Early Phase Clinical Trial Incorporating Lung Function Imaging Into Radiation Therapy for Lung Cancer Patients
Phase: NA
Conditions: Lung Neoplasms, Lung Cancer
Sponsor: University of Colorado, Denver

COMIRB #14-1856 
Version Date: 5.16.19 
PI: Dr. Vinogradskiy 
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COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD (COMIRB) 
CAMPUS BOX F-490 
TELEPHONE: 303-724-1055 
FAX: 303-724-0990 
 
 
Protocol #: 14-1856 
 
Protocol Title: 
Early phase clinical trial incorporating lung function imaging into radiation 
therapy for lung cancer patients 
 
Sponsor-Investigator and 
Lead Principal Investigator: 
Yevgeniy Vinogradskiy PhD (Radiation Oncology) 
Lead Site: 
University of Colorado 
 
Participating Site: Beaumont Health System, Royal Oak, MI 
 
 
 
 
Version Date: 5.16.2019 

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Definitions 
 
UCCC 
University of Colorado Cancer Center 
Beaumont 
William Beaumont Hospital 
Lead PI 
Yevgeniy Vinogradskiy 
Site PI 
Inga Grills 
PFT 
Pulmonary Function Testing 
CT 
Computed Tomography 
4DCT 
4-Dimensional Computer Tomography 
4DCT-Ventilation 
4DCT based ventilation imaging 
PET 
Positron Emission Tomography 
Nuclear Medicine VQ 
Nuclear Medicine Ventilation-Perfusion 
CTCAE 
Common Terminology Criteria for Adverse 
Events 
QOL 
Quality of life 
DVH 
Dose-volume histogram 
AE 
Adverse Event 
SAE 
Serious Adverse Event 
 
 
1.0 Objectives 
 
1.1 
Primary Objective 
The proposed study is in the field of thoracic radiation oncology where radiation therapy is used to treat 
lung cancer. The primary objective of the early phase clinical trial will be to evaluate the safety and preliminary 
efficacy of performing functional avoidance radiation therapy for lung cancer patients using 4DCT-ventilation 
imaging. 4DCT-ventilation is an imaging modality that uses anatomical CT imaging data acquired as part of 
routine clinical care for lung cancer patients1 to calculate lung function images2, 3 (Figure 1). We propose to use 
4DCT-ventilation for thoracic functional avoidance. Functional avoidance implies placing and optimizing the 
radiation treatment beams to avoid the functional portions of the lung as displayed by the 4DCT-ventilation. 
Standard radiation therapy does not take into account the patient’s regional variation in lung function and treats 
the lung as a homogenous organ when delivering radiation. 4DCT-ventilation measures which areas of the lung 
are used for breathing and functional avoidance will allow physicians to spare these regions when delivering 
radiation. The idea is that avoiding functional portions of the lung will decrease the rate of thoracic side-effects 
from radiation. Our goal will be to accrue 67 lung cancer patients from 2 institutions (University of Colorado and 
Beaumont Health System) for an early phase prospective study evaluating functional avoidance. As noted in 
section 7.3, patients will count towards study accrual if they have a thoracic toxicity evaluation 3 months after 
completing radiotherapy. To account for screen fails and patient dropout we anticipate we will need to consent 
110 patients to reach our 67 patient clinical trial goal. Our primary objective will be to determine whether 
functional avoidance is safe and results in acceptable thoracic clinical toxicity. 
 
1.2 
Secondary Objectives 
A list of secondary objectives is shown below. In addition to the primary objective of clinical toxicity, in 
secondary objectives 1 and 2 we will assess radiation treatment response using imaging-based changes and 
pulmonary function test (PFT) data. In objective 3 we plan to compare our novel imaging modality, 4DCT- 
ventilation, to other forms of lung function imaging in a prospective setting. Objectives 4 and 5 will aim to develop 
preliminary results for the design of a large scale, randomized trial. 
1. Assess imaging-based changes in the lung due to the radiation therapy 

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2. Assess changes in PFT due to the radiation therapy 
3. Compare 4DCT-ventilation with other lung function assessment methods 
4. Assess the percentage of patients that are eligible for functional avoidance in a prospective setting 
5. Assess preliminary efficacy results for the generation of data for a large scale, randomized, multi- 
institutional clinical trial 
 
1.3 
Study Design 
The schema for the proposed study is 
shown in Figure 2 including whether the 
procedure is considered standard of care (SOC) 
or research (R). 
Step 1: Subject Enrollment and Screening: 
Biopsy proven lung cancer patients receiving 
definitive radiation therapy (defined as receiving 
45-75 Gy) will be eligible to be enrolled in the 
study. As part of routine clinical care each 
patient will undergo 4D computed tomography 
(4DCT) imaging. We will use the 4DCT data to 
calculate 4DCT-ventilation images. The 4DCT- 
ventilation images will be assessed for lung 
function defects. Patient receiving definitive 
radiation therapy and who display a clinically 
significant reduction in regional ventilation will be 
eligible for the trial. 
Step 2: Functional avoidance plan generation: Subjects will have a functional avoidance plan generated under 
the guidance of a radiation oncologist and a radiation physicist. We will use the subject’s 4DCT-ventilation 
imaging to design radiation treatment plans that avoid functional portions of the lung while still delivering the 
prescribed dose to the target and respecting dose tolerance limits for other thoracic organs at risk. 
Step 3: Pre-treatment lung function assessment: Subjects will undergo pre-treatment lung function assessment 
including: clinical assessment by a radiation oncologist using the NCI’s Common Terminology Criteria for 
Adverse Events (CTCAE) toxicity scoring system4, thoracic quality of life (QOL) questionnaires, 4DCT-ventilation 
imaging, nuclear medicine ventilation-perfusion (VQ) imaging, Positron Emission Tomography (PET) imaging, 
radiographic injury assessment using CT imaging, and PFTs. 
Step 4: Radiation therapy treatment: The functional avoidance radiation therapy plan will be delivered using a 
standard course of radiation treatment on a linear accelerator. The subject will be assessed each week by a 
radiation oncologist for side effects from the radiation treatment. 
Step 5: Post-treatment lung function assessment: After completion of radiation therapy the subject will undergo 
post-treatment lung function assessment using all modalities used to assess function during pre-treatment. 
Assessment will include: clinical assessment by a radiation oncologist using the CTCAE scoring system, thoracic 
QOL questionnaire, PFTs, CT imaging, 4DCT-ventilation imaging, nuclear medicine VQ imaging, and PET 
imaging. The clinical assessment and subject questionnaire will be done on the last day of treatment and at 3, 
6, and 12 months post therapy. The imaging and PFT studies will all be done at 3 months post therapy only (with 
the exception of the CT study which will be done at 1 year post therapy). The thoracic clinical toxicity for functional 
avoidance radiation therapy will be assessed using clinical end points (clinical CTCAE toxicity grade and subject 
questionnaire) and quantitative pulmonary assessment studies (PFT and imaging). 
0% 
Function 
Figure 1: An example image of a 4DCT- 
ventilation functional image overlaid with a 
standard lung CT. 
100% 
Function 

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Step 1: Patient Enrollment and Screening 
• 
Biopsy proven lung cancer patients receiving definitive radiation therapy (defined as 45-75 Gy) 
• 
Patient is 18 years of age or older, Patient signs study enrollment form 
• 
4DCT imaging (SOC), 4DCT-ventilation image formation and assessment (R) 
• 
Noted 4DCT-ventilation defect, 15% regional reduction in 4DCT-ventilation (R) 
• 
Clinical assessment by radiation oncologist (SOC) 
Step 2: Functional avoidance radiation therapy planning 
• 
Generate function avoidance radiation plan using 4DCT-ventilation imaging (R) 
• 
Functional avoidance plan has to meet target prescription dose and organ at risk dose limits (SOC) 
• 
Plan approval by radiation oncologist (SOC) 
 
Step 3: Pre-treatment lung function assessment 
• 
Thoracic QOL questionnaire (R) 
• 
Imaging assessment: 4DCT-ventilation (SOC), nuclear medicine VQ (SOC), PET imaging (SOC) 
• 
PFT testing (SOC) 
Step 4: Delivery of functional avoidance radiation therapy plan 
• 
Subject undergoes radiation therapy using functional avoidance plan (R) 
• 
Weekly visit with radiation oncologist to assess potential side effects from radiation (SOC) 
 
Step 5: Post treatment lung function assessment 
• 
Clinical assessment by radiation oncologist on the last day of radiation treatment and at 3 months, 6 
months, and 12 months post therapy (SOC) 
• 
Thoracic QOL questionnaire on last day of treatment, 3, 6, and 12 months post therapy (R) 
• 
Imaging assessment at 3 months post therapy: 4DCT-ventilation (R), nuclear medicine VQ (R), PET 
imaging (SOC); Imaging assessment at 1 year: standard follow CT imaging (SOC) 
• 
PFT at 3 months post therapy (R) 
Figure 2: Clinical trial schema. Abbreviations: R=Research, SOC=Standard of care 
 
 
 
2.0 Background and Significance 
 
2.1 
Radiation therapy for lung cancer 
Lung cancer remains a major public health problem. There will be an estimated 240,000 new lung cancer 
cases in 2014. Lung cancer is the number one cause for cancer related deaths in the United States. Five year 
survival rates for patients with lung cancer have been reported to be as low as 15%5. Radiation therapy is 
considered one of the primary definitive treatment options for patients with lung cancer. Up to 80% of patients 
with lung cancer receive radiation therapy. The success of radiation therapy in the lung has been limited by 
normal tissue radiation dose tolerance limits. In other words, the dose that can be delivered to the tumor is limited 

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by the radiation tolerance of the surrounding healthy lung. Serious and sometimes life-threatening thoracic side 
effects from radiation therapy generally occur in 25% of patients with rates as high as 50% cited6. The thoracic 
side-effects are a serious limitation to the patient’s quality of life following radiation treatment. Additionally, the 
fear of causing these life threatening thoracic side effects limits radiation doses that physicians are able to safely 
deliver to the tumor. 
 
2.2 
Imaging in radiation therapy 
The current standard of care in thoracic radiation therapy does not take into account the patient’s regional 
lung function distribution. In other words, the radiation treatment plan is designed assuming homogenous lung 
function throughout the lung. However, studies have shown that is not the case, and up to 70% of lung cancer 
patients can have spatial ventilation defects due to their tumor, areas of prior irradiation, or non-oncologic lung 
conditions such as chronic obstructive pulmonary disease (COPD)6-8. There is emerging evidence to suggest 
that incorporating lung function imaging into radiation therapy can reduce the risk of thoracic side effect7, 9-12. 
Our proposed new lung function imaging, which we refer to as 4DCT-ventilation, is especially suited for 
radiation therapy and has great potential to improve quality of life for lung cancer patients. 4DCT-ventilation 
imaging is accomplished via an algorithm that uses data acquired as part of routine clinical care. Nearly every 
one of our lung cancer patients undergoes four-dimensional computed tomography (4DCT) imaging1, 13. 4DCT 
images provide a ‘movie’ of the moving lung anatomy and help clinicians design radiation treatment plans that 
account for the patient’s breathing motion. Our algorithm uses the 4DCT data to calculate 4DCT-based lung 
ventilation images by calculating a density-change between different phases of the breathing cycle2, 3. The theory 
behind this algorithm is that the density in a given voxel is proportional to the amount of air present and therefore 
the difference in density provides the amount of air movement; which is the definition of ventilation. The result of 
the algorithm is a 3D spatial map of ventilation (Figure 1). 4DCT-ventilation provides an excellent way to visualize 
which portions of the lung are functional and used for breathing. 4DCT-ventilation has been validated against 
other ventilation imaging modalities (nuclear medicine and Magnetic Resonance Imaging for example) with 
promising results14-18. 
The major advantage of 4DCT-ventilation is that the functional information is obtained with no extra 
imaging procedures necessary; our proposed imaging modality only requires software processing on already 
obtained 4DCT images. Because 4DCTs are acquired as part of routine care, 4DCT-ventilation imaging does 
not burden the patient with an extra imaging procedure, reduces the imaging related cost, and spares the patient 
from any unnecessary radiation exposure. 4DCT-ventilation has superior spatial resolution (compared to nuclear 
medicine ventilation) and by definition combines function information (ventilation) with anatomic information (CT). 
 
2.3 
4DCT-Ventilation based functional avoidance 
Our group, as well as others, have proposed to use 4DCT-ventilation for functional avoidance radiation 
therapy planning7, 19, 20. Functional avoidance means placing and optimizing the radiation treatment beams to 
avoid the functional portions of the lung. The idea is that if functional portions of the lung received less radiation 
dose, thoracic side effects from the radiation treatment would decrease. 4DCT-ventilation measures which areas 
of the lung are used for breathing and can allow for avoidance of these regions when delivering radiation. The 
concept of functional avoidance is demonstrated in Figure 3. Two different radiation treatment plans are shown 
for the same patient. Each image shows the CT scan, overlaid 4DCT-ventilation functional information, tumor 
location, and the radiation isodose lines. The ventilation image shows which portions of the lung are used for 
breathing with the bright colors representing functional portions and the dark tones displaying ventilation defect 
areas. The presented patient displays a ventilation defect posterior to the tumor and functional portions in areas 
lateral to the tumor. The patient’s clinically used plan is shown on the left and demonstrates that the 25 Gy 
isodose line (shown in green) engulfs functional lung. The functional avoidance plan is shown on the right and 
is able to successfully avoid the functional portion of the lung with the 25 Gy isodose line by placing more dose 
posterior to the tumor. 

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3.0 Preliminary data 
 
3.1 4DCT-ventilation method development: 
Our retrospective results demonstrate that 4DCT-ventilatin is ready to be prospectively used on human 
subjects. The image calculation techniques have been developed, 4DCT-ventilation has been validated, and 
functional avoidance has been retrospectively demonstrated. 
Our group presented the initial work for the 4DCT-ventilation calculation concept 21. Since then, our team 
2, 3, 22 as well as others 23, 24 have extensively developed 4DCT-ventilation imaging techniques. We will briefly 
describe the image formulation process. The input into the algorithm is a data set of 4DCT images 13, 25. 4DCT 
images provide a ‘movie’ of the moving lung anatomy and help clinicians design radiation treatment plans that 
account for the patient’s breathing motion. Our method uses the 4DCT data to map lung voxels from the inhale 
to exhale phases 26 of the breathing cycle and calculate a density change between the 2 phases. The theory is 
that the density in a given voxel is proportional to the amount of air present and therefore the difference in density 
provides the amount of air movement; which is the definition of ventilation. The result is a 3D spatial map of 
ventilation that provides an excellent way to visualize which portions of the lung are functional and used for 
breathing (Figure 1). 4DCT-ventilation is ready to be prospectively used on patients because there will be no 
change to the imaging procedure as seen by the patient; our novel imaging method only requires software 
processing on already clinically established imaging. 
 
3.2 Validation of 4DCT-ventilation: Before 4DCT-ventilation can be implemented clinically it needed to be 
validated. In a retrospective study we compared 4DCT-Ventilation imaging to the established method of nuclear 
medicine ventilation imaging with promising results18. Nuclear medicine VQ images, although limited in certain 
aspects, are considered the current gold standard for ventilation imaging. Nuclear medicine VQ images are 
generated with the patient inhaling a radioactive aerosol with radiation detectors capturing the photons emitted 
from the patient. A patient example with good agreement between nuclear medicine ventilation and 4DCT- 
ventilation image is shown in Figure 4. Both the 4DCT-ventilation imaging and the nuclear medicine ventilation 
image demonstrate a major ventilation defect in the left upper lobe. Overall, our study demonstrated good 
agreement between 4DCT-ventilation imaging and nuclear medicine VQ imaging using radiologist observations 
and quantitative metrics. We performed another validation by comparing 4DCT-ventilation to PFT data and 
0% 
Figure 3: Illustration of the functional avoidance concept. Two treatment plans are presented, each shows 
the CT, overlaid 4DCT-ventilation functional image, tumor location, and radiation isodose distribution. 
The plan on the left is the clinically used plan and displays dose in the functional portions of the lung 
while the plan on the right is the functional avoidance plan which spares functional lung. 
100% 
Functional Avoidance Plan 
Standard plan 

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showed a good correlation between the two 
methods of measuring lung function27. PFTs 
present an established way of a lung function 
and our study demonstrated that 4DCT- 
ventilation is able to reliably predict global 
lung function. Other studies have shown 
similar promising validation results comparing 
4DCT-ventilation to nuclear medicine14, 16, 
helium based MRI17, PET imaging using 
gallium28, xenon based CT15, and PFT data14. 
The validation work has demonstrated that 
4DCT-ventilation can reliably demonstrate 
global lung function and is ready to be used 
prospectively in the treatment of lung cancer 
patients 
 
3.3 Functional avoidance: Studies have proposed the concept of functional avoidance7, 8, 10, 12, 19, 29, 30. Early 
studies suggested performing functional avoidance using nuclear medicine ventilation imaging 8, 12, 29. However, 
these theoretical studies did not result in clinical trials because of the inherent limitations of nuclear medicine 
(VQ) imaging which has limited spatial resolution, suffers from a significant artifact where the aerosol gets stuck 
in the airways, and is not readily available to all oncology clinics 18. 4DCT-ventilation addresses these 
shortcomings with improved spatial resolution, no aerosol requirement, and the convenience of being able to 
calculate images using data acquired as part of routine care in radiation oncology clinics. 
Three important findings have come out of functional avoidance work focused on 4DCT-ventilation 2, 7. 
First, studies have demonstrated that it is possible to avoid functional portions of the lung without reducing dose 
to the tumor or compromising on tolerance limits for significant thoracic organs (spinal cord, heart, and 
esophagus)9, 10. These results assure that by using functional avoidance we will not sacrifice any current 
standards of care for lung cancer patients. Second, in a novel study we showed that 4DCT-ventilation functional 
information predicts for clinically significant radiation toxicity31. The concept is illustrated in Figure 3, which shows 
one patient who developed clinically significant radiation side effects and another patient who did not. Both 
patients received identical radiation doses to the lung. Patient 2, who received radiation dose to functional 
portions of the lung, developed serious lung toxicity, while patient 1, who received dose to the non-functioning 
portions, did not develop any pulmonary complications. Our retrospective results suggest that prospectively 
incorporating 4DCT-ventilation imaging can reduce clinical toxicity. 
 
 
 
 
 
 
 
 
 
 
 
Figure 5: Example of a patient who did not develop radiation side effects (Patient 1) and a patient who 
developed clinical lung toxicity (patient 2). The red arrow highlights that the patient that developed 
toxicity received dose to the functional portions of the lung while the patient who did not develop side- 
effects received dose to the non-functioning lung. 
 
 
 
 
 
 
 
 
 
Figure 4: A comparison showing good agreement 
between nuclear medicine ventilation (left) and 4DCT- 
ventilation (right). 

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The third important finding is that up to 70% of lung cancer patients treated with radiation therapy can have 
regionally variant (non-homogenous) lung function with major ventilation defects; suggesting that a significant 
portion of the lung cancer population could benefit from functional avoidance32. 
 
3.4 Toxicity assessment: 
There has been significant effort in the field of radiation oncology to assess thoracic toxicity after radiation 
therapy. The primary toxicity for thoracic radiation therapy is radiation pneumonitis. Radiation pneumonitis results 
in cough, shortness of breath, and can be fatal if left untreated. Clinically significant radiation pneumonitis (as 
defined by the NIH4) generally occurs in 25% of patients with rates as high 50% published6, 33, 34. In addition to 
clinical toxicity, studies have characterized lung function changes using QOL questionnaires35, PFTs36, and lung 
imaging2, 31, 37-40. The toxicity work demonstrates that the radiation response of the lung can be very complex as 
the radiation damage can be juxtaposed with functional improvement due to tumor regression. We provide two 
significant examples from our work of differing lung responses for 2 different patients (Figure 4). In the images 
on the left we use 4DCT-ventilation to demonstrate improvement in lung function throughout therapy as the tumor 
shrinks and on the right we use PET imaging to demonstrate significant radiation damage (9, 43). The toxicity 
studies provide the necessary methods for us to assess our hypothesis that functional avoidance reduces the rate 
of toxicity and underline the importance of obtaining a complete set of lung function data to assess treatment 
response. 
 
We believe the necessary retrospective work in 4DCT-ventilation has been complete: the imaging 
calculation techniques have been optimized2, 3, 16, 41, 4DCT-ventilation has been retrospectively validated14-16, 18, 
the functional avoidance concept has been retrospectively demonstrated32, and tools have been developed to 
quantitatively and qualitatively evaluate lung function. The next logical step in the progress of 4DCT-ventilation 
is to prospectively incorporate the imaging modality into radiation therapy through a functional avoidance clinical 
trial. Our clinical trial proposes an important pilot study incorporating 4DCT-ventilation into clinical practice. 
4DCT-ventilation presents many exciting applications in radiation therapy, all without burdening the patient with 
an extra imaging procedure. Our project proposes a rigorous study to evaluate the safety of functional avoidance. 
 
4.0 
Research Methods 
 
4.1 
Outcome Measures 
1. Primary outcome measure: To assess safety we will evaluate the rate of CTCAE defined radiation 
pneumonitis 
2. Primary outcome measure: CTCAE toxicity for the spinal cord, esophagus, and heart. 
3. Primary outcome measure: Changes in subject reported thoracic QOL outcomes from pre-treatment 
to post-treatment. 
Figure 4: Example of 2 different patterns of lung response to 
radiation. The 4DCT-ventilation images of the patient on the 
left show gradual lung re-ventilation as the tumor shrinks. 
The PET image of the patients above shows significant 
inflammation in the area of delivered dose 
Week 7 
Week 5 
Week 1 
Week 3 
PET Imaging 
4DCT-Ventilation Imaging 

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4. Primary outcomes measure: Overall survival at 1 year post radiation therapy. 
 
5. Secondary outcome measure: Quantitative and qualitative changes in 4DCT-ventilation imaging 
from pre-treatment to post-treatment. 
6. Secondary outcome measure: Quantitative and qualitative changes in nuclear medicine VQ imaging 
from pre-treatment to post-treatment. 
7. Secondary outcome measure: Quantitative and qualitative changes in PET imaging from pre- 
treatment to post-treatment. 
8. Secondary outcome measure: Quantitative and qualitative changes in 1 year follow up CT imaging. 
We will determine whether the subject had grade 2+ CTCAE defined radiation fibrosis which is 
determined as radiographic fibrosis in 25-50% of the ipsilateral lung. 
9. Secondary outcome measure: Changes in PFT assessment from pre-treatment to post-treatment. 
10. Secondary outcome measure: The percentage of subjects who have significant ventilation defects 
as defined in section 5.4. 
 
4.2 
Subject Eligibility and Description of Enrolled Population 
The subject has to meet the trial inclusion and exclusion criteria in Table 1 to be eligible for the study. 
 
Table 1: List of trial inclusion and exclusion criteria. 
Inclusion criteria 
1. Diagnosis of pathologically confirmed lung cancer by tumor biopsy and/or fine-needle 
aspiration 
2. Lung Cancer patients that will undergo definitive radiation therapy defined as 45-75 Gy as 
part of standard of care for their disease. 
3. 18 years of age or older 
4. Signed informed consent 
5. Planned curative intent chemotherapy, delivered either concurrently or sequentially in 
combination with radiotherapy 
6. The patient’s 4DCT-ventilation image meets the heterogeneity criteria outlined in section 5.4 
Exclusion criteria 
1. Patients receiving Stereotactic Body Radiation Therapy 
2. Patient receiving palliative radiation therapy (defined as less than 45 Gy) 
 
Inclusion criteria 1-4 above represents patient and clinical factors. Inclusion criteria 5 above represents 
the functional imaging status. Consultation with a multi-disciplinary team including a physicist, radiation 
oncologist, radiologist, and pulmonologist is encouraged. 
 
Subjects enrolled in the study will be biopsy proven lung cancer patients receiving definitive radiation 
therapy. The definitive radiation therapy criteria is designed to rule out any patients receiving palliate care. The 
enrolled subjects will have a lung function profile that displays a significant ventilation defect. The idea is that if 
the subject has homogenous lung function, there is no basis to preferentially spare any regions, and functional 
avoidance is not necessary. On the other hand, if the subject has spatially variant lung function, functional 
avoidance can be used to avoid the active portions of the lung. Our inclusion criteria will ensure that the 
population enrolled in the trial will be the group of patients that can benefit most from functional avoidance. If the 
patient does not fit either clinical or imaging trial inclusion criteria, or is found to be ineligible due to exclusions 
criteria, it will in no way affect their ability to receive appropriate care from their chosen providers. 
 
4.3 
Research plan 

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The study schema is shown in Figure 1 and a table of the procedures experienced by the patient/subject 
is shown in Table 2. The table in Appendix A provides a snapshot of the study assessments. We will divide our 
clinical protocol into 5 steps: 1) Screening 2) Functional avoidance planning 3) Pre-treatment lung function 
assessment 4) Radiation therapy treatment delivery 5) Post-treatment lung function assessment. 
 
4.4 
Step 1: Screening 
The start of the screening process will occur when a patient is referred to radiation oncology for radiation 
treatment. The patient will have to have a diagnosis of pathologically confirmed lung cancer by tumor biopsy 
and/or fine-needle aspiration. Patients with both non-small cell lung cancer (NSCLC) (all histologies) and small 
cell carcinomas will be eligible to enroll in the trial. The patient will undergo a standard consultation with the 
radiation oncologist. During consultation it will be determined if the patient meets clinical criteria which includes 
a prescription of definitive radiation treatment (defined as 45-75 Gy), is 18 years of age or older. Patients will be 
offered the study and asked to sign consent after the initial consultation occurs. Patients at any stage of disease 
will be eligible; however, based on our definitive radiation therapy inclusion criteria our subject cohort will 
primarily consist of stage III lung cancers. The definitive radiation treatment criteria of doses ranging from 45 to 
75 Gy is specifically designed to exclude patients receiving Stereotactic Body Radiation Therapy (SBRT). While 
patients receiving SBRT may benefit from functional avoidance; there are unique demands in the treatment 
planning aspects of SBRT and we believe it would be prudent to evaluate functional avoidance in patients treated 
with conventional fractionation prior to implanting functional avoidance in patients receiving SBRT. 
The patient will also undergo 4DCT imaging as standard of care. The 4DCT data will be used to calculate 
4DCT-ventilation images and the patient’s 4DCT-ventilation image will be assessed for image heterogeneity 
using the criteria defined in section 5.4. Patients have to meet both clinical and imaging criteria to proceed with 
functional avoidance radiation therapy. 
There are other patient and clinical factors that need to be considered with respect to radiation 
pneumonitis: chemotherapy regimen, immunotherapy status, smoking status, baseline lung function, and tumor 
location. There is no consensus in the literature regarding the effect of chemotherapy regimen, smoking status, 
baseline lung function, and tumor location on toxicity. For example, some studies note that certain chemotherapy 
agents (carboplatin/paclitaxel)42 increase risk of radiation pneumonitis, while other studies do not find any 
relationship between chemotherapy regimen and risk of toxicity43-45. Similarly, the effect of smoking status on the 
risk of developing radiation pneumonitis is inconclusive. Certain studies site that smoking decreases risk of 
toxicity6, 46, 47, some studies suggest inconclusive results45, 48, while another cohort of studies suggests smoking 
increases chances of radiation pneumonitis49, 50. Generally, baseline lung function has been shown not to have 
an impact on the chances of developing toxicity45, 51 with a few counter-examples suggesting that toxicity and 
baseline lung function may be related52. Several early studies suggested that patients with tumors located in the 
lower lobe maybe at an increased risk of toxicity53, however, other work has shown no correlation between tumor 
position and toxicity54. Similar to other co-variates, there has been mixed data on whether immunotherapy has 
an impact on toxicity. We have decided to not exclude patients from the protocol based on chemotherapy 
regimen, immunotherapy status, smoking status, baseline lung function, and tumor position due to the 
inconclusive results presented in the literature. We will record these patient and clinical factors (along with other 
metrics) and evaluate whether each factor had an impact on the risk of developing radiation pneumonitis using 
analysis of variance (ANOVA). 
 
To homogenize the study population, one of the study inclusion criteria is that there must be a planned 
curative intent chemotherapy, to be delivered either concurrently or sequentially in combination with 
radiotherapy. However, there will be situations where the decision to administer chemotherapy will change after 
consent has been administered. Whether the patient is receiving chemotherapy does not increase any risk to 
the subject in the study and functional radiotherapy has been found to have a theoretical benefit for patients 
being treated both with and without chemotherapy7, 10, 14. The study will perform a 2nd chemotherapy eligibility 
check prior to the start of radiation treatment to check whether the patient is still scheduled to receive 
chemotherapy. In the event that the chemotherapy plan changes after the consent, it will be up to discretion of 
the PI whether to have the patient remain in the study. 

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4.5 
Step 2: Functional avoidance plan generation 
A functional avoidance plan will be generated under the guidance of a radiation oncologist and a radiation 
physicist. The plan will use the patient’s 4DCT-ventilation image to design radiation treatment that avoid 
functional portions of the lung. The functional avoidance plan will be quantitatively and qualitatively assessed 
using the criteria outlined in section 5.5. The calculation and evaluation of the 4DCT-ventilation image and 
functional avoidance plan generation will be done within a 2 week time frame and will not require any additional 
actions from the patient. 
 
Table 2: Timeline of clinical protocol events experienced by the patient. 
Study phase 
Suggested Timeline 
Procedure 
Seen by Subjects 
Standard of 
care (SOC) or 
research (R) 
Screening 
-28 days from time 
subject signs 
consent form 
Consultation with Radiation Oncologist 
SOC 
4DCT imaging 
SOC 
Patient signs consent form 
R 
Pre-treatment 
lung function 
imaging 
Prior 3 months or as 
late as 1 week into 
radiation therapy 
QOL questionnaire 
R 
Nuclear medicine VQ scan 
SOC/R 
PET imaging 
SOC 
PFT testing 
SOC 
Treatment 
3-8 weeks 
Delivery of radiation therapy 
SOC 
End of 
treatment visit 
Within the final week 
of radiation therapy 
Visit with Radiation Oncologist 
SOC 
QOL questionnaire 
R 
3 month follow 
up visit 
1-5 months from the 
completion of 
radiation therapy 
Appointment with Radiation Oncologist 
SOC 
QOL questionnaire 
R 
3 month follow 
up lung 
function 
assessment 
2-9 months from the 
completion of 
radiation therapy 
4DCT-ventilation imaging 
R 
Nuclear medicine VQ imaging 
R 
PET imaging 
SOC 
PFT testing 
R 
6 month follow 
up visit 
5-9 months from the 
completion of 
radiation therapy 
Appointment with Radiation Oncologist 
SOC 
QOL questionnaire 
R 
12 month 
follow up visit 
and imaging 
9-14 months from the 
completion of 
radiation therapy 
Visit with Radiation Oncologist/Clinical Toxicity 
Assessment 
SOC 
QOL questionnaire 
R 
CT imaging 
SOC 
 
4.6 
Step 3: Pre-treatment lung function assessment 
Once the subject has enrolled in the study they will undergo a series of lung function evaluations to 
establish a baseline. Lung function evaluation will include CTCAE clinical toxicity assessment, thoracic QOL 
questionnaire (SOC), PET imaging (SOC), nuclear medicine VQ imaging (SOC/R), and PFT testing (SOC). If 
the subject had imaging or PFT testing done within the prior 3 months, it will be acceptable to use those data for 
the study. Otherwise, the testing and imaging studies should be done as close as possible to study registration. 
It should be noted that although the primary objective of the proposed study is to evaluate clinical toxicity, the 

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QOL questionnaire, PFT testing, and imaging studies will enable us to evaluate subclinical toxicity and provide 
further details for the subjects that do experience clinical toxicity. 
 
4.7 
Step 4: Radiation therapy treatment delivery 
The subject will undergo a standard course of radiation therapy (SOC). The radiation treatment plan used 
to treat the subject will be the functional avoidance plan. The subject will be treated with external beam radiation 
therapy using a linear accelerator. On-board imaging on the linear accelerator will be used to set-up the subject 
to the same daily treatment position. Each week the subject will have a standard visit with the radiation oncologist 
to manage any side effects that may arise while the subject is undergoing radiation therapy. 
 
4.8 
Step 5: Post-treatment lung function assessment 
At various time points after the completion of therapy the subject will undergo a complete evaluation of 
lung function status using all modalities applied to assess lung function prior to therapy. These lung function 
assessments will include clinical toxicity assessment using the CTCAE scoring system, QOL questionnaire, 
4DCT-ventilation imaging, nuclear medicine VQ imaging, PET imaging, CT imaging, and PFT testing. On the 
last day of treatment the subject will have a visit with the radiation oncologist which will include a clinical 
assessment of lung function using CTCAE criteria (SOC) and a thoracic QOL questionnaire (R). At 3 months 
from completion of radiation therapy the subject will have a visit with the radiation oncologist which will include 
CTCAE clinical assessment of lung function (SOC) and fill out the QOL questionnaire (R). In addition, at 3 months 
post therapy the subject will undergo 4DCT-ventilation imaging (R), PET imaging (SOC), nuclear medicine VQ 
imaging (R), and PFT testing (R). The 3 month time point was chosen for follow up imaging because the highest 
probability of developing radiation pneumonitis occurs at 3 months after the completion of radiation therapy 55. 
We will evaluate radiographic fibrosis using 1 year follow up CT imaging (SOC). Radiographic fibrosis will be 
defined as 25-50% of the ipsilateral lung having fibrotic presentation on 1 year follow up CT imaging. At 6 and 
12 months from completion of radiation therapy the subject will have a visit with the radiation oncologist which 
will include a CTCAE clinical assessment of lung function (SOC) and fill out the QOL questionnaire (R). 
 
5.0 
Description of events 
 
5.1 
Subject enrollment and initial visit with radiation oncologist 
The subject will have a pre-treatment, standard of care work-up visit with the radiation oncologist. During 
the visit, the radiation oncologist will perform a standard work-up to assess whether the subject is a good 
candidate for radiation therapy. The radiation oncologist will also determine whether the subject meets clinical 
criteria for trial enrollment. The subject will be clinically eligible if they have biopsy proven lung cancer, are 
prescribed definitive radiation therapy (defined as 45-75 Gy), are at least 18 years of age, and sign the informed 
consent. The radiation oncologist will perform a baseline clinical assessment of pre-treatment lung function using 
the CTCAE V4.0 toxicity scoring system4. The primary end-point will be the rate of CTCAE defined grade 2+ 
radiation pneumonitis6. Radiation pneumonitis is the most serious and prevalent toxicity after radiation therapy, 
is a severe impairment on the subject’s quality of life, and can result in treatment related death. CTCAE defined 
radiation pneumonitis is the standard clinical metric used to evaluate thoracic toxicity and was one of the main 
end-point in a recent seminal national lung cancer clinical trial (RTOG 0617). CTCAE grading criteria for radiation 
pneumonitis is provided in Table 3. 
 
Table 3: CTCAE grading criteria for radiation pneumonitis. 
 
Grade 
Description 
1 
Asymptomatic; clinical or diagnostic observations only; 
intervention not indicated 
2 
Symptomatic; medical intervention indicated; limiting 
instrumental Activities of Daily Living (ADL) 

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3 
Severe symptoms; limiting self-care ADL; oxygen indicated 
4 
Life-threatening respiratory compromise; urgent 
intervention indicated (e.g.,tracheotomy or intubation) 
5 
Death 
 
5.2 
CT and 4DCT Imaging 
Two sets of CT imaging will be acquired during the subject’s initial visit as standard of care: a non-gated 
CT and a gated-4DCT. 4DCTs are standard CT images resolved into different phases of the breathing cycle and 
provide physicians with a ‘movie’ of the moving lung anatomy. 4DCTs allow physicians to account for breathing 
motion throughout the course of radiation therapy by enabling them to evaluate and encompass the motion of 
the tumor throughout the breathing cycle. As standard of care, every lung cancer subject receiving definitive 
radiation treatment will undergo standard 4DCT imaging in our department. In add to 4DCT imaging, the subject 
will undergo a standard non-gated CT scan to be used for treatment planning and dose calculations. During both 
sets of imaging, the subject will be placed in radiation treatment position and be immobilized using an alpha 
cradle or any other immobilization techniques deemed necessary by the radiation oncologist. Abdominal 
compression will be allowed at the discretion of the radiation oncologist. 
 
5.3 
4DCT-ventilation image generation 
4DCT-ventilation images will be generated from the already acquired 4DCT data. It should be underlined 
that 4DCT-ventilation image generation will not require any additional action from the subject; we will use 4DCT 
data already acquired as part of the treatment process. We will use our software to generate ventilation images 
from the acquired 4DCT data2, 3, 7, 18, 22. Briefly, our algorithm calculates a density-change between different 
phases of the breathing cycle. The theory behind the algorithm is that the density in a given CT voxel is 
proportional to the amount of air present and therefore the difference in density provides the amount of air 
movement; which is the definition of ventilation. The result of the algorithm is a 3D spatial map of the ventilation 
(Figure 1) which provides information about which portions of the lung are used for breathing. 
 
5.4 
4DCT-ventilation image assessment criteria 
The 4DCT-ventilation image will be assessed for image defect presence. Subjects will be allowed to 
proceed with functional avoidance only if they have a significant ventilation defect. Ventilation defects are 
indicated by a heterogeneous image with distinct areas of low and high lung function (examples shown in Figures 
1, 3, and 4). The idea is that if the subject has homogenous lung function, there is no basis to preferentially spare 
any regions, and functional avoidance is not necessary. On the other hand, if the subject has regionally variant 
lung function, functional avoidance can be used to spare functional lung. We will apply both quantitative and 
clinical image heterogeneity criteria. The eligibility criteria for the 4DCT-ventilation image assessment will be: 
 
1) Noted ventilation defect (scored as a binary yes or no) by the radiation oncologist and 
2) 15% reduction in regional lung function. 
 
Consultation with a multi-disciplinary team including a physicist and nuclear medicine radiologist will be 
encouraged. The radiation oncologist, physicist, and nuclear medicine radiologist have extensive experience 
with interoperation of 4DCT-ventilation images18. For a quantitative assessment, we will calculate the percent 
ventilation in each lung third (superior, middle, and inferior portions for each lung). These metrics are used 
clinically to assess ventilation and are intended to reflect regional and lobar ventilation18. If the subject’s 4DCT- 
ventilation image shows a regional reduction in ventilation of 15% in one of the lung thirds the subject will be 
eligible for the trial. The 15% reduction in regional lung function was taken from our previous work which showed 
15% reduction to be indicative of significant ventilation defects32. The 4DCT-ventilation image inclusion criteria 
are designed to include subjects with heterogeneous ventilation that can benefit from functional avoidance. It 
should be noted that 4DCT-ventilation image assessment will not require any additional effort from the subject. 

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5.5 
4DCT-ventilation functional avoidance plan generation 
A functional avoidance radiation therapy plan will be generated using the 4DCT-ventilation image. The 
generation of the plan will not require any action from the subject. The first portion of the planning process will 
be done in the same manner as a standard radiation therapy plan for lung cancer patients. The following steps 
describe the standard of care portion for the treatment planning process for lung cancer patients: 
 
Radiation therapy will be delivered using external beam radiation. Allowed delivery techniques include 
3D conformal techniques, intensity modulated radiation therapy (IMRT), arc therapy, or non-coplanar techniques 
at the discretion of the treating radiation oncologist. 
 
Target volumes will be approved by the treating radiation oncologist, using the information obtained 
through clinical examination, the CT and 4DCT scan acquired within the radiation oncology department, and 
histologic specimens when available. When feasible and necessary, the subject’s diagnostic images (CT scan, 
MRI study, or PET/CT imaging) will be fused with the simulation scan to delineate standard International 
Commission on Radiation Units56 target volumes described below. 
 
Gross Tumor Volume (GTV) – All known disease (including nodal disease) detected by the above methods. 
 
Internal Gross Tumor Volume (iGTV) – GTV plus margin for the tumor motion assessed from the 4DCT imaging. 
 
Clinical Target Volume (iCTV) – iGTV plus the region at risk for microscopic spread. This target volume will be 
added at the physician’s discretion. 
 
Planning Target Volume (PTV) – iGTV or iCTV plus a margin to account for subject movement and daily setup 
error. 
 
Organ at Risk (OAR) Volumes – Delineation of the pertinent organs at risk will include the lung, heart, esophagus, 
and spinal cord. Other OARs may be delineated at the discretion of the radiation oncologist. 
 
The radiation doses to the PTV and OARs will be in line with current standards of care for lung cancer 
noted in the National Comprehensive Cancer Network Guidelines57. Doses will range from 45-75 Gy and be 
delivered in 15-35 fractions. Prescriptions will be made such that 95% of the PTV will receive at least 95% of the 
prescription dose. Guidelines for OARs are listed in Table 4 and are in line with national recommendation57, 58. 
Final treatment radiation dose and regimen along with OAR constraints will be at the discretion of the radiation 
oncologist. 
 
Table 4: Organ at risk dose constraints 
Target 
Dose-volume constraint 
Total Lung (defined as Total Lung minus 
GTV) 
Mean Lung Dose ≤ 20Gy 
Spinal Cord 
Max dose ≤ 50 Gy 
Esophagus 
V50Gy≤40%, mean ≤35 Gy 
Heart 
V40Gy≤40%, mean ≤34 Gy 
 
The following portion provides a description of the functional avoidance portion of the planning process 
which is novel to the proposed protocol and is currently not standard of care. The first step will be to use 4DCT- 
ventilation images to create a contour of the functional portions of the lung. The contour will be created using 
semi-automated methods and will be called the ‘functional avoid contour.’ The functional avoid contour will 
represent the most active portions of the lung. The functional avoid contour, PTV, and other OAR contours will 
then be imported into the treatment planning system and used in the optimization process for the radiation 
treatment plan. Effort will be made to reduce dose to the functional avoid contour while still delivering the 

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prescribed dose to the PTV and respecting dose limits to other OARs. Optimizing and shaping the dose 
distribution throughout different anatomy is a standard operation within the treatment planning system software. 
The unique aspect of functional avoidance is that the functional avoid contour will be included in the optimization 
process. It should be noted that the goals of delivering the total dose to the PTV and not-exceeding doses to 
OARs will not be sacrificed in favor of reducing dose to the functioning lung. The priority for the optimization will 
be 1) Deliver the prescribed dose to the PTV 2) Meet the dose limits for OARs 3) Reduce dose to functional lung. 
This prioritization is designed to ensure that every functional avoidance plan will meet current standards of care. 
Final radiation dose calculations for the functional avoidance plan will be done with heterogeneity 
corrections. Once a functional avoidance plan is made we will calculate standard dose metrics for the PTV, 
OARs, and functional regions. Standard dose metrics include the 3D isodose distribution, dose volume 
histograms (DVHs), mean doses, max doses, and volume receiving a certain dose (Vdose). For example, we 
will calculate the mean lung dose (MLD), max spinal cord dose, and the volume of the PTV receiving at least 
95% of prescription. 
In addition to standard metrics, we will calculate the combination of dose and function descriptive metrics 
that will allow us to evaluate how much of the functional lung was spared. Rather than evaluating dose alone, 
these metrics will combine dose and function. One of the metrics we will evaluate is the functional mean lung 
dose (fMLD). To calculate the fMLD, at each point in the lung the dose will be multiplied by the ventilation 
weighting and the functionally weighted doses in the lung will be averaged to calculate fMLD. The dose will be 
‘de-valued’ in regions of poor ventilation and be ‘emphasized’ in regions of functional lung. The physician will 
review the dose-function metrics along with the rest of treatment plan and dose criteria and assess final approval 
of the treatment plan. 
 
5.6 
Pre-treatment lung function assessment, imaging, and PFT testing 
Subjects will undergo a full pre-treatment lung function evaluation to establish a baseline. Subjects will 
undergo clinical, imaging, and PFT based testing. During the initial visit, the radiation oncologist will assess 
subject clinical lung function status using the standard CTCAE toxicity scoring system4. The primary end-point 
evaluated will be grade 2 or higher (referred to as grade 2+) radiation pneumonitis which is defined as 
Symptomatic; medical intervention indicated; limiting instrumental Activities of Daily Living. Although we do not 
expect the subject to have clinical toxicity before treatment, it will be important to establish a baseline. 
In addition, it is imperative to collect subject reported outcomes to aide with the interoperation of the 
study, identify potential toxicity interventions (6), evaluate cost effectiveness, and because there may be a 
disconnect between physician and patient reported outcomes. Furthermore, a recent analysis of a recent national 
lung cancer clinical trial (RTOG 0617) revealed subject report QOL predicted for the worsening overall survival 
results in the high dose arm (7). To evaluate QOL, we will use the lung cancer subscale (LCS) of the FACT- 
Trials Outcome Index (FACT-TOI). FACT-TOI is a measure that sums the functional well-being, physical well- 
being, and the lung cancer subscale. The questionnaire is brief, user friendly, and has been validated. Most 
importantly, the FACT-TO1 questionnaire has been extensively used for measuring QOL for subjects with lung 
cancer, including in the RTOG 0617 protocol. 
The subject will undergo nuclear medicine VQ imaging. Pre-treatment nuclear medicine VQ imaging is 
standard of care for lung cancer patients and used to evaluate pre-treatment lung function. Nuclear medicine 
ventilation images are generated with the subject inhaling a radioactive aerosol (technetium diethylene triamine 
pentaacetic acid) and radiation detectors capturing the photons emitted from the subject. Nuclear medicine 
perfusion is generated with intravenous injection of a radioactive technetium macro aggregated albumin and 
radiation detectors capturing the photons emitted from the subject. The nuclear medicine imaging will be done 
in the department of radiology and will be supervised by the radiologist involved with the protocol who has 
previously been involved with the proposed18. 
Subjects will undergo pre-treatment PET imaging to perform tumor staging. All PET imaging will be done 
on a PET/CT scanner and will include a CT for attenuation correction and for anatomical information overlay. 
PET imaging will be done in the department of radiology and be supervised by the radiologist involved with the 

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protocol. We will use the staging PET to assess image features that have been shown to predict for lung toxicity40. 
For either the nuclear medicine VQ imaging or PET imaging, it will be acceptable to use any images acquired 
within 3 months prior to step 1 enrollment. Otherwise, the subject should have nuclear medicine VQ imaging and 
PET imaging completed as close as possible to the study enrollment date. 
The subject will undergo PFT testing. Pre-treatment PFTs are standard of care for definitive lung cancer 
patients and are used to assess pre-treatment lung function. PFTs use spirometry to measure air flow. We will 
acquire standard PFT metrics including: lung volumes, the forced expiratory volume in 1 second (FEV1), the 
forced vital capacity (FVC), the ratio of FEV1/FVC, and Carbon Monoxide Diffusing Capacity (DLCO). PFT 
acquisition will be supervised by the pulmonologist involved in the proposed protocol who has previously been 
involved with the proposed research27. Both absolute and relative PFT values will be recorded. 
The primary objective of the study is to assess clinical toxicity using the CTCAE scoring system. The 
QOL, imaging, and PFT data are being collected to provide additional imperative information on the subjects 
lung function and to help assess our ability to reduce toxicity with functional avoidance. 
 
5.7 
Radiation therapy 
The patient’s functional avoidance plan will be used to deliver radiation therapy treatment. Treatment will 
be performed on a linear accelerator with on-board imaging capabilities to help align the subject to the same 
treatment position daily. Throughout treatment, the subject will have a weekly evaluation with the radiation 
oncologist to help manage health problems should any arise. 
 
5.8 
End of treatment visit with radiation oncologist 
The subject will have a standard of care end of treatment visit with the radiation oncologist. During the 
visit the radiation oncologist will assess whether the subject has received any immunotherapy, has any new 
complications related to radiation treatment and perform a clinical assessment of lung function. Lung function 
assessment will be performed using the CTCAE scoring system4. In addition to pneumonitis for the lung, we will 
assess CTCAE toxicity for other, less common thoracic conditions including esophagitis, radiation myelopathy, 
and pericarditis for the esophagus, spinal cord, and heart respectively. During the consultation the subject will 
also be asked to fill out a thoracic QOL questionnaire designed to evaluate the subject’s lung function. 
 
5.9 
3 Month follow up visit with radiation oncologist 
The subject will have a standard of care 3 month follow up visit with the radiation oncologist. During the 
consult the radiation oncologist will assess whether the subject has any new complications related to radiation 
treatment and perform a clinical assessment of lung function. Lung function assessment will be performed using 
the standard CTCAE V 4.0 toxicity scoring system4. CTCAE toxicity will be assessed for the lung as well as other 
thoracic organs including the esophagus, heart, and spinal cord. During the visit the subject will also be asked 
to fill out a thoracic QOL questionnaire. 
 
5.10 
3 month post therapy lung function imaging 
The subject will undergo imaging studies to assess lung function at 3 months post radiation therapy. We 
will have the subject undergo 4DCT imaging in the department of radiation oncology and calculate 4DCT- 
ventilation from the 4DCT images. The 3 month follow up 4DCT-ventilation imaging will provide us with an 
imaging assessment of lung function and enable us to evaluate lung function changes due to the radiation 
therapy by comparing pre-treatment 4DCT-ventilation images with post-treatment 4DCT-ventilation images. Post 
treatment 4DCT-ventilation is not standard of care and is specific to the proposed protocol. The risk to the subject 
is the additional radiation dose from the 4DCT imaging. The radiation dose to the subject from a single 4DCT 
scan is on the order of 3 cGy59. The typical dose used for radiation treatment will be about 6000 cGy (60Gy). 
Therefore, the 3 cGy additional dose from the imaging represents 0.05% additional dose compared to what the 
subject will have received during radiation therapy. The additional 0.05% increase in radiation dose can be 
justified by the lung function information gained from the imaging study. 

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The subject will also undergo nuclear medicine VQ imaging at 3 months after the completion of radiation 
treatment. Nuclear medicine VQ imaging will allow us to evaluate changes in lung function due to the radiation 
therapy and allow us to prospectively compare our way of imaging ventilation to the current clinical standard. 
Post treatment nuclear medicine VQ imaging is not standard of care and is specific to the proposed research. 
The only risk to the subject is the additional radiation dose. The radiation doses from nuclear medicine VQ 
imaging is less than 1 cGy60. The 1 cGy additional dose represents a 0.02% increase in dose compared to what 
the subject received during radiation therapy. The additional 0.02% increase in radiation dose can be justified by 
the lung function information gained from the imaging. 
The subject will undergo PET imaging at 3 months post radiation therapy. Three month follow up PET 
imaging is standard of care for lung cancer patients and enables clinicians to assess treatment response and 
evaluate for any distant metastasis61. We will use PET imaging to provide an additional assessment of lung 
function and aid with the evaluation of post-treatment lung function changes. All post-treatment imaging will be 
done on the same scanner as used for pre-treatment imaging and use the same imaging parameters. The 
consistency in scanner and imaging parameters will aid in the quantification of changes. 
 
5.11 
3 month pulmonary function testing 
The subject will undergo PFT testing at 3 months post therapy. We will use the PFT data to provide 
additional evaluation metrics of lung function changes due to radiation therapy. Post treatment PFTs are not 
standard of care for lung cancer patients (unless the patient has newly developed respiratory symptoms); 
however, we do not believe the additional PFT testing poses any increased risk to the subject. 
 
5.12 
6 Month follow up visit with radiation oncologist 
The subject will have a standard of care 6 month follow up visit with the radiation oncologist. During the 
visit, the radiation oncologist will determine whether the subject has any issues due to the radiation treatment 
and perform a clinical assessment of lung function. Lung function assessment will be performed using the 
standard CTCAE V 4.0 toxicity scoring system4. CTCAE Toxicity will be assessed for the lung as well as other 
thoracic organs including the esophagus, heart, and spinal cord. During the visit the subject will also be asked 
to fill out a thoracic QOL questionnaire. 
 
5.13 
12 Month follow up CT imaging 
The subject will undergo standard CT imaging at 12 months post radiation therapy. We will use the CT 
imaging to determine whether the subject has grade 2+ CTCAE defined radiation fibrosis. Grade 2 radiation 
fibrosis is defined as 25-50% of the ipsilateral lung having fibrotic presentation. The radiologist involved in the 
protocol has experience in diagnosing radiographic pulmonary injury. 
 
5.14 
12 Month follow up visit with radiation oncologist 
The subject will have a standard of care 12 month follow up visit with the radiation oncologist. During the 
consult, the radiation oncologist will determine whether the subject has any issues due to the radiation treatment 
and perform a clinical assessment of lung function. Lung function assessment will be performed using the 
standard CTCAE V 4.0 toxicity scoring system4. CTCAE Toxicity will be assessed for the lung as well as other 
thoracic organs including the esophagus, heart, and spinal cord. During the consultation the subject will also be 
asked to fill out a thoracic QOL questionnaire. 
It should be noted that if the subject is unwilling or unable to attend the 3, 6, or 12 month follow up visit; 
the protocol will allow for a toxicity assessment over the phone or by reviewing the subject’s medical chart. 
 
5.15 Summary of risks and justifications 
The unique features of the proposed clinical trial that deviate from standard of care are the 4DCT- 
ventilation imaging and functional avoidance radiation therapy. We have underlined in the proposal how 4DCT- 

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ventilation is ready for use in human subjects. 4DCT-ventilation is accomplished with a novel method that uses 
data acquired as part of routine care. The input into our novel algorithm is 4DCT data. 4DCTs are standard of 
care and are used to provide a ‘movie’ of the moving lung anatomy to help clinicians design radiation treatment 
plans that account for the subject’s breathing motion. 4DCT imaging is an established technique in radiation 
therapy that has been around since 2002. Because 4DCT-ventilation only requires software processing on 
already obtained 4DCT images, we believe our novel imaging modality does not pose any additional risk to the 
subject. We have validated 4DCT-ventilation imaging against other forms of ventilation imaging. 
We have put multiple measures in place to ensure the safety of functional avoidance radiation therapy. 
First and foremost we will use strict target and organ at risk evaluation criteria that are standard of care for lung 
cancer patients; helping ensure that the functional avoidance plan meets the current standards for radiation 
treatment of lung cancer. The trial also provides the radiation oncologist with final authority over the approval of 
the functional avoidance plan; therefore, if they do not feel comfortable with any aspect of the plan, the plan will 
not be used for treatment. The subject will also undergo frequent mid and post-treatment evaluation of lung 
function; helping ensure that if thoracic toxicity arises it will be caught at an early stage. Study participants will 
receive involved and complex clinical care within the department, and as such will have constant contact with 
clinicians who can detect and avoid potential risks related to the study. If the subject does experience radiation 
pneumonitis, they will be treated with a standard course of steroids and be referred to pulmonology in the event 
that symptoms do not resolve. It should be noted, if the subject does not fit trial inclusion criteria or they chose 
to discontinue participation for any reason, it will in no way affect their ability to receive appropriate care from 
their chosen providers. We will also build in a 2 stage trial design. 
The subject will undergo 3 additional follow up examinations that are not considered standard of care: 
the 3 month follow up nuclear medicine VQ imaging, 3 month follow up 4DCT-ventilation imaging, and PFT 
testing. The additional PFT testing does not pose any increased risk to the subject. The increased risk to the 
subject from the nuclear medicine VQ and 4DCT imaging is the increased radiation dose. The radiation dose 
from a 4DCT scan is 3 cGy and the radiation dose from a nuclear medicine VQ scan is 1 cGy for a total extra 
radiation dose of 4 cGy. As part of their radiation treatment, the subject typically receives 6000 cGy, therefore 4 
cGy represents an increase in 0.07% of the total dose delivered to the subject. We will abide by the principles of 
ALARA (As Low As Reasonably Achievable) with respect to imaging radiation dose. We believe the ability to 
quantitatively evaluate lung function with VQ and 4DCT-ventilation imaging justifies the minimal increase in 
radiation dose to the subject. 
 
6.0 
Potential Scientific Problems 
 
A challenge of any clinical trial is whether there will be enough subjects to demonstrate statistically 
significant results. Our primary objective will be to demonstrate safety by comparing the rate of grade 2+ radiation 
pneumonitis in our study cohort with the pneumonitis rate of 25% quoted with current standard of care 
techniques6 (see section 7.1 for full statistical calculations). There are 3 possible outcomes: our pneumonitis rate 
is lower than 25%, is not statistically different from 25%, or is significantly higher than 25%. We expected the 
toxicity rates in our early phase trial to be lower or equivalent to 25%. In the unlikely event that the toxicity rates 
with our trial are higher than toxicity with standard therapy; we will take that as a strong indication that our 
proposed imaging based therapy should not be considered for a large scale trial. If the toxicity rates are not 
statistically different from 25%, we will perform further evaluation using quality of life metrics and imaging based 
end-points. 
One of the challenges of the proposed work is that analyzing lung response to radiation therapy can be 
complex as the injury due to radiation dose is sometimes juxtaposed by improvement expected from tumor 
regression. In some instances subjects who do not develop clinical toxicity still develop imaging based changes 
and subjects who do develop clinical toxicity display important information in their imaging profiles. We hope to 
address the complexity of treatment assessment by acquiring and analyzing a complete data set of lung function 
which must include imaging and functional end-points in addition to clinical toxicity. 

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7.0 
Data analysis plan 
 
7.1 
Statistics for primary objectives 
Our primary objective is to assess the safety and preliminary efficacy of 4DCT-ventialtion functional 
avoidance. We will assess safety using clinical outcomes. The primary clinical outcome used will be the rate of 
CTCAE defined grade 2+ radiation pneumonitis. To assess safety, we will calculate the crude rate of grade 2+ 
radiation pneumonitis in our population and compare the results to a historical control. The rate of grade 2+ 
pneumonitis with current standard of care techniques has been quoted to be 25%6 on average. Based on 
previous studies, we hypothesize we can reduce the radiation pneumonitis rate to 12% with functional avoidance. 
Using a binomial distribution (given the toxicity/no toxicity end-point), current toxicity rates of 25%, our 
hypothesized rate of 12%, and a study power of at least 80%, we calculate 67 subjects needed for the study. As 
noted in section 7.3, patients will count towards study accrual if they have a thoracic toxicity evaluation at the 3 
months post radiotherapy follow-up time point. To account for screen fails and patient dropout we anticipate we 
will need to consent 110 patients to reach our 67 patient clinical trial goal. A Simon’s two-stage design will be 
applied in order to stop the trial early if the rate of radiation pneumonitis is significantly higher than 25%. If there 
is any dropout during the trial, new subjects will be added in to warrant the evaluable number of subjects as 
planned. We will aim to evaluate equal number of patients from each institution to mitigate any factors associated 
with a given institution. 
Similar to radiation pneumonitis, we will report toxicity rates for other thoracic organs and their associated 
binomial exact 95 CIs. In a descriptive manner we will compare our toxicity rates with those noted in the literature. 
Specifically, we will use historical toxicity rates of 25% for esophagitis58, 15% for pericarditis58, 1% for spinal cord 
radiation myelopathy58. 
Questionnaire QOL changes between pre-treatment and post-treatment will be characterized using 
standard descriptive metrics: means, medians, ranges, and standard deviations. Our primary hypothesis is that 
subjects on our trial will have less clinically significant decline in QOL (as measured by FACT-T0I) compared to 
current standard of care. Clinically significant decline will be defined as percentage of subjects with >2 point 
difference (out of a 5 point scale) of the LCS. The end-point used for our primary hypothesis will be the 3 month 
post therapy time point questionnaire. We will compare our results to the QOL results achieved with current 
standard of care. We will focus particularly on the QOL results from RTOG 0617 which found clinically significant 
QOL decline in 46% of subjects in the high dose arm and in 31% of subjects in the low dose arm. Although the 
primary hypothesis centers on the lung cancer subscale, physical and functional well-being data will also be 
collected and analyzed. We will use a one-sample t-test, Wilcoxon-Mann-Whitney test, and chi-squared 
distribution to analyze our results. The subject reported QOL questionnaires will provides us with an imperative 
tool for us to evaluate subject reported outcomes and determine the effectiveness of our novel treatment 
technique. Finally, we will assess overall survival and progression free survival using the Kaplan-Meier method. 
Survival (and reason for death) at 12 months will be recorded for the study. 
There are several covariates which may influence the risk of radiation pneumonitis including smoking 
status and type of chemotherapy regimen. We will use analysis of variance for regression to assess the effect of 
chemotherapy and smoking status on toxicity rates in our study. 
 
 
We hope to demonstrate safety by showing that functional avoidance results in similar or reduced 
radiation pneumonitis rates when compared to current standard of care techniques. We aim to show that there 
are no unintended consequences in using functional avoidance in terms of overall survival and toxicity to other 
thoracic organs including the cord, heart, and esophagus. 
 
7.2 
Statistics for secondary objectives 
We will assess imaging and PFT based treatment response using radiologist observations and 
quantitative regional changes. Regional fibrosis, ventilation, and PET-based changes will be described using 
descriptive statistics (median, range, standard deviation) and evaluated using correlation coefficients, linear and 

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logistic regression, and dice similarity analysis. Correlation coefficients and regression analysis will enable us to 
quantify the magnitude and direction (stable, improvement, regression) of imaging and functional related 
changes. 

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One of the secondary objectives will be to compare 4DCT-ventilation to other forms of functional imaging 
in a prospective setting. We will compare 4DCT-ventilation with both nuclear medicine VQ imaging and PET 
imaging. Comparisons will be done using radiologist clinical observations and quantitative regional values. 
Quantitative results will be analyzed using bland-altman plots. 
Another secondary objective will be to assess the percentage of subjects that were eligible for functional 
avoidance. The percentage will be calculated by taking the ratio of subjects that had lung function profiles suitable 
for functional avoidance and subjects that were clinically eligible (receiving 45-75 Gy). Retrospectively, we have 
estimated that 70% of subjects receiving 45-75 Gy have heterogeneous lung function profiles and would be 
eligible for functional avoidance32. The data in our clinical trial will enable us to validate the 70% eligibility metric 
in a prospective setting; which will be critical for the design of a large scale trial. 
 
7.3 
Suggested Timeline 
We would like to accrue 67 subjects for our study in 2 years with about half (35) of those being accrued 
at our institution. In total, we see about 150 lung cancer patients a year. About 100 of the 150 patients fit the 
clinical profile for definitive radiation therapy (receiving 45-75 Gy). Of the 100 patients, 50 will have lung function 
profiles that fit the criteria outline in section 5.4. Assuming a 60% enrollment rate and a 30% drop out rate we 
expect approximately 21 subjects per year to enroll and complete our trial. Therefore we believe a conservative 
estimate for the required 35 subject trial accrual is 2 years. Beaumont Health System sees about 170 lung cancer 
patients annually. Based on the numbers listed above, they will also be able to accrue the required 35 subjects 
for the protocol. As detailed below, patients will count towards study accrual if they have a thoracic toxicity 
evaluation 3 months after completing radiotherapy. To account for screen fails and patient dropout we anticipate 
we will need to consent 110 patients to reach our 67 patient clinical trial goal. 
It should be noted that we will use radiation pneumonitis at 3 months after the completion of therapy as 
our primary end-point. Therefore, if subjects drop out after the 3 month time point they will still be counted towards 
accrual and if they drop out prior to the 3 month follow up time point they will not be counted toward accrual. We 
will record and evaluate radiation pneumonitis at 1 year post therapy as a secondary end-point using the 
available data. Subjects who wish to discontinue study procedures at any point during the study have the option, 
as indicated in the consent form, to remain in the study and allow follow-up data to be collected. This choice to 
discontinue active study participation and only allow follow-up data collection will be documented. 
 
8.0 Summary of knowledge to be gained 
 
The most important knowledge we hope to gain is the evaluation of the safety and preliminary efficacy of 
4DCT-ventilation functional avoidance. Specifically, we hope to show that 4DCT-ventilation is safe and does not 
results in increased toxicity when compared to current standard of care therapy techniques. Theoretically, 
functional avoidance radiation therapy should be safe because we are meeting current standards of care and 
should be effective because we are sparing functional portions of the lung. However, the safety of the novel 
treatment techniques needs to be demonstrated prospectively before functional avoidance can be implemented 
in a large scale randomized clinical trial. In order to properly assess the efficacy of functional avoidance we 
estimate a 200 subject, randomized, multi-institutional study is needed. Before resources are committed for a 
large scale, 200 subject trial, a study is needed that prospectively demonstrates safety and provides preliminary 
efficacy results. Our clinical trial can demonstrate that 4DCT-ventilation based functional avoidance is safe, 
develop the evaluation metrics, and provide efficacy results that will pave the way for a large scale randomized 
study. 
Our imaging based secondary end-points will provide an invaluable addition to the primary clinical 
outcomes and are a must for a complete assessment for functional avoidance. Assessing lung response to 
radiation is complex as treatment related changes can be juxtaposed with improvement from tumor regression. 
Our study will provide a complete assessment of lung function including clinical end-points, imaging, and PFTs. 
With the complete lung function data set we will be able to perform a full characterize of lung response and 

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analyze each method of assessing lung function. Our clinical protocol proposes a prospective, rigorous, and safe 
study to evaluate the integration of 4DCT-ventilation functional avoidance into radiation therapy clinical practice. 
 
9.0 Data and safety monitoring plan 
 
The Lead Principal Investigator (PI) will be responsible for monitoring the trial per the trial monitoring 
plan, in addition to overseeing the safety and efficacy of the trial, executing the data and safety monitoring (DSM) 
plan, and complying with all reporting requirements to local and federal authorities. This oversight will be 
accomplished through additional oversight from the Data and Safety Monitoring Committee (DSMC) at the 
University of Colorado Cancer Center (CU Cancer Center). The DSMC is responsible for ensuring data quality 
and subject safety for all clinical studies at the CU Cancer Center. A summary of the DSMC’s activities is as 
follows: 
• 
Conduct of internal audits 
• 
Ongoing review of all serious adverse events (SAEs), unanticipated problems (UAPs) and 
reportable adverse events (AEs) 
• 
Has the authority to close and/or suspend trials for safety or trial conduct issues 
• 
May submit recommendations for corrective actions to the CU Cancer Center’s Executive 
Committee 
 
Per the CU Cancer Center Institutional DSM Plan, Serious Adverse Events (SAEs), Unanticipated 
Problems (UAPs) and reportable Adverse Events (AE)s are reported to the DSMC, IRB, and Lead PI per study 
protocol. All SAEs, UAPs and reportable AEs are to be reported to the CU Cancer Center DSMC within 5 
business days of receiving notification of the occurrence. If the AE or SAE occurs at CU Cancer Center it will be 
reported to the Lead PI who will then report it to the DSMC and IRB. If the AE or SAE occurs at Beaumont it will 
be reported to the Site PI, then reported it to the Lead PI, and the Lead PI will report to DSMC and IRB. 
Each subject’s treatment outcomes will be discussed by the Site PIs and Clinical Research Coordinators 
(CRCs) at regularly scheduled disease-oriented working group meetings. Data regarding number of subjects, 
significant toxicities, dose modifications, and treatment responses will be discussed and documented in the 
meeting’s minutes. 
The Lead PI will provide a DSM report to the CU Cancer Center DSMC on a six month basis. The DSM 
report will include a protocol summary; current enrollment numbers; summary of toxicity data to include specific 
SAEs, UAPs and AEs; any dose modifications; all protocol deviations; and protocol amendments. The DSM 
report to the DSMC will also include, if applicable, the results of any efficacy data analysis conducted, as well. 
As the Lead PI in this multi-site trial, the Lead PI is responsible for organizing and conducting 
teleconferences with all participating sites once every 2 months. The Lead PI will also be responsible for including 
data from all of the participating sites within the overall trial’s six month DSM report to the DSMC to include 
minutes from bi-monthly PI teleconferences. Each participating site will be responsible for submitting the results 
and recommendations from the DSMC’s six month review to their IRB of record at the time of continuing review. 
Each aspect of the clinical trial will undergo quality assurance and quality control. The subject’s radiation 
treatment will be subject to standard radiation therapy quality assurance including an independent treatment plan 
check by a physicist and radiation oncologist as well as standard quality assurance for the linear accelerators. 
The protocol team will meet twice a year to discuss and review the data for each subject enrolled on the trial. 
All data will be stored in institutional servers with restricted access protocols. Data being analyzed will be 
recorded and identified by subject code numbers only. Only members of the investigative group will have access 
to secured files or to the master list for subject code numbers and will be well educated regarding the protection 
of subjects’ rights to confidentiality. Identities of participants will not be revealed in the publication or presentation 
of any results from this project. 

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9.1 
Procedures for Adverse Events - Definitions and Reporting Criteria 
9.1.1 Definitions 
The definition of “related” being that there is a reasonable possibility that the treatment 
caused the adverse event. 
 
An adverse event is UNEXPECTED when the specificity or severity is not consistent with 
the current expectations of treatment complications. 
 
Adverse Event (AE) 
An AE will be defined as any untoward medical occurrence in a patient or clinical trial 
subject which does not necessarily have a causal relationship with the treatment. An AE can, 
therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medical treatment or procedure 
regardless of whether it is considered related to the medical treatment or procedure (attribution 
of unrelated, unlikely, possible, probable, or definite). Abnormal laboratory values or diagnostic 
test results constitute adverse events only if they induce clinical signs or symptoms or require 
treatment or further diagnostic testing. 
An AE will be recorded for events related to pneumonitis, esophagitis, dyspnea, fistula, events 
that involved pulmonary or vascular hemorrhage, or cardiac toxicities. Any AEs noted in the 
patients chart by the radiation oncologist during scheduled study visits will be recorded as AEs. 
 
Serious Adverse Event (SAE) 
A serious adverse event is any untoward medical occurrence resulting in one or more of 
the following: 
• 
Results in death 
• 
Is life-threatening (defined as an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the patient or may 
require intervention (e.g., medical, surgical) to prevent one of the other serious 
outcomes listed in the definition above). Examples of such events include, but are 
not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions not resulting in hospitalization; or 
the development of drug dependency or drug abuse. 
• 
Events unequivocally due to disease progression, including the development of 
metastatic disease, will not be reported. 
 
 
9.2 
Discontinuation of treatment 
Study patients who have completed all study procedures and have undergone 1 year follow up will have 
completed the study. At least 3 months follow up is required to count towards enrollment in the study. Study 
patients may be prematurely terminated from the study for the following reasons: 

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• 
Physician, PI, and/or patient decides to discontinue treatment for reasons other than an AE 
• 
Noncompliance with the study protocol 
• 
Development of unrelated illness which compromises further participation in the study 
• 
The subject is lost to follow up (no further data collection or 
• 
submission will be expected) 
• 
The subject withdraws consent (no further data collection or submission will be expected) 
 
At termination, ongoing AEs are to be recorded, including any new AEs reported at the end of the study. 
Any unresolved AE at discontinuation of the study treatment should be followed until they have resolved or 
stabilized. Subjects may choose to stop study treatment for any reason without jeopardizing their relationship 
with healthcare providers. 
 
10.0 
Study Monitoring and Frequency of Monitoring Visits 
 
The monitoring for this trial will be carried out in full compliance with all Good Clinical Practice (GCP) 
Guidelines, COMIRB policies and regulations and all applicable federal regulations. This study will monitored for 
its entire duration until the investigation is completed. 
A site initiation visit (SIV) will be conducted for all participating sites prior to enrolling any subjects into 
this trial to document full training of all study personnel who will be delegated any specific task on the study. This 
visit includes but is not limited to training on the IRB approved study protocol, regulatory requirements for study 
conduct including but not limited to GCP guidelines, reporting of adverse events, the review of study personnel’s 
roles and responsibilities, completion of the Delegation of Authority Log and Protocol Training, review of the 
monitoring plan as outlined in the protocol, and to review data collection and proper source documentation 
procedures. 
The monitor will perform both on-site interim monitoring visits and remote monitoring off-site for all 
participating sites in this study. Data that is collected during the duration of this trial will be reviewed by the 
sponsor to identify data discrepancies, inconsistencies or any unclear information both on-site and remotely. In 
order to reconcile data discrepancies, queries will be sent electronically to the site(s) for data that requires 
clarification. 
Due to the nature of this trial being a multi-center IIT (Investigator-Initiated Trial) with the CU Cancer 
Center as the coordinating site, as well as an early phase radiation therapy trial, this study is considered to be 
high risk and will need consistent routine monitoring visits. An initial monitoring visit will be performed within 2- 4 
weeks of the first subject being enrolled into the trial. Subsequently, this study will then be monitored every 8- 
12 weeks on-site, with remote monitoring in-between scheduled on-site visits, as necessary based on the study 
needs, at all participating sites. 
The monitor will perform routine on-site monitoring visits that include but are not limited to: 
• 
Interface with the PI at each visit if possible, to discuss any findings, address concerns, and to 
update the PI and site staff on current study progress. 
• 
Subject source documentation verification and subject eligibility 
• 
Informed Consent review 
• 
Verify radiation treatment 
• 
Protocol adherence 
• 
Review Case Report Forms and the Redcap electronic database 
• 
Regulatory documents review 
• 
Review and determine if all Adverse Events and Serious Adverse Events have been 
appropriately reported within the specified time periods required by the protocol, GCP, the IRB 
and any other applicable regulatory requirements 

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The Monitor may remotely review the following but is not limited to in-between interim visits: 
• 
Query follow-up and resolution from on-site monitoring visits 
• 
Adverse event and Serious adverse event review 
• 
Electronic database verification and data clarification 
• 
Communication between Monitor, the PI and study personnel via email and/or telephone 
 
After monitoring visits are completed, the monitor will evaluate and summarize the results after each 
monitoring visit in a written report. This report will include all pertinent findings during the monitoring visit including 
all identifiable and reportable data and non-compliant problems ongoing in the study and recommend resolutions 
for noted deficiencies. Any noted deficiencies that are in need of resolution will need a corrective plan of action 
by the PI and/or research staff. 
The PI will receive a post interim monitoring visit follow-up letter 7 to 10 business days following the 
completion of the monitoring visit, documenting study progress and any pertinent findings and outstanding action 
items that need to be resolved. The PI will need to sign and date the letter after reviewing, and keep the original 
on site. The Monitor may review the letter at the next subsequent visit to ensure it has been reviewed, signed 
and dated by the PI in a timely manner. 
Upon completion or termination of the study, the sponsor will ensure that each participating site undergo 
a site Close-out Monitoring visit prior to final closure of the study. The Monitor will assure that all necessary site 
close-out procedures and activities have been completed which include but are not limited to query resolution, 
Case Report Form completion, notification to local IRB and regulatory authorities of study closure, record 
retention arrangements finalized, AE and SAE resolution, and all essential documents are available and present 
in the PI’s file. The Monitor will complete a final close-out report documenting completion of the Close-out 
Monitoring visit and forward a study Close-out follow up letter to the PI(s) at the participating site(s) to be 
reviewed, signed and dated, and file a copy on site for record retention. 
 
 
 

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11.0 
References 
 
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Y.Y. Vinogradskiy, R. Castillo, E. Castillo, A. Chandler, M.K. Martel, T. Guerrero, "Use of weekly 4DCT-based 
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16 
R. Castillo, E. Castillo, M. McCurdy, D.R. Gomez, A.M. Block, D. Bergsma, S. Joy, T. Guerrero, "Spatial 
correspondence of 4D CT ventilation and SPECT pulmonary perfusion defects in patients with malignant airway 
stenosis," Physics in Medicine and Biology 57, 1855-1871 (2012). 
17 
L. Mathew, A. Wheatley, R. Castillo, E. Castillo, G. Rodrigues, T. Guerrero, G. Parraga, "Hyperpolarized He-3 
Magnetic Resonance Imaging: Comparison with Four-dimensional X-ray Computed Tomography Imaging in Lung 
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18 
Y. Vinogradskiy, P.J. Koo, R. Castillo, E. Castillo, T. Guerrero, L.E. Gaspar, M. Miften, B.D. Kavanagh, 
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Imaging: A Clinical Validation Study," International Journal of Radiation Oncology Biology Physics 89, 199-205 

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(2014). 
19 
T. Yamamoto, S. Kabus, J. von Berg, C. Lorenz, P.J. Keall, "Impact of Four-dimensional CT-derived Pulmonary 
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20 
T. Yamamoto, S. Kabus, J. von Berg, C. Lorenz, P.J. Keall, "IMPACT OF FOUR-DIMENSIONAL COMPUTED 
TOMOGRAPHY PULMONARY VENTILATION IMAGING-BASED FUNCTIONAL AVOIDANCE FOR LUNG 
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21 
T. Guerrero, K. Sanders, J. Noyola-Martinez, E. Castillo, Y. Zhang, R. Tapia, R. Guerra, Y. Borghero, R. Komaki, 
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Biology* Physics 62, 630-634 (2005). 
22 
R. Castillo, E. Castillo, J. Martinez, T. Guerrero, "Ventilation from four-dimensional computed tomography: density 
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23 
J.M. Reinhardt, K. Ding, K. Cao, G.E. Christensen, E.A. Hoffman, S.V. Bodas, "Registration-based estimates of 
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25 
E. Rietzel, T.S. Pan, G.T.Y. Chen, "Four-dimensional computed tomography: Image formation and clinical 
protocol," Medical Physics 32, 874-889 (2005). 
26 
E. Castillo, R. Castillo, B. White, J. Rojo, T. Guerrero, "Least median of squares filtering of locally optimal point 
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27 
Y. Vinogradskiy, R. Castillo, E. Castillo, T. Guerrero, M. Miften, B. Kavanagh, M. Martel, L. Schubert, "TU-C-12A- 
10: BEST IN PHYSICS (IMAGING)-Correlating 4DCT-Ventilation with Clinical Pulmonary Function Test Data," 
Medical Physics 41, 465-465 (2014). 
28 
J. Kipritidis, S. Siva, M.S. Hofman, J. Callahan, R.J. Hicks, P.J. Keall, "Validating and improving CT ventilation 
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29 
L.B. Marks, G.W. Sherouse, M.T. Munley, G.C. Bentel, D.P. Spencer, "Incorporation of functional status into 
dose-volume analysis," Medical Physics 26, 196-199 (1999). 
30 M.M. Miften, S.K. Das, M. Su, L.B. Marks, "Incorporation of functional imaging data in the evaluation of dose 
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31 
Y. Vinogradskiy, R. Castillo, E. Castillo, S.L. Tucker, Z. Liao, T. Guerrero, M.K. Martel, "Use of 4-Dimensional 
Computed Tomography-Based Ventilation Imaging to Correlate Lung Dose and Function With Clinical Outcomes," 
International Journal of Radiation Oncology Biology Physics 86, 366-371 (2013). 
32 Y. Vinogradskiy, L. Schubert, R. Castillo, E. Castillo, M. Martel, T. Guerrero, M. Miften, "TU‐A‐WAB‐05: Using 4DCT‐
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34 
M.K. Martel, R.K. Ten Haken, M.B. Hazuka, A.T. Turrisi, B.A. Fraass, A.S. Lichter, "Dose-volume histogram and 
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35 
F.B. Zimmermann, H. Geinitz, S. Schill, A. Grosu, U. Schratzenstaller, M. Molls, B. Jeremic, "Stereotactic 
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36 
M.L. Hernando, L.B. Marks, G.C. Bentel, S.-M. Zhou, D. Hollis, S.K. Das, M. Fan, M.T. Munley, T.D. Shafman, 
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37 
Q. Diot, B. Kavanagh, T. Schefter, L. Gaspar, K. Stuhr, M. Miften, "Regional Normal Lung Tissue Density 
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38 
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39 
M.R. McCurdy, R. Castillo, J. Martinez, M.N. Al Hallack, J. Lichter, N. Zouain, T. Guerrero, "[< sup> 18</sup> F]- 

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FDG uptake dose–response correlates with radiation pneumonitis in lung cancer patients," Radiotherapy and 
Oncology 104, 52-57 (2012). 
40 
T. Guerrero, V. Johnson, J. Hart, T. Pan, M. Khan, D. Luo, Z. Liao, J. Ajani, C. Stevens, R. Komaki, "Radiation 
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41 
K. Ding, J.E. Bayouth, J.M. Buatti, G.E. Christensen, J.M. Reinhardt, "4DCT-based measurement of changes in 
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42 
D.A. Palma, S. Senan, K. Tsujino, R.B. Barriger, R. Rengan, M. Moreno, J.D. Bradley, T.H. Kim, S. Ramella, L.B. 
Marks, "Predicting radiation pneumonitis after chemoradiation therapy for lung cancer: an international individual 
patient data meta-analysis," International Journal of Radiation Oncology* Biology* Physics 85, 444-450 (2013). 
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Appendix A – A snapshot of study assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Procedures 
 
 
Screening 
Pre-
treatment 
lung 
function 
imaging 
 
 
Treatment 
 
End of 
treatment 
Visit 
 
 
Follow up 
3 month 
follow up 
visit 
3 month follow 
up lung function 
assessment 
6 month 
follow up 
visit 
12 month 
follow up 
visit and 
imaging 
 
Suggested 
timelines 
-28 days 
from time of 
consent 
Prior 3 months 
or as late as 1 
week into 
radiation 
therapy 
3-8 
weeks 
Within the 
final week 
of    
radiation 
therapy 
1-5 months 
from 
completion 
of radiation 
therapy 
2-9 months from 
completion of 
radiation therapy 
5-9 months 
from 
completion 
of radiation 
therapy 
9-14 
months 
from 
completion 
of 
radiation 
therapy 
Procedures 
 
Informed consent 
X 
Confirm eligibility 
(Inclusion/exclusion 
criteria) 
X 
Radiation 
Oncologist visit 
(Adverse Event 
Assessment) 
X 
X 
X 
X 
X 
 
QOL questionnaire 
X 
X 
X 
X 
X 
PFT 
X 
X 
4DCT Imaging 
X 
X 
Nuclear medicine 
VQ scan 
X 
X 
PET Imaging 
X 
X 
CT Imaging 
X 
X 
 
Radiation therapy 
X