.1. Prior (within last 6 months) or future planned therapeutic surgery for the treatment of 
the existing lung cancer 

 
6 
3.2.2. Prior thoracic radiotherapy 
3.2.3. Severe COPD defined as disease requiring an inpatient stay for respiratory 
deterioration within the past 3 months 
3.2.4. Oxygen dependence of > 2 L/min continuously throughout the day at baseline 
3.2.5. Known underlying collagen vascular disease or intrinsic lung disease that could 
complicate expected sequelae of radiation (idiopathic pulmonary fibrosis, Wegener’s 
granulomatosis) 
3.2.6. Uncontrolled intercurrent illness including, but not limited to ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements 
3.3. 
Inclusion of Women and Minorities 
Female and male patients of all ethnic groups will be eligible for treatment in these 
protocols.  
4. 
RANDOMIZATION PROCEDURES 
Patients may not undergo protocol procedures prior to signing consent. All patients must meet 
eligibility criteria listed in Section 3 and provide written informed consent. The study 
coordinator will verify eligibility, assign a case number, and register the patient in the UWCCC 
ONCORE database after simulation and after all eligibility criteria have been met. Information to 
be recorded  
The following information will be recorded for each subject enrolled: 
• Protocol number 
• Patient’s name and initials 
• Patient’s medical record number 
• Patient demographic data including gender, birth date and race. 
• Signed patient consent forms 
• HIPAA authorization form 
4.1. 
Randomization between Therapy Arms 1 & 2 
Patients will be randomized between two arms.  Subjects in the first arm will receive 
conventional treatment planning as described in sections 5.5.1 through 5.5.3.  Subjects in 
the second arm will also receive treatment plans that meet all the criteria of the first arm, 
but their treatment plans will include strategies to reduce pulmonary function damage 
following radiation therapy as described in section 5.5.4.  Randomization will be 
performed by the data management team using a random number generator application 
(developed by Randomness and Integrity Services Ltd., Dublin, Ireland) that is a web 
based application that can also run on an Apple iPhone, iPad, or iPod touch running iOS 
5.1.1 or later. 
Amend 3/15/22 
The Hypo-fractionation patient cohort has reached accrual of 60 subjects (30 
conventional treatment planning, and 30 optimized planning). 
 

 
7 
The Conventional Fractionation cohort has accrued 46/60, however the treatment 
assignment of conventional treatment planning versus optimized planning is unbalanced, 
with 27 assigned to the standard dose specification planning and 19 assigned to the 
optimized treatment planning.  
Accrual has significantly slowed and we are accruing 1 subject every 4-8weeks.   In light 
of the extremely low accrual we will assign the next 8 subjects to to the optimized 
treatment plan to balance the study arms  to ensure each arm has adequate enrollment for 
proper statistical analysis.  When the arms are balanced, we will proceed with 
randomization via random.org until one arm reaches 30, then the remaining subjects will 
be placed in the remaining open arm. 
5. 
PROCEDURES 
Potential subjects will be identified through multidisciplinary lung tumor board, consults, and the 
radiation oncology clinic. Consent will be obtained prior to initial radiotherapy treatment 
simulation. One biopsy site is adequate for multiple sites of thoracic disease, as the primary 
endpoint of the study is the assessment of normal lung tissue response to delivered radiation. 
5.1. 
Baseline Standard of Care Assessments 
5.1.1. 4DCT. For standard of care radiation treatment planning 
5.1.2. Pulmonary function tests. Include spirometry, diffusion capacity (DLCO),  and lung 
volumes (FEV, FEV1)  
5.2. 
Baseline Research Assessments 
5.2.1. 4DCT. This is ordered in addition to the standard 4DCT performed for RT-simulation 
5.2.2. Patient self-assessment.   Assessment is based on a modified Borg scale, which has a 
history of use in pulmonary labs, with a scale of 1 (resting comfortably in a chair with 
no effort) to 10 (the most exertion and difficult breathing ever experienced) 
5.2.3. RTOG defined acute toxicity evaluation. Evaluate both lung and esophageal 
toxicity (Appendix B) 
5.2.4. RTOG late toxicity evaluation. Evaluate lung, esophageal, skin, subcutaneous 
tissue, spinal cord, heart, and bone (Appendix C) 
5.2.5. Constitutional assessment: quantify nausea, vomiting, diarrhea and other symptoms 
prior to initiating chemoradiation and any medications used for these symptoms 
5.3. 
4-Dimensional Computed Tomography (4DCT) Imaging 
4DCT imaging is performed at simulation (treatment planning) in all patients. This first 
4DCT is clinically indicated for radiation simulation as a standard procedure. This 
clinical imaging data will also be used for research in this protocol to evaluate the 
biomechanical tissue elasticity of the lungs. Lung tissue elasticity is being used as a 
surrogate for ventilation, which in turn is a component of pulmonary function.  Because 
the goal of the research arm is to reduce pulmonary function damage, changes in lung 
tissue elasticity will be quantified using 4DCT and it’s essential the changes observed be 
distinguished from random changes in our measurement.  Consequently, each subject will 
receive two 4DCT scans at each time point in order to quantify the repeatability of the 
measure of tissue elasticity and to demonstrate the changes following RT are greater than 
the expected variation from the procedure itself.  The results from both 4DCT scans will 

 
8 
be used by taking the geometric mean of the tissue elasticity measures of scan 1 and scan 
2 at each time point.  
Subjects will undergo a total of 7 research-ordered 4DCT scans: one at simulation, and 
two scans at each of the 3 post-radiation therapy time points (3, 6, and 12 months). Each 
4DCT scan delivers approximately 75 mSv, which is the average value observed over 10 
patients in our clinic using the newly installed Siemens Edge scanner.  The Background 
Equivalent Radiation Time (BERT) is 25 years for each 4DCT scan, where the 
background radiation is assumed to be 3 mSv per year. To place this radiation exposure 
into further context, the radiation dose from the 7 research-ordered 4DCT scans (0.53 
Gy) represents less than 1% of the radiation dose the patient will receive from their 
radiation therapy treatments. In an effort to make the radiation doses from the 4DCT 
scans “as low as reasonably achievable,” the radiation dose subjects receive for each 
4DCT scan has recently been reduced by 2-3 times LOWER than prior care at UWHC.  
This reduction has been made possible by the improved radiation detection technology on 
the Siemens Edge CT scanner in Radiation Oncology.  If further dose reduction can be 
accomplished by additional technologies or software development, these too will be 
implemented. 
5.4. 
Localization 
Either portal imaging, daily cone beam, and/or optical surface tracking is acceptable for 
this study according to standard care. If cone beam imaging is prescribed by the treating 
radiation oncologist, the cone beam images will be utilized for correlative studies.  
5.5. 
Radiation Therapy  
The criteria and specifications below in sections 5.5.1 through 5.5.3 are applicable for 
both the standard of care arm (Arm 1) and the research arm (Arm 2), while those in 
section 5.5.4 are applicable to the research arm only. 
5.5.1. Dose specification. Radiation doses between 60-66 Gy using standard fractionation 
(1.8-2.0 Gy/fx) and stereotactic body radiation therapy (SBRT) hypofractionation 
schemes used at UWHCC will be utilized.  60 subjects of each fractionation type 
(standard and hypofractionation) will be included.  Treatment volumes will be at the 
discretion of the treating radiation oncologist and should follow standard of care at 
UWHC. 
5.5.2. Treatment planning and target volumes. The critical structures will be in 
accordance with RTOG 0617. 
5.5.3. Radiation dose limits for critical structures. Normal anatomy to be outlined on 
each CT image will include the lungs (right and left done separately), heart, skin, 
esophagus and spinal cord. Normal tissue constraints shall be prioritized in the 
following order for treatment planning: 1=spinal cord, 2=lungs, 3=esophagus, 
4=brachial plexus, and 5=heart 
Spinal Cord: The spinal cord dose limitation is the highest priority dose constraint 
and thus must be met irrespective of other constraints. Total “direct” plus “scatter” 
dose to the spinal cord must not exceed 50.5 Gy for standard fractionation.  Doses for 
hypofractionation will follow recommendations in RTOG 0618, 0813, or 0915 based 
on fraction size. 
Lungs: The dose-volume constraint to the lungs is the second highest priority and 
must be met, except if it conflicts with the cord dose constraints. For standard 

 
9 
fractionation, the volume of both lungs that receive more than 20 Gy (the V20) 
should not exceed 37% of the total. Alternatively, the mean lung dose should 
optimally be ≤ 20 Gy. (By total lung volume we mean the total lung minus the CTV).  
Doses for hypofractionation will follow recommendations in RTOG 0618, 0813, or 
0915 based on fraction size. 
Brachial Plexus: Brachial plexus doses should be kept <66 Gy for standard 
fractionation.  Doses for hypofractionation will follow recommendations in RTOG 
0618, 0813, or 0915 based on fraction size.  
Esophagus: The mean dose to the esophagus is optimally kept below 34 Gy.[47] This 
is not an absolute requirement, but is strongly recommended unless other, more 
critical constraints force the situation. The V60 (% volume of esophagus exceeding 
60 Gy) should be calculated for each patient for standard fractionation.  Doses for 
hypofractionation will follow recommendations in RTOG 0618, 0813, or 0915 based 
on fraction size. 
Heart: The following limits are recommended: 60 Gy to <1/3, 45 Gy to <2/3, and 40 
Gy to <100% of the heart for standard fractionation.  Doses for hypofractionation will 
follow recommendations in RTOG 0618, 0813, or 0915 based on fraction size. 
5.5.4. Research Arm (Arm 2) Only - Planning strategy to reduce pulmonary function 
damage.  
Subjects in the second arm will also receive treatment plans that meet all the criteria 
of the first arm, but their treatment plans will include strategies to reduce pulmonary 
function damage following radiation therapy.  The strategy to reduce pulmonary 
function damage, described below, will be implemented during treatment planning.  
In brief, radiation dose distributions will be designed to “redistribute” the radiation 
dose away from lung regions with high tissue elasticity.  Lung tissue elasticity is 
calculated from measures of tissue expansion that occurs during respiration.  
Specifically, the Jacobian determinant of the transformation matrix between the CT 
scan acquired when the subject has reached the end of exhale and the scan acquired 
when the subject has reached the end of inhale.  These images, which are extracted 
from the 4DCT data, allow the creation of lung tissue elasticity maps like the ones 
shown in Figure 3 below.  

 
10 
 
Subjects randomized to this arm of the trial will have the same prescribed radiation 
dose to the tumor volume and held to the same radiation dose criteria as the subjects 
in the standard of care arm. The fundamental difference will be radiation doses for 
these subjects will be redistributed away from regions predicted to cause the greatest 
reduction in pulmonary function if damaged.  For example, to treat the tumor in the 
images above (slightly medial to the dashed blue lines), circumferential radiation 
beams restricted to the lower lobes of the lung (green regions) would be chosen over 
beams that enter or exit the higher tissue expansion regions of the right middle lobe or 
right upper lobe (blue & purple regions).  
Pre-radiation therapy 4DCT images (Section 5.3.1) will be used to identify regions-
of-interest (ROI) uniquely utilized in this planning strategy.  These ROIs including 
anatomical regions (airway tree, pulmonary vasculature, heart, and lobar regions of 
the lung) and functional regions (regions of the lung discretized by the amount of 
tissue expansion that occurs during ventilation). Although tissue expansion is 
determined at a 1mm3 resolution, the ROIs will be grouped in 0.05 bins of expansion 
(typically from 1.05 up to 1.5). Airway tree branches and pulmonary vasculature 
supporting lung regions of high tissue expansion will be preferentially avoided as 
well.  Radiation therapy treatment planning will be calculated using an inverse 
optimization technique, relying on dose objectives specified for each ROI.  The 
penalty or “cost function” for failing to meet the specified dose objective will 
increase linearly with radiation dose, while the weight for each cost function will be 
determined from the slope of the dose response curve for each ROI. The inverse 
optimization algorithm will minimize the sum of the cost functions for all dose 
objectives created in the treatment plan.  These dose objectives will be added to the 
dose objectives utilized in the conventional arm of this study (Sections 5.5.1 – 5.5.3).  
5.6. 
Chemotherapy 
Chemotherapy is at the discretion of the treating physician and will follow standard of 
care.  The chemotherapeutic agents, dosing and the number of cycles during and after RT 
will be recorded. 

 
11 
5.7. 
Study Procedures and Walkthrough 
5.7.1. Radiation therapy planning simulation. RT simulation will consist of 4DCT 
imaging as per Department of Human Oncology’s standard of care. A second research 
4DCT will be acquired at this time point. 
5.7.2. Pulmonary function tests. The subject will be sent to the pulmonary function lab for 
spirometry, and DLCO. The pulmonary function tests may be done on the same day, 
but must be completed before the subject receives the first fraction of radiation 
therapy.  
5.7.3. Dosimetric planning. Performed according to standard of care. 
5.7.4. Treatment. Subjects will be treated once daily or every other day if receiving SBRT. 
The respiratory surrogate systems will be used daily during radiation therapy 
treatment per standard clinical practice to monitor respiratory motion. 
5.7.5. Post-treatment 4DCTs. Three more 4DCT imaging sets will be obtained, at 3 
months, 6 months, and 12 months after the last radiation treatment (10 week window: 
– 2 weeks/+8weeks). These 4DCT must be performed on the Radiation Oncology 
Siemens Edge. These are research-designated 4DCTs and will not be used for clinical 
care.  
5.7.6. Post-treatment PFT. Subjects will undergo PFT at the 3 month, 6 month, and the 12 
month imaging to obtain spirometric, and DLCO measurements. These will be 
performed for research purposes. 
5.7.7. Follow-up. Subjects will have follow-up appointments with their radiation oncologist 
every 3 months for the first year, every 4 months for year two, and every 6 months for 
years 3-5. Follow-up mirrors that of RTOG-0117, enabling time-point comparisons. 
Data to be collected are outlined in section 11 (measurement of effect). The follow-up 
time points are consistent with standard of care post radiation disease monitoring. 
5.8. 
General Concomitant Medication and Supportive Care Guidelines 
Concomitant care is not affected by this study. Subjects may receive full concomitant and 
supportive care. 
5.9. 
Duration of Therapy 
Therapy will consist of 60-66 Gy in subjects receiving conventional radiation therapy and 
40-60 Gy in subjects receiving SBRT.  All therapeutic doses delivered on this protocol 
are consistent with standard of care radiation therapy dosing. 
Subjects will have research 4DCT scans and research pulmonary functions performed 3, 
6, and 12 months post completion of radiation therapy. These visits will coincide with the 
standard of care clinic visits which occur every 3 months during year one.  
5.10. 
Duration of Follow Up 
Subjects will have life-long follow-up for this study to prospectively quantify radiation-
related sequelae. The follow-up schedule is consistent with standard of care follow-up 
schedules for this patient population. The first study-defined follow-up appointment will 
be 3 months (10 week window: – 2 weeks to +8weeks) after completing radiation 
therapy. With approval of PI, subjects can miss this follow-up appointment and continue 
on the study.  

 
12 
Long term, follow-up will follow standard of care based on subjects disease status at each 
follow-up.  Pertinent late radiation toxicities will be dictated by the treating physician and 
subsequently graded.  
5.11. 
Adjuvant Therapy 
Subjects who have left study, or who have completed their chemo-radiation treatment, 
may continue therapy at the discretion of their treating medical and radiation oncologists. 
This treatment is beyond the scope of the protocol, as these patients have completed 
participation in the protocol. Adjuvant therapy information will be collected for statistical 
purposes. 
5.12. 
Assessments 
5.12.1. Lung tissue elasticity evaluation using 4DCT. Subjects will undergo research-
ordered 4DCT scans at simulation, 3 months, 6 months and 12 months post-radiation. 
5.12.2. Patient self-assessment will be documented using a modified Borg scale, which has 
a history of use in pulmonary labs, with a scale of 1 (resting comfortably in a chair 
with no effort) to 10 (the most exertion and difficult breathing ever experienced). 
5.12.3. Pulmonary Function Tests will include FEV1, FVC, DLCO measurements 
5.12.4. RTOG defined acute toxicity evaluation. Evaluate both lung and esophageal 
toxicity. 
(Appendix 
B). 
Radiation 
Oncologist 
evaluation 
weekly 
during 
chemoradiation, at radiation therapy fini, and at 3-month follow-up. 
5.12.5. RTOG late toxicity evaluation. Evaluate lung, esophageal, skin, subcutaneous 
tissue, spinal cord, heart, and bone (Appendix C). Evaluation by Radiation Oncologist 
at 6 month follow-up and beyond. 
5.12.6. Constitutionalassessment: quantify nausea, vomiting, diarrhea and other symptoms 
and any medications used for these symptoms. Done weekly during chemoradiation 
and at follow-up appointments.  
6. 
DOSING DELAYS/DOSE MODIFICATIONS 
Not applicable. If radiation dose needs to be modified or delayed, this is per standard of care and 
beyond the scope of this study. A note will be made in the study chart regarding any changes to 
radiation dose and any breaks in radiation therapy. 
 
7. 
ADVERSE EVENTS: 
 
The risks of harm for those subjects randomized to the research arm (arm 2) is equivalent to the 
control arm:  optimized treatment plans in the research arm will be designed to meet the same 
dose specifications to organs-at-risk. In other words, when comparing the control and research 
arm: 
· the same radiation doses will be delivered to the tumors 
· the same radiation dose limits will be achieved for all normal tissues 
 
There are minimal additional risks associated with the research procedures of 4DCT and PFT’s.  
The most significant risk from 4DCT is the increased radiation exposure which will be less than 
1% of the dose received from the prescribed radiation therapy. Subjects may experience 

 
13 
discomfort from laying on their back during additional 4DCT scans.  Each 4DCT scan will last 
90 seconds.  It is anticipated that patients will spend approximately 10-15 minutes on their back 
to position and collect the scans. 
 
PFT’s have the following associated risks: the test requires subjects to breathe in and out quickly, 
which may cause them to feel dizzy or faint. The test may increase the risk of asthma attack in 
those with asthma. In very rare cases, PFTs may cause a collapsed lung.  
  
Patients will receive standard of care therapeutic radiation therapy dosing as part of this study.  
Toxicities associated with therapeutic radiation include: Reversible or permanent alopecia, bone 
marrow toxicity, skin reactions, and esophagitis are expected side effects of radiation therapy. 
Radiation-induced myocarditis or transverse myelitis rarely occur at doses lower than 50 Gy. 
Radiographic evidence of radiation change and subsequent fibrosis of the lung will occur within 
lung volume receiving first 6-12 months after initiation of treatment.  
Acute (within 90 days post RT completion) and late radiation toxicities ( > then 90 days post RT 
completion) will be recorded with special attention to the toxicities listed in appendix B and C.  
Any treatment interruption will be based on treating physician judgement and be documented as 
part of the study toxicity assessments. 
7.1. 
Adverse Events Characteristics   
This trial will be focused on the radiation toxicities experienced by patients who receive 
either SOC radiation treatment planning or the “optimized” treatment planning thus the 
toxicities recorded in this protocol will focus only on toxicities that can be at least 
possibly attributed to the radiation treatment. 
RTOG (Radiation Therapy Oncology Group) has developed both acute and late radiation 
toxicities that occur in lung cancer patients.  These toxicities and grading criteria are 
outlined in appendix B (acute toxicities) and Appendix C (late radiation toxicities). 
In addition, 15% subjects who undergo chest radiation experience rib fractures.  We will 
track rib fractures using the CTACAE 4.03 term “fracture” to ensure that “optimized" or 
experimental arm patients frequency and severity of fractures don’t exceed control arm 
subjects or historical frequency.  
 
Changes in Pulmonary function tests 
We will utilize the criteria used in RTOG0813 to quantify changes in pulmonary function 
testing. 
RTOG0813 Criteria  
Patients enrolled to this study are allowed to have some degree of impaired pulmonary 
function as measured by pulmonary function tests (PFTs), including Forced Expiratory 
Volume in 1 second (FEV1), Forced Vital Capacity (FVC), and Diffusing Capacity for 
Carbon Monoxide (DLCO). The Common Toxicity Criteria (CTCAE), v. 4 includes 
specified criteria for grading adverse events related to these PFT parameters under the 
system organ class of Investigations. The grading criteria for these PFT changes use the 
“percent predicted” values from 0-100% which are recorded on the patient’s PFT report. 
A percent predicted of 90% conveys that the patient is able to perform the PFT test to a 

 
14 
result that is 90% of what would be expected for the normal general population of the 
same height, age, and sex. The CTCAE version 4 specified grading criteria for PFTs 
assumes that all patients have normal baseline pulmonary function. This assumption is 
not appropriate for this protocol enrolling patients with abnormal baseline function.  
 
As a remedy to monitor treatment effects on PFTs, we will define a protocol specific 
toxicity classification for PFTs that adjusts for baseline abnormalities. Changes that occur 
after therapy will be referenced to the baseline for a given patient, which will be 
abnormal for most patients. We have defined a proportional decline from the baseline. 
Grade 1 toxicity will be a decline from baseline to a level 0.90 times the baseline, grade 2 
will be a decline to a level 0.75 of baseline, grade 3 will be a decline to a level 0.5 of 
baseline, grade 4 will be a decline to a level 0.25 of baseline, and grade 5 will be death. 
This scheme is depicted in the table below and graphically represented in the figure 
below. See appendix D 
 
As an example, a patient who enters the study with a percent predicted DLCO of 55% 
who experiences a post treatment decline to a percent predicted DLCO of 40% would 
have a grade 3 event in the original CTCAE version 4 criteria; however, under this 
modified PFT toxicity classification for patients with abnormal baseline, his decline 
would constitute a decrease to 0.72 of the baseline value which is between 0.75 and 0.5 
or a grade 2 event.  
   
 
 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ for expedited reporting 
purposes only. 
Attribution of the AE: 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment. 
• Unlikely – The AE is doubtfully related to the study treatment. 
• Unrelated – The AE is clearly NOT related to the study treatment. 
 
Adverse Event Reporting 
Adverse events (AEs) and serious adverse events (SAEs) will be recorded in study 
database. All SAEs will be reported to the lung DOWG, UWCCC, and UW HS-IRB 
per policy. Reporting criteria are summarized in Table 1. 
An AE is an undesirable medical occurrence (sign, symptom, or diagnosis) or 
worsening of a pre-existing medical condition (diabetes, congestive heart failure, 
rheumatoid arthritis) that occurs after initiation of the investigational product whether 
or not it is considered to be investigational product related.  A worsening of an 
existing medical condition is one that was present at baseline (e.g., cancer, diabetes, 
migraine headaches, gout) and became more severe, more frequent, or increased in 
duration during investigational product treatment. = 
Expected events - Expected events are those that have been previously identified as 
resulting from treatment of lung cancer with radiation. These are defined above for 

 
15 
acute and late toxicities (section 8, appendix B and C). For purposes of this study, 
reporting requirements are determined by the assessment of the following adverse 
event characteristics: the type or nature of the event; the severity (grade); the 
relationship to the study therapy (unrelated, not likely, possibly, likely, or definitely 
related), and whether the event is expected or unexpected. 
Recommended assessment steps include: 
• Identification of adverse event. 
• Determine whether the adverse event is expected or unexpected. 
• Grading the severity of the adverse event using the appropriate set of criteria; 
CTCAE v.4.03 (General, unexpected). 
• Determination as to whether the adverse event is related to the study therapy 
using the following categories: Unrelated, Possible, Probable, and Definite 
 
For the purpose of this study acute radiation adverse event information will be 
collected through 90 day (3 month) post radiation visit.  After the 90 day (3 month 
visit)  visit only events specific late radiation treatment effects will be collected ( 
appendix C) and any adverse events that result from the 4DCT and PFT’s. 
 
An SAE is defined by regulatory agencies as one that suggests a significant hazard or 
side effect, regardless of the investigator or sponsor’s opinion on the relationship to 
investigational product.  This includes, but may not be limited to, any event that (at 
any dose): 
• Is fatal 
• Is life threatening (places the subject at immediate risk of death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Is a persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Any event that does not exactly meet this definition yet, in the investigator’s 
opinion represents a significant hazard can be assigned the “other significant 
hazard” regulatory reporting serious criteria 
• Additionally, important medical events that may not be immediately life 
threatening or result in death or hospitalization but that may jeopardize the subject 
or require intervention to prevent one of the outcomes listed above, or result in 
urgent investigation, may be considered serious.  Examples include allergic 
bronchospasm, convulsions, and blood dyscrasias. 
 
Note: All deaths on treatment require both routine and expedited reporting regardless 
of causality. Attribution to treatment or other cause must be provided. “On treatment” 
is defined begins with the radiation simulation planning session and ends 30 days post 
completion of radiation therapy.  
All adverse events deemed to be related by the investigator to the radiation therapy as 
listed in section 8, appendix B and C will be collected and recorded throughout the 
study period beginning with the signing of the informed consent through the day 
patient is removed from the study or the date of death or 5 years after completion of 
the radiation therapy. 

 
16 
All serious adverse events that occur after the subject has signed the informed consent 
form must be reported to University of Wisconsin Carbone Cancer Center Data 
Safety 
and 
Monitoring 
Board 
and 
other 
regulatory 
agencies. 
 
Grade 4 and 5 serious adverse events occurring greater then 30 days post RT AND 
thought to be possibly related to the RT or study procedures (4DCT’s and/or PFT’s) 
will be collected and submitted within 24 hrs with a full report within 10 working 
days of discovery or notification of the event via the same mechanism. 
 
Table 1. Expedited reporting requirements for adverse events that occur within 30 days of the last 
dose of protocol RT and thought to be at least possibly related to protocol RT 
FDA Reporting Requirements for Serious Adverse Events (21 CRF Part 312) 
NOTE: Investigators MUST immediately report to the PI, UWCCC and UW IRB per policy ANY 
Serious Adverse Events, whether or not they are considered related to the investigational 
agent(s)/intervention (21 CFR 312.64). FDA Med Watch (3500A) will be submitted for grade 4 
and 5 events at the discretion of the sponsor-investigator. 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• Death. 
• A life-threatening adverse event. 
• An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• A congenital anomaly/birth defect. 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria* MUST be immediately reported to 
the UWCCC within the timeframes detailed in the table below:   
Hospitalization 
Grade 1 and Grade 2 
Timeframes 
Grade 3 
Time Frames 
Grade 4 & 5 
Timeframes 
Resulting in 
hospitalization  ≥ 
24 hrs 
Not required 
 
10 Calendar Days 
24 Hour; 5 Calendar Days 
Not resulting in 
Hospitalization ≥ 
24 hrs 
Not required 
 
10 Calendar Days 
• See section 8.0, appendix B ,C  and D for listing of toxicities 
• Grade 3 toxicities resulting in hospitalization with attribution of probably or definitely related 
to chemotherapy will be exempt from expedited reporting 
Expedited AE reporting timelines are defined as: 
• 24-Hour; 5 Calendar Days – The AE must initially be reported within 24 hours of learning of 

 
17 
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour 
report. 
• 10 Calendar Days – A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE 
1 Serious adverse events that occur more than 30 days after the RT dose and have an attribution of 
possible, probable, or definite related to radiation or other study procedures (4DCT and PFTs) 
require reporting as follows: 
 
Expedited 24-hour notification followed by complete report within 10 working days for: 
• All Grade 4, and 5 AEs 
 
8. 
CORRELATIVE/SPECIAL STUDIES: CLOSED TO ADDITIONAL SAMPLE 
COLLECTIONS 
8.1. 
Correlative Objective 
Changes in inflammation blood markers at 3, 6, 9 and 12 months after radiation therapy 
when compared to baseline.  Plasma TGF-β1 will be measured by molecular specific 
Enzyme Linked Immune Sandwich Assay (ELISA). The levels of plasma cytokines will 
be measured by ready to use kits for the concentrations of 29 proinflammatory cytokines, 
including G-CSF, IL-1α, IL-1β, IL-1ra, IL-6, IL-8, IP-10, MCP-1, MIP-1, TGF-α, and 
TNF-α. 
8.2. 
Correlative lab study 
Patients will be offered the opportunity to participate in the correlative components of the 
study, however participation will be optional.  Whole blood, plasma, and serum samples 
will be drawn within 2 weeks prior to radiation therapy and then drawn 3, 6, 9 and 12 
months after radiation therapy.   
Platelet-poor plasma will be obtained for cytokine assays; serum samples will be used 
for, cell death assays and other markers as indicated; buffy coat will be used for genomic 
studies including methylation analysis. Plasma TGF-β1 will be measured by molecular 
specific Enzyme Linked Immune Sandwich Assay (ELISA). The levels of plasma 
cytokines will be measured by ready to use kits, such as LINCOplex (microsphere-based 
sandwich immunoassay) for the concentrations of 29 proinflammatory cytokines, 
including G-CSF, IL-1α, IL-1β, IL-1ra, IL-6, IL-8, IP-10, MCP-1, MIP-1, TGF-α, and 
TNF-α. RILT will be diagnosed and graded based on CTCAE 4.  For genomic studies, 
we will focus our efforts on (but not limited to) global SNP and DNA methylation as well 
as SNP and methylation analysis of TGFβ1, tissue plasminogen activator (tPA) and 
angiotensinconverting enzyme (ACE), which are associated with radiation-induced 
thoracic toxicity such as radiation induced lung injury. Genetic variations within 
functional locus of these genes will be assessed for in each patient by using gene specific 
PCR technology. Such SNP studies will be performed using polymerase chain reaction 
(PCR) and allele specific primers.   Genome wide methylation profiling will be 
performed using the Illumina Infinium HumanMethylation450 BeadChip array which 
examines the methylation status of 485,577 CpG sites distributed throughout the whole 
genome, covering 96% of CpG islands and 99% of RefSeq genes.  Methylation status of 
select genes of interests will also be validated using pyrosequencing.  Bioinfomatic 
methodology may be applied for data analysis.  Blood markers (cytokine and genomics) 

 
18 
during early course of treatment will be correlated to clinical outcome including tumor 
control. 
Blood (whole blood, plasma and serum) will be processed by the UWCCC BioBank 
(Translational Science BioCore). 30 ml peripheral blood (two 10 ml EDTA tubes and one 
10 ml SST tube) will be taken from each patient at each time point. 
Blood—Plasma: 10 ml of blood will be collected in one EDTA (purple top) tube 
twice. Blood will be inverted 6-7 times to ensure adequate mixing with anticoagulant, 
then centrifuged within one hour of collection in a standard clinical centrifuge at 
3000g at 4°C for 10 minutes. If the interval between specimen collection and 
processing is anticipated to be greater than one hour, the specimens are kept on ice 
until centrifuging can begin.  Samples will be carefully pipetted in up to ten 1.5 ml 
cryovials as 1.0 ml aliquots of plasma. Care will be taken to avoid pipetting any blood 
cells or buffy coat (red/white blood cells). Plasma samples will be labeled and 
cryovials will be stored at -80°C. 
Blood–Serum: 10 ml of blood will be collected without coagulants in one SST (red 
top) tube. Blood will sit at room temperature for 30 min to allow clot formation, then 
centrifuged in a standard clinical centrifuge at 3000g at 4°Cfor 10 minutes. Samples 
will be transferred into up to ten 1.5 ml cryovials as ~1ml aliquots of separated 
serum. Serum samples will be labeled and cryovials will be stored at -80°C. 
Blood—Whole Blood: 10 ml of blood will be collected in one EDTA (purple top) 
tube. Blood will be inverted 6-7 times to ensure adequate mixing with anticoagulant 
and then carefully pipetted into three to five 1.5 ml cryovials as 0.5 ml aliquots of 
whole blood. Samples will be labeled and cryovials will be stored at -80°C. 
Initial collected specimens will be labeled with the patient name, date, time and time 
point collected. A completed specimen collection flow sheet will accompany each 
specimen. 
In an effort to protect the patient’s identity in the laboratory, the stored frozen 
samples will be identified by a code that can be linked back to the patient by the 
investigators, but not other laboratory personnel. 
Blood collections will be scheduled at baseline, which will be within 2 weeks of 
radiation therapy beginning, and then 3 months, 6 months, 9 months, and 12 months 
after the completion of radiation therapy. 
8.3. 
Correlation with daily localization imaging 
Images acquired for daily localization may show changes in lung tissue that occur during 
therapy.  These images may also be investigated as described in secondary endpoints 
(Section 10.2) 
9. 
 
STUDY CALENDAR 
 
Pre 
study1 
Simulation 
Weekly 
during  
Rt 
3 mo 
post 
6 mo 
post 
12 mo 
post 

 
19 
H & P 
X 
 
 
X 
X 
X 
KPS 
X 
 
X 
X 
X 
X 
Weight 
X 
 
X 
X 
X 
X 
Informed 
Consent 
X 
 
 
 
 
 
4DCT 
 
X3 
 
X 
X 
X 
PFT’s2 and pt 
self assessment 
 
X4 
 
X5 
X5 
X5 
Toxicity 
Assessment 
X 
 
X 
X 
X 
X 
 
10. MEASUREMENT OF EFFECT 
The aims of this proposal are to use quantitative imaging to characterize pulmonary 
biomechanics, improve pulmonary function following RT by utilizing per-RT pulmonary 
function data to avoid regions of the lung with high function, and gather outcomes data to further 
refine our radiation dose response model. The primary endpoint is changes in pulmonary 
function, based on changes in tissue elasticity measured from 4DCT.  Secondarily we will 
evaluate global measures of change using routine pulmonary function tests. 
10.1. 
Primary endpoint 
Lung tissue elasticity changes. The primary endpoint of this study will be the ratio of the 
tissue elasticity map following RT to the elasticity map before RT (i.e., the Jacobian ratio 
of (post RT /pre RT)) calculated from 4DCT at 3 months post-RT.  Based on the 
randomness of our measurement technique, diminished expansion (i.e. substantial 
change) is defined as a Jacobian ratio <0.94 (i.e., less than 94% of the pre-RT value). 
10.2. 
Secondary endpoints   
10.2.1. Lung tissue elasticity changes 
Temporal changes in reduced elasticity. Since the differences in expansion may 
increase with time, we will investigate these same changes during therapy (using 
localization images acquired per 5.4) and at 6 and 12 months post-RT. 
10.2.1.1. 
Temporal changes in increased elasticity. At 3, 6 and 12 months post-RT 
we will determine the volume of lung where expansion is improved (Jacobian 
ratio (post-RT/pre-RT) > 1.06)  
10.2.1.2. 
Temporal changes in fraction of expanding lung. At 3, 6 and 12 months 
post-RT we will determine the volume of lung where “meaningful” expansion 
occurs (Jacobian post-RT > 1.1).  
10.2.1.3. 
Validation of dose response model. Validation in consistency of tissue 
elasticity changes measured with values predicted based on existing radiation 
dose response curves. 

 
20 
10.2.2. Global measures of change 
10.2.2.1. 
Pulmonary Function Tests.  Changes in patient self-assessment, forced 
vital capacity (FVC), forced expiratory volume in one second (FEV1), and 
diffusion lung capacity for carbon monoxide (DLCO).  All metrics will be 
evaluated at 3, 6, and 12 months post-RT in comparison to values pre-RT. 
10.2.2.2. 
Inflammation.  Plasma TGF-β1 will be measured by molecular specific 
Enzyme Linked Immune Sandwich Assay (ELISA). The levels of plasma 
cytokines will be measured by ready to use kits for the concentrations of 29 
proinflammatory cytokines, including G-CSF, IL-1α, IL-1β, IL-1ra, IL-6, IL-8, 
IP-10, MCP-1, MIP-1, TGF-α, and TNF-α. 
10.2.3. Repeatability of 4DCT based measures of lung tissue elasticity 
10.2.3.1. 
Variation of the tissue elasticity calculated between scan 1 and scan 2 at 
each time point will be quantified and compared to longitudinal changes in 
tissue elasticity. 
10.3. 
Data collection 
10.3.1. 4DCT data and radiation dose distribution data 
10.3.2. Respiratory surrogate data. Collected from standard treatment techniques, used to 
assess tumor motion through time and space.  
10.3.3. Daily images acquired for patient alignment and motion management. Collected from 
standard treatment techniques. 
10.3.4. RTOG toxicity data and constitutional symptoms 
10.3.5. Pulmonary function tests, including FEV, FEV1 and DLCO. 
10.3.6. Patient self-assessment  
10.3.7. RTOG acute radiation morbidity scoring scheme. Utilized for RTOG 9311, these 
criteria will be reviewed at radiation therapy fini and at the 3-month post-radiation 
follow-up appointment. 
10.3.8. RTOG late radiation morbidity scoring scheme. Utilized for RTOG 0117, these side 
effects will be collected at follow-up visits after 90 days post-radiation.  
11. STATISTICAL CONSIDERATIONS 
11.1. 
Study Design/Endpoints 
The primary endpoint of this study will be the ratio of the tissue elasticity map following 
RT to the elasticity map before RT (i.e., the Jacobian ratio of (post RT /pre RT)) 
calculated from 4DCT at 3 months post-RT.  Based on the randomness of our 
measurement technique, diminished expansion is defined as a Jacobian ratio <0.94 (i.e., 
less than 94% of the pre-RT value). Data for the analysis will consist of the voxel-
specific ratios of tissue elasticity measures from scans being compared. The primary and 
secondary endpoints at 3, 6, and 12 months post-RT include: (i) the volume of lung 
where diminished expansion occurs (Jacobian ratio (post RT /pre RT)<0.94), (ii) the 
volume of lung where expansion is improved (Jacobian ratio (post RT /pre RT)>1.06),  
(iii) the volume of lung where “meaningful” expansion occurs (Jacobian post-RT > 1.1), 
and (iv) clinically observed pulmonary toxicity determined by PFT endpoints, and (v) 
changes in inflammation as determined from blood serum. 

 
21 
Some subjects may have multiple sites of disease treated within the thorax.  Since these 
subjects will be treated at all sites with either the control (Arm 1) or experimental (Arm 
2) treatment plan, and since the primary endpoint of the study is the assessment of normal 
lung tissue response to delivered radiation, these subjects represent a single sample 
within our analysis. 
Power analysis shows the planned enrollment of 60 subjects per cohort will ensure 90% 
power to detect mean difference of 4% in the lung tissue elasticity (percentage of the lung 
with a Jacobian ratio post-RT/pre RT < 0.94), based on 6.3% deviation in this measure 
from 13 subjects in our preliminary data. If the normality assumptions of ANOVA are 
not satisfied, nonparametric rank-based tests will be used instead. All statistical tests will 
be two-sided and assessed for significance at the 5% level, and will be performed by the 
UW-Madison Department of Biostatistics and Medical Informatics. 
 
Update as of 2/3/2021:  The statistics are based on 30 subjects reaching the 3 month 
followup time point. To date 106 have been enrolled but 14 did not complete the 3 month 
imaging time point. Therefore we are adding numbers to replace those subjects and to 
allow an addtional 5 subjects to ensure we complete the protocol and meet the study 
objectives. 
 

 
22 
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26 
 
APPENDIX A: PERFORMANCE STATUS CRITERIA 
 
 
 
 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 

 
27 
APPENDIX B: Radiation Therapy Oncology Group Acute toxicity 
(baseline, during RT, 3 month post-RT) 
Lung 
0 
None 
1 
Mild symptoms of dry cough or dyspneal on exertion 
2 
Persistent cough requiring narcotic, antitussive agents; or 
Dyspnea with minimal effort but not at rest 
3 
Severe cough unresponsive to narcotic antitussive agent; or 
Dyspnea at rest; or, 
Clinical or radiographic evidence of pneumonitis; or, 
Intermittent oxygen or steroids may be required 
4 
Severe respiratory insufficiency; or, 
Continuous oxygen or assisted ventilation required 
5 
Death 
 
Esophageal 
0 
None 
1 
Mild dysphagia or odynophagia; or, 
Requires topical anesthetic or non-narcotic analgesics; or, 
Requires soft diet 
2 
Moderate dysphagia or odynophagia; or, 
Requires narcotic analgesics; or, 
Requires puree or liquid diet 
3 
Severe dysphagia or odynophagia with dehydration or weight loss 
(>15% from pretreatment baseline) requiring nasogastric feeding; 
or, 
I.V. fluids; or, 
Hyperalimentation 
4 
Complete obstruction, ulceration, perforation, or fistula 
5 
Death 
 
Weight loss 
0 
None 
1 
5 to <10% form baseline; intervention not indicated 
2 
10 - <20% from baseline; nutritional support indicated 
3 
≥ 20% from baseline; tube feeding or TPN indicated 
 
 
 
 
 
 
 

 
28 
APPENDIX C: Radiation Therapy Oncology Group Late toxicity 
(6 months post-RT and beyond) 
Lung 
0 
None 
1 
Mild symptoms (dry cough); or, 
Slight radiographic appearances 
2 
Moderate symptomatic fibrosis or pneumonitis (severe cough); or, 
Low-grade fever; or, 
Patchy radiographic appearance 
3 
Severe symptomatic fibrosis or pneumonitis; or, 
dense radiographic changes 
4 
Severe respiratory insufficiency; or, 
continuous oxygen or assisted ventilation required 
5 
Death 
 
Esophageal 
0 
None 
1 
Mild fibrosis; or, 
slight difficulty in swallowing solids (no pain on swallowing) 
2 
Unable to take solid food normally; or, 
Swallowing semi-solid food 
Dilation indicated 
3 
Severe fibrosis; or, 
Able to swallow only liquids; 
Pain upon swallowing; 
Dilation required 
4 
Necrosis/perforation 
5 
Death 
 
Skin 
0 
None 
1 
Slight atrophy; or, 
Pigmentation change; or, 
Some hair loss 
2 
Patchy atrophy; or, 
Moderate telangiectasia; or, 
Total hair loss 
3 
Marked atrophy; or, 
Gross telangiectasia 
4 
Ulceration 
 
Subcutaneous tissue 
0 
None 
1 
Slight induration (fibrosis) and loss of subcutaneous fat 
2 
Moderate fibrosis but asymptomatic; or, 
Slight field contracture (<10% linear reduction) 
3 
Severe induration and loss of subcutaneous tissue; or, 
Field contracture (>10% linear measurement)  
4 
Necrosis 
 
 

 
29 
 
Radiation Therapy Oncology Group Late toxicity 
(6 months post-RT and beyond) 
Spinal cord 
0 
None 
1 
Mild L’Hermitte’s syndrome 
2 
Severe L’Hermitte’s syndrome 
3 
Objective neurological findings at or below cord level treatment 
4 
Mono, para, quadriplegia 
 
Heart 
0 
None 
1 
Asymptomatic or mild symptoms; or, 
Transient T-wave inversion & ST changes; 
Sinus tachycardia >110 (at rest) 
2 
Moderate angina on effort; or, 
Mild pericarditis (normal heart size); or, 
Persistent abnormal T-wave and ST changes; or, 
Low ORS 
3 
Severe angina; or 
Pericardial effusion; or 
Constrictive pericarditis; or 
Moderate heart failure; or 
Cardiac enlargement; or 
EKG abnormalities 
4 
Tamponade; or 
Severe heart failure; or 
Severe constrictive pericarditis 
 
Bone Fracture 
0 
None 
1 
Asymptomatic; clinical or diagnostic observations only; 
intervention not indicated 
2 
Symptomatic but non-displaced; immobilization indicated 
3 
Severe symptoms; displaced or open wound with bone exposure; 
disabling; operative intervention indicated 
4 
Life-threatening consequences; urgent intervention indicated 
 

 
30 
APPENDIX D: RTOG PULMONARY FUNCTION TOXICITY CRITERIA 
 (baseline and at 3, 6 and 12 months; coinciding with 4DCT scans) 
 
The SBRT Pulmonary Toxicity Scale  
 
Grade 
 
 
 
 
Adverse Event 
1 
2 
3 
4 
5 
FEV-1 Decline 
0.90-0.75 
times the patient’s 
baseline value 
<0.75-0.50 
times the 
patient’s 
baseline value 
<0.50-0.25 
times the patient’s 
baseline value 
<0.25 times the 
patient’s 
baseline value 
Death 
Forced Vital 
Capacity Decline 
0.90-0.75 
times the patient’s 
baseline value 
<0.75-0.50 
times the 
patient’s 
baseline value 
<0.50-0.25 
times the patient’s 
baseline value 
<0.25 times the 
patient’s 
baseline value 
Death 
DLCO Decline 
0.90-0.75 
times the patient’s 
baseline value 
<0.75-0.50 
times the 
patient’s 
baseline value 
<0.50-0.25 
times the patient’s 
baseline value 
<0.25 times the 
patient’s 
baseline value 
Death 
 
 

 
31 
 
APPENDIX E: PATIENT SELF ASSESSMENT CRITERIA 
 
Modified Borg Scale 
G. Borg, Psychophysical bases of perceived exertion, Med Sci Sports Exerc, 14 (1982), pp. 377–381 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
32 
 
APPENDIX F: UWCCC DATA SAFETY MONITORING PLAN 
 
Oversight And Monitoring Plan  
The UWCCC Data and Safety Monitoring Committee (DSMC) is responsible for the regular review 
and monitoring of all ongoing clinical research in the UWCCC. A summary of DSMC activities are 
as follows:  
• Reviews all clinical trials conducted at the UWCCC for subject safety, protocol compliance, and 
data integrity.  
• Reviews all Serious Adverse Events (SAE) requiring expedited reporting, as defined in the 
protocol, for all clinical trials conducted at the UWCCC, and studies conducted at external sites 
for which UWCCC acts as an oversight body.  
• Reviews all reports generated through the UWCCC DSMS elements (Internal Audits, Quality 
Assurance Reviews, Response Reviews, Compliance Reviews, and Protocol Summary Reports)  
• Notifies the protocol Principal Investigator of DSMC decisions and, if applicable, any 
requirements for corrective action related to data or safety issues.  
• Notifies the CRC of DSMC decisions and any correspondence from the DSMC to the protocol 
Principal Investigator.  
• Works in conjunction with the UW Health Sciences IRB in the review of relevant safety 
information as well as protocol deviations, non-compliance, and unanticipated problems reported 
by the UWCCC research staff.  
• Ensures that notification is of SAEs requiring expedited reporting is provided to external sites 
participating in multi-institutional clinical trials coordinated by the UWCCC. 
 
Monitoring And Reporting Guidelines  
UWCCC quality assurance and monitoring activities are determined by study sponsorship and risk level 
of the protocol as determined by the PRMC. All protocols (including Intervention Trials, Non-
Intervention Trials, Behavioral and Nutritional Studies, and trials conducted under a Training Grant) are 
evaluated by the PRMC at the time of committee review. UWCC monitoring requirements for trials 
without an acceptable external DSMB are as follows: 
Intermediate Monitoring Protocols subject to intermediate monitoring generally include UW 
Institutional Phase I/II and Phase II Trials.  These protocols undergo review of subject safety at 
regularly scheduled DOWG meetings where the results of each subject’s treatment are discussed 
and the discussion is documented in the DOWG meeting minutes.  The discussion includes the 
number of subjects enrolled, significant toxicities, dose adjustments, and responses observed.  
Protocol Summary Reports are submitted on a semi-annual basis by the study team for review by 
the DSMC. 
 
Review and Oversight Requirements 
Serious Adverse Events requiring reporting within 24 hours (as described in the protocol) must also be 
reported to the Data and Safety Monitoring Committee (DSMC) Chair via an email to 
saenotify@uwcarbone.wisc.edu within one business day. The OnCore SAE Details Report must be 
submitted along with other report materials as appropriate (NCI AdEERS form or FDA Medwatch Form 
#3500 and/or any other documentation available at that time of initial reporting). The DSMC Chair will 
review the information and determine if immediate action is required. Within 10 working days, all 
available subsequent SAE documentation must be submitted electronically along with a 24 hour follow-

 
33 
up SAE Details Report and a completed UWCCC SAE Routing Form to 
saenotify@uwcarbone.wisc.edu. All information is entered and tracked in the UWCCC database. The 
Principal Investigator notifies all investigators involved with the study at the UWCCC, the IRB, the 
sponsor, and the funding agency and provides documentation of these notifications to the DSMC. If the 
SAE occurs on a clinical trial in which the UW PI serves as the sponsor-investigator, the PI reviews the 
event to determine whether the SAE requires reporting to the FDA and other participating investigators. 
For a multiple-institutional clinical trial the PI is responsible for ensuring SAEs are reported to the FDA 
as well as to all participating investigators 
 
Serious Adverse Event-Reported within 10 Days 
Serious Adverse Events requiring reporting within 10 days (as described in the protocol) must also be 
reported to the Data and Safety Monitoring Committee (DSMC) Chair via an email to 
saenotify@uwcarbone.wisc.edu. The OnCore SAE Details Report must be submitted along with other 
report materials as appropriate (NCI AdEERS form or FDA Medwatch Form #3500 and/or any other 
documentation available at that time of initial reporting). The DSMC Chair will review the information 
and determine if further action is required. All information is entered and tracked in the UWCCC 
database. The Principal Investigator notifies all investigators involved with the study at the UWCCC, the 
IRB, the sponsor, and the funding agency and provides documentation of these notifications to the 
DSMC. If the SAE occurs on a clinical trial in which the UW PI serves as the sponsor-investigator, the 
PI reviews the event to determine whether the SAE requires reporting to the FDA and other participating 
investigators. For a multiple-institutional clinical trial the PI is responsible for ensuring SAEs are 
reported to the FDA as well as to all participating investigators. 
 
Sponsor-Investigator Responsibilities for SAE Review 
In the event the UWCCC Principal Investigator is acting as the Sponsor-Investigator (i.e., the PI holds 
the IND), the PI assumes responsibilities of the study sponsor in accordance with FDA 21 CFR 312.32. 
In this capacity, the UWCCC PI reviews all reports of serious adverse events occurring on the study at 
the UWCCC and participating external sites and makes a determination of 1) suspectedness (i.e., 
whether there is a reasonable possibility that the drug caused the AE); and 2) unexpectedness in the 
context of theis study.  SAE with suspected causality to study intervention deemed unexpected are 
reported as IND safety Reports by the UWCCC PI to the FDA, all participating investigators on the 
study, within 15 calendar days.  All fatal or life-threatening SAE that are unexpected and have suspected 
causality to the study intervention will be reported by the UWCCC PI to the FDA, all participating 
investigators on the study within 7 calendar days. 
 
Study Progress Review 
Protocol Summary Reports (PSR) are required to be submitted to the DSMC in the timeframe 
determined by the risk level of the study (quarterly; semi-annually; or annually). The PSR provides a 
cumulative report of SAEs, as well as instances of non-compliance, protocol deviations, and 
unanticipated problems, toxicities and responses that have occurred on the protocol in the timeframe 
specified. PSRs for those protocols scheduled for review are reviewed at each DSMC meeting. 
 
Protocol Summary Reports enable DSMC committee members to assess whether significant benefits or 
risks are occurring that would warrant study suspension or closure. This information is evaluated by the 
DSMC in conjunction with other reports of quality assurance activities (e.g., reports from Internal 
Audits, Quality Assurance Reviews, etc.) occurring since the prior review of the protocol by the DSMC. 
Additionally, the DSMC requires the study team to submit external DSMB or DSMC reports, external 

 
34 
monitoring findings for industry-sponsored studies, and any other pertinent study-related information. 
 
In the event that there is significant risk warranting study suspension or closure, the DSMC will notify 
the PI of the DSMC findings and ensure the appropriate action is taken for the protocol (e.g., suspension 
or closure). The DSMC ensures that the PI reports any temporary or permanent suspension of a clinical 
trial to the sponsor (e.g., NCI Program Director, Industry Sponsor Medical Monitor, Cooperative Group 
Study Chair, etc.) and other appropriate agencies. DSMC findings and requirements for follow-up action 
are submitted to the CRC 
 
Expedited Reporting Of Serious Adverse Events 
Depending on the nature, severity, and attribution of the serious adverse event an SAE report will be 
phoned in, submitted in writing, or both according to Table  below. All serious adverse events must also 
be reported to the UWCCC Data and Safety Monitoring Committee Chair. All serious adverse events 
must also be reported to the UW IRB (if applicable), and any sponsor/funding agency not already 
included in the list. Determine the reporting time line for the SAE in question by using the following 
table. Then refer to sections A and B below if the SAE occurred at the UWCCC or sections C and D if 
the SAE occurred at 1 South Park, Johnson Creek, or a WON Site. 
 
SAE Requiring [24] Hour Reporting Occurs at UWCCC: 
1. Report to the UWCCC:  
Reference the SAE SOP (Standard Operating Procedure) and the SAE Reporting Workflow for 
DOWGs on the UWCCC website (http://www.uwccc.wisc.edu) for specific instructions on how and 
what to report to the UWCCC for [24] hour initial and follow-up reports. A follow-up report is 
required to be submitted within 5 days of the initial [24] hour report.  
For this protocol, the following UWCCC entities are required to be notified:  
a) saenotify@uwcarbone.wisc.edu  
b) John Bayouth, Ph.D., UWCCC PI  
c) Diana Trask, UWCCC Radiotherapy PM  
d) Any other appropriate parties listed on the SAE Routing Form (for follow-up reports only)  
 
2. Report to the IRB:  
Consult the UW-IRB website for reporting guidelines 
 
SAE Requiring [10] Day Reporting Occurs at UWCCC:  
1. Report to the UWCCC:  
Reference the SAE SOP and the SAE Reporting Workflow for DOWGs on the UWCCC website 
(http://www.uwccc.wisc.edu) for specific instructions on how and what to report to the UWCCC for 
[10] day reports.  
For this protocol, the following entities are required to be notified: 
a) saenotify@uwcarbone.wisc.edu  
b) Any appropriate parties listed on SAE Routing Form  
 
2. Report to the IRB:  
Consult the UW-IRB website for reporting guidelines. 

 
35 
 
Other Reporting Requirements  
Reporting to the FDA  
Serious Adverse Events occurring on studies on which a UW PI is acting as sponsor-investigator must 
be reported to the FDA within the appropriate time frame. Mandatory and voluntary reporting guidelines 
and instructions are outlined on the FDA website: 
http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm 
 
Table 1. Expedited reporting requirements for adverse events that occur within 30 days of the last 
dose of protocol RT and thought to be at least possibly related to protocol RT 
FDA Reporting Requirements for Serious Adverse Events (21 CRF Part 312) 
NOTE: Investigators MUST immediately report to the PI, UWCCC and UW IRB per policy ANY 
Serious Adverse Events, whether or not they are considered related to the investigational 
agent(s)/intervention (21 CFR 312.64). FDA Med Watch (3500A) will be submitted for grade 4 
and 5 events at the discretion of the sponsor-investigator. 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• Death. 
• A life-threatening adverse event. 
• An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• A congenital anomaly/birth defect. 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria* MUST be immediately reported to 
the UWCCC within the timeframes detailed in the table below:   
Hospitalization 
Grade 1 and Grade 2 
Timeframes 
Grade 3 
Time Frames 
Grade 4 & 5 
Timeframes 
Resulting in 
hospitalization  ≥ 
24 hrs 
Not required 
 
10 Calendar Days 
24 Hour; 5 Calendar Days 
Not resulting in 
Hospitalization ≥ 
24 hrs 
Not required 
 
10 Calendar Days 
• See section 8.0, appendix B, C  and D for listing of toxicities 
• Grade 3 toxicites resulting in hospitalization with attribution of probably or definitely related 
to chemotherapy will be exempt from expedited reporting 
Expedited AE reporting timelines are defined as: 
• 24-Hour; 5 Calendar Days – The AE must initially be reported within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-

 
36 
hour report. 
• 10 Calendar Days – A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE 
1 Serious adverse events that occur more than 30 days after the RT dose and have an attribution of 
possible, probable, or definite related to radiation or other study procedures (4DCT and PFTs) 
require reporting as follows: 
 
Expedited 24-hour notification followed by complete report within 10 working days for: 
• All Grade 4, and 5 AEs