MRI-only Radiation Therapy Workflow With Continuous Positive Airway Pressure (CPAP) for Motion Management in the Abdomen
Phase: NA
Conditions: Carcinoma Liver, Carcinoma, Pancreatic
Sponsor: Albert Einstein College of Medicine

IRB NUMBER: 2017-7745
IRB APPROVAL DATE: 02/02/2018
MRI-only Radiation Therapy Workflow with Continuous Positive Airway Pressure (CPAP) for Motion Management in the Abdomen
Version date: 09/05/2017
1
MRI-only Radiation Therapy Workflow with Continuous 
Positive Airway Pressure (CPAP) for Motion 
Management in the Abdomen 
Principal Investigators:
Madhur Garg, M.D. (Radiation Oncology) 
Shu-Hui Hsu, Ph.D. (Radiation Oncology) 
Wolfgang A. Tomé, Ph.D., FAAPM (Radiation Oncology)
Investigators:
William Bodner, M.D. (Radiation Oncology)
Craig Branch, Ph.D. (Radiology)
Rafi Kabarriti, M.D. (Radiation Oncology)
Michael Lipton, M.D. (Radiology)
Nitin Ohri, M.D. (Radiation Oncology)
Qi Peng, Ph.D. (Radiology)
Ali Sadoughi, M.D. (Interventional Pulmonology & 
Bronchoscopy)

IRB NUMBER: 2017-7745
IRB APPROVAL DATE: 02/02/2018
MRI-only Radiation Therapy Workflow with Continuous Positive Airway Pressure (CPAP) for Motion Management in the Abdomen
Version date: 09/05/2017
2
Table of Contents
1.
PROTOCOL SUMMARY AND/OR SCHEMA ……………………………………….. 4
2.
INTRODUCTION AND BACKGROUND……………………………………………… 6
2.1. Background ………………………………………………………………………... 6
2.1.1. MRI-only Radiation Therapy Workflow ……………………....................
6
2.1.2. Continuous Positive Airway Pressure (CPAP) for Motion management  7
2.2. Hypotheses…………………………………………………………………………
7
2.3. Aims………………………………………………………………………..............
7
3.
INCLUSION/EXCLUSION CRITERIA…………………………………………………. 8
3.1. Selection of Patient Subjects at the Albert Einstein College of Medicine/
Montefiore Medical Center…………………………………………………………. 8
3.2. Selection of Healthy Volunteers at the Albert Einstein College of Medicine/
Montefiore Medical Center…………………………………………………………. 8
4.
STUDY DESIGN AND METHODS…………………………………………………….. 9
4.1. Recruitment of Subjects……..........................................................................
9
4.2. Registration Procedures……..........................................................................
9
4.3. Study Design……………………………………………………………………….. 9
4.3.1. A Volunteer Study to Optimize MRI Scanning Protocols with and 
without CPAP………………………………………………………………..... 9
4.3.2. Image Acquisitions: CT, MRI, CBCT and orthogonal kV/MV images….. 10
4.3.3. CPAP Procedures for Eligible Patients Enrolled in Arm 2………………..10
4.3.4. Methodology Development to Create Pseudo-CT from MRI and 
Its Evaluation…………………………………………………………………..11
4.3.5. Methodology Development to Create Pseudo-MRI from CBCT and 
Its Evaluation…………………………………………………………………..11
4.3.6. Study of the Potential Role of 4D-MRI in Treatment Planning and 
Image Guidance………………………………………………………………11 
4.3.7. CPAP Effect on Motion Reduction and Clinical Treatment Outcome…..12
4.4. Clinical MRI Assessment…………………………………………………………..12
5.
STATISTICAL CONSIDERATIONS …………………………………………………. 12
5.1. Statistical Considerations for Specific Aim 1…………………………………….12
5.2. Statistical Considerations for Specific Aim 2…………………………………… 12
6.
EXPECTED ADVERSE EVENTS ……………………………………………………. 13
6.1. MRI Scans…………………………………………………………………………. 13
6.2. CPAP………………………………………………………………………………   13
7.
PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK …………….  14

IRB NUMBER: 2017-7745
IRB APPROVAL DATE: 02/02/2018
MRI-only Radiation Therapy Workflow with Continuous Positive Airway Pressure (CPAP) for Motion Management in the Abdomen
Version date: 09/05/2017
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7.1. Human Subjects Involvement and Characteristics ……………………………. 14
7.2. Source of Materials ……………………………………………………………….. 14
7.3. Potential Risks and Protection against Risks ………………………………….. 14
7.4. Recruitment and Informed Consent …………………………………………….. 14
8.
DATA AND SAFETY MONITORING PLAN ………………………………………… 14
9.
REFERENCES………………………………………………………………………….. 15
APPENDIX I
OVERSIGHT AND MONITORING PLAN………………………………………………… 17
MONITORING AND REPORTING GUIDELINES………………………………………. 17
EXPEDITED REPORTING OF ADVERSE EVENTS…………………………………… 19

IRB NUMBER: 2017-7745
IRB APPROVAL DATE: 02/02/2018
MRI-only Radiation Therapy Workflow with Continuous Positive Airway Pressure (CPAP) for Motion Management in the Abdomen
Version date: 09/05/2017
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1.
PROTOCOL SUMMARY AND/OR SCHEMA

Specific Objectives
o
To explore the feasibility of using Magnetic Resonance Imaging (MRI) alone in abdominal
radiation therapy for treatment planning and target localization
o
To demonstrate continuous positive airway pressure (CPAP) in motion reduction for
abdominal radiation therapy

Eligibility
o
Patients who have liver or pancreas tumors and will be treated with radiation therapy
Patients who are able to commit to Magnetic Resonance Imaging (MRI)

Required Sample Size
o
A maximum of 47 subjects (42 patients + 5 healthy volunteers) over a 24-month period

Study Design and Methods
o
All patients participating in the study will receive standard radiation therapy.
o
Source of data for the study include CT, MRI, cone beam-CT (CBCT) and orthogonal
kV/MV images and treatment plans. 
o
Patients will undergo both CT and MRI prior to abdominal radiation therapy and CBCT
and orthogonal kV/MV images prior to each treatment delivery. 
o
A two arm study will be performed and patients will be enrolled into a given arm
according to their eligibility. Arm 1 is for patients that are either not eligible for CPAP or 
that are unable to tolerate CPAP. These patients will undergo breath-hold and 4D 
imaging for both CT and MRI without CPAP. Arm 2 is for patients that are eligible for 
CPAP and able to tolerate CPAP. These patients will undergo breath-hold CT without 
CPAP, 4D-CT with and without CPAP and 4D-MRI with CPAP.
o
Two specific aims will be investigated. In Aim 1, we will explore the feasibility of using a
MRI-only in Radiation Oncology workflow. A probabilistic classification method will be 
utilized to generate a pseudo-CT from MRI to support treatment planning and image 
guidance for radiation therapy. The quality of the pseudo-CT will be evaluated by 
comparing it with CT. In addition, the reverse mapping will be investigated to create 
pseudo-MRI from CBCT to improve visualization of treatment targets and soft tissue prior 
to treatment delivery. In Aim 2, we will evaluate the utility of CPAP as a novel motion 
reduction methodology for patients with liver and pancreas cancer, to this end CT images 
with and without CPAP will be used. The evaluation will be based on the changes of 
motion magnitude, the achievable volumetric reduction in treatment target volumes, and 
doses to the targets and critical organs.  

IRB NUMBER: 2017-7745
IRB APPROVAL DATE: 02/02/2018
MRI-only Radiation Therapy Workflow with Continuous Positive Airway Pressure (CPAP) for Motion Management in the Abdomen
Version date: 09/05/2017
5

Schema
Sample size: a maximum of 42 patients
Assessment

Eligibility
Patient with liver or pancreas tumors and MRI- and CPAP- screening
complete
o
Arm 1: Not eligible for CPAP
o
Arm 2: Eligible for CPAP

Obtain informed consent
Register patient
Image acquisitions

Arm 1: breath-hold CT, 4D-CT, breath-hold MRI and 4D-MRI
without CPAP

Arm 2: breath-hold CT without CPAP, 4D-CT with and without
CPAP and 4D-MRI with CPAP 
 Standard radiation therapy for liver or pancreas tumors

Planning on clinical CT scans

Conventional fractionation or hypo-fractionation

3D-conformal radiation therapy or IMRT

Free-breathing treatment or gated treatment

Image guidance prior to each treatment (orthogonal images and
CBCT)   

I
IRB NUMBER: 2017-7745
IRB APPROVAL DATE: 02/02/2018
MRI-only Radiation Therapy Workflow with Continuous Positive Airway Pressure (CPAP) for Motion Management in the Abdomen
Version date: 09/05/2017
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2.
INTRODUCTION AND BACKGROUND
2.1
Background
Radiation therapy is a technique that delivers high doses to tumors while minimizing doses to 
neighboring normal tissues in order to achieve optimal treatment outcome. Therefore, this 
technique requires high accuracy in target localization, one of major issues that are still being 
investigated in radiation therapy. Accurate targeting is particularly challenging when treating 
abdominal tumors, such as liver and pancreatic tumors, due to organ motion and the difficulty of 
distinguishing lesions from neighboring normal tissues using routine Computed Tomography (CT) 
images that are usually utilized for radiotherapy treatment planning. 
In order to clearly identify lesions for radiation therapy, Magnetic Resonance Imaging (MRI) is 
often used due to its superior soft tissue visualization. MRI also has a potential for measuring 
biological functions and physiology using various functional imaging modalities, such as dynamic 
contrast-enhanced and diffusion-weighted images. These advantages allow MRI to be used for 
more accurate delineation of tumors and critical organs compared to CT and for treatment 
response assessment. However, MRI is not often used as a sole imaging modality in the radiation 
therapy workflow since the lack of electron density information precludes heterogeneity 
corrections, which are part of the standard of care in radiation therapy treatment planning. The 
use of multi-imaging modalities in the workflow requires an imaging registration step and 
therefore introduces uncertainties and errors (particularly in contouring) which are then 
propagated throughout the entire course of radiotherapy. To reduce these uncertainties, it has 
become of interest to streamline the workflow by implementing MRI alone in the planning 
process. Investigating the possibility of using MRI alone in the radiation therapy workflow is 
worthwhile for abdominal radiation therapy. The reason is that MRI is a necessary imaging 
modality to provide good tissue contrast for contouring abdominal tumors, and the registration 
uncertainty is likely larger in the abdomen than other body sites due to breathing and 
gastrointestinal motions. 
In regard to organ motion, the largest motion of abdominal tumors and organs is caused by 
breathing, which complicates the planning process and affects the accuracy of radiation delivery. 
The American Association of Physics in Medicine (AAPM) Task Group 76 has recommended
several methods to manage respiratory motion, and also recommended that respiratory
management methods be considered if target motion is greater than 5 mm, or if normal tissue
sparing is gained[1]. These methods include motion-encompassing methods, motion reduction
methods and real-time tumor tracking methods. Motion-encompassing methods apply a motion
margin to the targets to account for respiratory motion, resulting in excess normal tissue being
irradiated. Current motion reduction methods use either breath-hold techniques or forced shallow 
breathing with abdominal compression. Real-time tumor tracking methods involve complicated 
techniques to detect the motion and dynamically reposition the radiation beam to follow tumor 
motions. Currently, there are no standard or best motion management options for all patients. 
However, motion reduction techniques may be simpler ways to address the motion issue while 
minimizing the injury to normal tissues. Current techniques to reduce the respiratory motion 
require either patient cooperation for breath-hold or abdominal compression, which may increase 
discomfort. 
2.1.1
MRI-only Radiation Therapy Workflow
Several methods have been investigated in order to generate electron density maps from MRI for 
treatment planning, such as methods that manually identify tissues types and assign bulk 
densities[2-5], atlas-based methods to automate the process in generating electron density 
maps[6-9], and voxel-based methods to account for individual differences that are typically 
lacking in atlas-based methods[10-14]. These studies have shown promising results in terms of 
pseudo-CT quality, and demonstrated the potential of using MRI alone in the workflow for brain 
and prostate radiation therapy. 

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IRB NUMBER: 2017-7745
IRB APPROVAL DATE: 02/02/2018
MRI-only Radiation Therapy Workflow with Continuous Positive Airway Pressure (CPAP) for Motion Management in the Abdomen
Version date: 09/05/2017
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These encouraging results have prompted us to investigate the feasibility of using MRI-only in the 
abdominal radiotherapy workflow. The goals of using MRI in this workflow include: (1) the 
delineation of targets and organs-at-risk for treatment planning with enhanced distortion and 
intensity corrections, (2) the generation of pseudo-CT for dose calculations as well as the 
generation of digital reconstructed radiographs (DRRs) for image guidance using bony anatomy, 
and (3) target localization for treatment verification by matching treatment MRI (for MRI on rail) or 
pseudo-MRI (created from Cone-Beam CT (CBCT) for Linear Accelerator (LINAC) with kilo-
voltage (kV) or mega-voltage (MV) on-board imager). To achieve the first goal, geometric 
distortions, intensity non-uniformity, and motion artifacts will need to be minimized to improve MR 
imaging quality for contouring and electron density mapping. To address the second goal, we will
explore a probabilistic classification method to generate pseudo-CT and DRRs from MRI. This
method accounts for individual differences and the mixing of tissue types within voxels that result
in the generated pseudo-CT close to true individual anatomy. To address the third goal of using
MRI for treatment guidance on the machines equipped with either MRI or kV- (or MV-) CBCT, we
will explore the potential of synthesizing pseudo-MRI from CBCT to compensate for the limitation
of CBCT in differentiating targets from normal tissues. Our proposed study incorporates MRI into 
treatment planning and image guidance workflow in order to improve the accuracy and ease of 
target delineation and localization for abdominal radiation therapy. The result will be not only 
useful in streamlining the radiation therapy workflow but could also be beneficial for attenuation 
corrections in PET-MRI.  
2.1.2
Continuous Positive Airway Pressure (CPAP) for Motion Management
Continuous positive airway pressure (CPAP) has been used in patients with obstructive sleep 
apnea to maintain airway patency. Other indications include respiratory distress secondary to 
suspected congestive heart failure, acute cardiogenic pulmonary edema, pneumonia, and chronic 
obstructive pulmonary disease (asthma, bronchitis, emphysema) [15-17]. This technique provides 
a constant stream of pressurized air to the upper airways and lungs using a small air pump, 
tubing, and face/nose mask and may reduce diaphragm motion. An initial study using CPAP for 
lung radiotherapy indicates that CPAP significantly reduced lung tumor motion compared with 
free breathing, and therefore reduces treatment volume as well as lung dose. This study has 
shown the potential of CPAP as a new motion management option in radiotherapy with good 
reproducibility, simple implementation, and less needs in active patient cooperation [18]. 
Given these advantages of CPAP, we propose to incorporate CPAP into MRI-only abdominal 
radiation therapy workflow for motion reduction. The goals of using CPAP in this workflow are: (1) 
to reduce motion artifacts that degrade the quality of MR images, the quality of the electron 
density mapping, and the accuracy of target delineation, and (2) to improve targeting accuracy 
during radiation delivery and thus reduce the injury to neighboring normal tissues.     
2.2
Hypotheses
Two primary hypotheses are considered in this study: (1) MRI-only abdominal radiation therapy 
will be a feasible workflow for treatment planning and target localization; (2) the use of CPAP will 
reduce tumor motion and change internal anatomy in a way that often protects critical organs, 
and thus allow precise radiation treatment for abdominal lesions while minimizing injury to 
neighboring normal tissues. We hypothesize that both technologies will be beneficial to patients 
with abdominal lesions.    
2.3
Aims
Specific Aim 1: (1) Investigate methods to generate pseudo-CT to support radiotherapy treatment 
planning and image guidance for abdominal treatments. (2) Explore the feasibility to map CBCT 
to MRI intensities for improving the visualization of tumors and/or soft tissues for on-line treatment 
verification using CBCT-based methods. (3) Evaluate the potential role of 4D MRI and their 
associated pseudo-CT in target delineation for treatment planning and target localization for 
image guidance. 

IRB NUMBER: 2017-7745
IRB APPROVAL DATE: 02/02/2018
MRI-only Radiation Therapy Workflow with Continuous Positive Airway Pressure (CPAP) for Motion Management in the Abdomen
Version date: 09/05/2017
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Specific Aim 2: Determine the effect of CPAP on pseudo-CT image quality, target delineation, 
tumor motion and dose to critical organs in abdominal radiotherapy.  
3.
INCLUSION/EXCLUSION CRITERIA
3.1
Selection of Patient Subjects at the Albert Einstein College of Medicine/Montefiore
Medical Center
To study the feasibility of a MRI-only workflow with/or without CPAP in abdominal radiation 
therapy, the following patients will be included:

Eligibility Criteria
Patients have liver or pancreas tumors (either primary tumors or metastases) and are
scheduled to be treated with radiotherapy (either 3D conformal or intensity-modulation 
radiotherapy (IMRT) with conventional or hypo- fractionation).
b.
KPS > 70
c.
If a biopsy is performed, the patient is at least 1 week post-biopsy.
d.
The patient’s age must exceed 18 years.
e.
The patients must be able to commit to T1-weighted, T2-weighted, Dixon fat and water,
ultrashort-TE, and other clinical or research MR sequence images prior to treatment. 
f.
CPAP Eligibility: CPAP is a safe, effective form of therapy with rare complications.
Relative contraindications include patients with bullous lung disease, fibrotic lung 
disease, Claustrophobia and recurrent sinus or ear infections. The absolute 
contraindications include obtundation /unconsciousness, chest wall trauma, suspected 
pneumothorax, persistent nausea/vomiting, active upper GI bleeding, history of recent 
gastric surgery, facial anomalies/trauma [15,16]. If there is any question about the above 
history and medical problems, the subject will be referred to a pulmonologist for 
consultation.
i.
The patients with above contraindications are not CPAP eligible and are enrolled
in Arm 1 for the protocol without CPAP
ii.
The eligible patients are enrolled in Arm 2 for the protocol with CPAP.
Exclusion Criteria:

Patients who meet the following criteria:
a.
Any medical condition, which would make the imaging studies unsafe or poorly tolerated
b.
Known allergic reaction to contrast or shellfish
c.
Implanted metal devices or foreign bodies that serve as a contraindication to MR imaging
d.
Creatinine > 1.4 mg/dl and Creatinine clearance < 20 mg/dl.
e.
Uncontrolled, clinically significant cardiac arrhythmias
f.
Severe claustrophobia
g.
Pregnant female
h.
KPS <70
3.2
Selection 
of 
Healthy 
Volunteers 
at 
the 
Albert 
Einstein 
College 
of 
Medicine/Montefiore Medical Center
To optimize the MRI scanning protocols with and without CPAP volunteers that meet the following 
eligibility criteria will be included:
Eligibilty Criteria
a.
KPS > 70
b.
The volunteers’ age must exceed 18 years.
c.
The volunteers must be able to undergo T1-weighted, T2-weighted, Dixon fat and water,
ultrashort-TE, and other clinical or research MR sequence images prior to treatment.

IRB NUMBER: 2017-7745
IRB APPROVAL DATE: 02/02/2018
MRI-only Radiation Therapy Workflow with Continuous Positive Airway Pressure (CPAP) for Motion Management in the Abdomen
Version date: 09/05/2017
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d.
CPAP Eligibility: CPAP is a safe, effective form of therapy with rare complications.
Relative contraindications include volunteers with bullous lung disease, fibrotic lung
disease, Claustrophobia and recurrent sinus or ear infections. The absolute
contraindications include obtundation /unconsciousness, chest wall trauma, suspected
pneumothorax, persistent nausea/vomiting, active upper GI bleeding, history of recent
gastric surgery, facial anomalies/trauma [15,16]. If there is any question about the above
history and medical problems, the volunteer will be not be included in the pilot study.
Exclusion Criteria:

Volunteers who meet the following criteria:
a.
Any medical condition, which would make the imaging studies unsafe or poorly tolerated
b.
Implanted metal devices or foreign bodies that serve as a contraindication to MR imaging
c.
Uncontrolled, clinically significant cardiac arrhythmias
d.
Severe claustrophobia
Pregnant female
f.
KPS <70
4.
STUDY DESIGN AND METHODS
4.1
Recruitment of Subjects
Patients having either liver or pancreas cancer, who will be treated with radiation therapy will be 
invited to participate in the study during patient consult.  
We will enroll up to five volunteers in the preliminary study to optimize the MR scanning protocols 
to be used in the patient study. We will place flyers to recruit healthy volunteers from Montefiore 
Medical Center or Albert Einstein College of Medicine. All eligible volunteers that can undergo 
CPAP and MRI scanning will be accepted into the volunteer study. No remuneration to volunteers 
will be offered and there are no potential benefits other than the Radiology read of the MRI for 
incidental findings. There are no risks to volunteers participating in the study related to radiation 
exposure because only MRI will be performed.    
4.2
Registration Procedures

Patients who agree to participate in the study and who provide written informed consent will
be enrolled.

Patients must meet all eligibility criteria listed in Section 3. The study coordinator will verify 
eligibility, assign a case number, and register the patient prior to study specific participation.  
The following information will be recorded:
o
Protocol number
o
Patient’s initials
o
Patient’s medical record number
o
Patient demographic data, including gender, birth date, and race.
4.3
Study Design
4.3.1
A Volunteer Study to Optimize MRI Scanning Protocols with and without CPAP      
Prior to enrolling patients in the study, a volunteer study will be conducted to optimize MRI 
scanning protocols with and without CPAP. The purpose of the volunteer study is to gain 
experience in using CPAP, to investigate appropriate MR imaging protocols with sufficient image 
resolution and contrast, and to test and streamline the workflow to minimize possible patient 
discomfort. Volunteers will not receive any MR contrast as part of their MR imaging and will be 
imaged two times once without the use of CPAP and once using CPAP employing the following 

IRB NUMBER: 2017-7745
IRB APPROVAL DATE: 02/02/2018
MRI-only Radiation Therapy Workflow with Continuous Positive Airway Pressure (CPAP) for Motion Management in the Abdomen
Version date: 09/05/2017
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MR sequences: T1-weighted, T2-weighted, Dixon fat/water, ultra-short TE and other clinical or 
research MR sequences.
4.3.2
Image Acquisitions: CT, MRI, CBCT and orthogonal kV/MV images
We are planning to enroll a maximum of 42 patients into this study. Prior to abdominal 
radiotherapy, all eligible participants will undergo both CT and MRI scans in the radiotherapy 
treatment position. Two scanning protocols (Arm 1 and Arm 2) will be performed according to 
their CPAP eligibility. 
(1) Arm 1: For patients not eligible for CPAP or unable to tolerate CPAP

Breath-hold CT and 4D-CT without CPAP

Breath-hold MRI and 4D-MRI without CPAP
o
T1-weighted, T2-weighted, Dixon fat/water, and ultra-short TE images
(2) Arm 2: For patients eligible for CPAP and able to tolerate CPAP

Breath-hold CT without CPAP

4D-CT with and without CPAP

4D-MRI with CPAP
o
T1-weighted, T2-weighted, Dixon fat/water, and ultra-short TE images
CT scans will be performed in the axial scanning mode with ~2 mm slice thickness over the entire 
abdomen region for treatment planning and dose calculations.  
MRI images using standard clinical imaging sequences will be acquired, including T1-weighted, 
T2-weighted, and Dixon fat and water images. Additional MRI scans, such as ultrashort-TE (UTE) 
images, will follow MRI safety guideline of FDA and will be optimized based on phantom and 
volunteer studies before clinical studies. Gadolinium-based contrast may be administered per 
institutional routine and research protocol. The MRI scanning sequences for these MRI images 
will be optimized to achieve optimal resolution (~ 2 mm) and contrast with minimized geometric 
distortion (< 2 mm). MR images will be used (1) to delineate the targets following the standard 
treatment planning process, and (2) to create pseudo-CT for dose calculations and to be 
compared with CT-based dose calculations.        
Patients will receive standard radiotherapy to liver or pancreatic lesions using 3D-conformal or 
IMRT techniques (using CT-based planning without CPAP motion management). Prior to each 
treatment delivery, patients will undergo kV/MV orthogonal images and CBCT scans, and the 
CBCT scans will be compared with the planned CT to verify treatment position. In off-line, the 
CBCT scans and kV/MV orthogonal images will be compared with pseudo-CT and DRRs that are 
created from pseudo-CT.
4.3.3
CPAP Procedures for Eligible Patients Enrolled in Arm 2
Before simulation and image acquisition with CPAP, patients will be fitted with a mask by a 
respiratory therapist and then undergo training on use of the CPAP device. Under physician 
supervision, patients will be instructed how to gradually increase air pressure from 5 cm H2O to 
the maximal comfortably tolerated level up to a maximum of 15 cm H2O. Patients were connected 
to CPAP for at least half an hour before undergoing image acquisition. 
If CT and MRI scans could not be performed at the same day, patients will be discharged home 
with their mask, hose, and filter and be asked to bring them for next image acquisition. Detailed 
procedures are described as below,
(1) Place patient in a sitting position
(2) Assess vital signs every 15 minutes in the first hour and then every half an hour while on
CPAP and monitor SpO2 continuously

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MRI-only Radiation Therapy Workflow with Continuous Positive Airway Pressure (CPAP) for Motion Management in the Abdomen
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(3) If systolic BP <90 mmHg contact Medical Control prior to beginning CPAP to assess
patient stability
(4) Begin at lowest level of positive pressure available
(5) Explain the procedure to the patient:
(6) Patient requires reassurance to be used effectively.
a.
Example: “You are going to feel some pressure from the mask”
(7) Place delivery device over mouth and/or nose. (depend on the type of mask is used)
Instruct patient to breath in through their nose slowly and exhale through their mouth as
long as possible (count slowly and aloud to four then instruct to inhale slowly).
(8) Check for air leaks
(9) Documentation on the patient care record should include:
a.
CPAP level
b.
Frequent SpO2 and Vital Sign assessment
c.
Any adverse reactions
4.3.4
Methodology Development to Create Pseudo-CT from MRI and Its Evaluation 
A method of using probabilistic classification of MRI to generate pseudo-CT has shown promising 
results in brain radiation therapy [11,19]. The probabilistic classification accounts for individual 
differences and the mixing of tissue types within voxel that result in the generated pseudo-CT 
close to true individual anatomy. We will first explore the potential of using this classification 
method to generate pseudo-CT in the abdomen, and then may explore a hybrid method (a 
combination of atlas- and voxel- based methods) to improve the quality of pseudo-CT. 
Probabilistic tissue classification is achieved via fuzzy c-means (FCM) clustering with a spatial 
constraint [11]. The FCM algorithm assigns voxels of the images a probability of belonging to a 
class. Membership probability in any given tissue class varies between zero and one. The 
membership for each voxel can be obtained by minimizing the objective function. Then relative 
attenuation properties are assigned based on the probability map and pseudo-CT is generated. 
To evaluate the quality of pseudo-CT in treatment planning, 3D-conformal and IMRT plans will be 
created on standard CT and then the plans will be mapped onto pseudo-CT. Dose distributions 
and dose volume histograms will be compared between the plans using CT and pseudo-CT 
datasets. 
To evaluate the quality of pseudo-CT in image guidance using bony structure, DRRs generated 
from pseudo-CT and CT will be both aligned to the orthogonal images that are taken prior to 
treatment. To evaluate the quality of pseudo-CT in image guidance using soft tissue, pseudo-CT 
and CT will be both aligned to CBCT that are taken prior to treatment. The accuracy of image 
alignment using pseudo-CT will be evaluated.
4.3.5
Methodology Development to Create Pseudo-MRI from CBCT and Its Evaluation
CBCT has a limitation in differentiating targets from normal tissues. To better visualize targets 
and soft tissues, the method to synthesize MRI will be explored. The proposed method will use 
planning MRI images and their associated pseudo-CT images as well as CBCT images. First, 
CBCT is registered to pseudo-CT using rigid or deformable registration. Second, the 
transformation information from the previous registration is applied to the planning MRI to 
generate a synthetic CBCT-based MRI for target localization and alignment during treatment.       
To evaluate the quality of pseudo-MRI in target localization and alignment, the alignment using 
pseudo-MRI and planning CT will be compared with the alignment using CBCT and planning CT.  
4.3.6
Study of the Potential Role of 4D-MRI in Treatment Planning and Image Guidance 
4D-CT is usually acquired for motion assessment and management when treating tumors in chest 
and abdomen. When contouring target volumes, internal target volume (ITV) is defined based on 
the 4D-CT dataset in order to account for target motion. For abdominal tumors, it is challenging to 
directly assess target motion on 4D-CT without contrast administration or implantation of fiducial 

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IRB APPROVAL DATE: 02/02/2018
MRI-only Radiation Therapy Workflow with Continuous Positive Airway Pressure (CPAP) for Motion Management in the Abdomen
Version date: 09/05/2017
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markers. Thus, replacement of 4D-CT with 4D-MRI would be a beneficial step for motion 
assessment and an important part in the MRI-alone workflow for abdominal radiotherapy. To 
investigate the role of 4D-MRI in treatment planning, ITVs contoured using 4D-CT and 4D-MRI 
will be compared, and their dosimetric impact will be also evaluated.  
4.3.7
CPAP Effect on Motion Reduction and Clinical Treatment Outcome
CT images will be acquired without and with CPAP for patients enrolled in Arm 2. Following 
routine contouring and planning procedures for abdominal treatment, gross tumor volume (GTV) 
and clinical target volume (CTV), ITV to account for tumor motion, and planning target volume 
(PTV) to account for setup errors will be identified and contoured on each CT dataset. Treatment 
plans will be generated on both CT datasets with their corresponding target contours using the 
same plan objectives. 
To evaluate motion reduction using CPAP, tumor excursion (in superior-inferior, right-left and 
anterior-posterior directions) and ITV will be calculated and compared between two datasets for 
Arm 2 participants. To evaluate the change on clinical outcome, dose metrics such as mean dose 
to critical organs and complication rates will be compared. 
4.4
Clinical MRI Assessment
All images will be reviewed by a board certified radiologist to assess for unexpected findings. In 
case of unexpected clinically relevant imaging findings the Study-PI, Dr. Madhur Garg, will inform 
study participants of these findings.
5
STATISTICAL CONSIDERATIONS
5.1 Statistical Considerations for Specific Aim 1
The primary clinical end point of specific aim 1 is to show the non-inferiority of the 4D-MR only 
workflow for ITV definition to that using 4D-CT. In the case of lung cancer Ehler et al. [20] have 
found using 4D-CT that different methodologies for the definition of the ITV yielded differences in 
ITV definition ranging from 1.7% to 43% with an average difference between methodologies of 
17.5% . The observed differences in volume definition where confined to the periphery of the ITV 
volume. Therefore a difference of no larger than 14% between the ITV defined using our 
proposed 4D MR workflow versus 4D CT is considered as not being clinically meaningful. Based 
on the literature assuming a standard deviation of 16.3% and a non-inferiority margin of 14% in 
ITV volume definition between 4D-MR and 4D-CT, we find that if there is truly no difference 
between the ITV definition using 4D-CT and the ITV definition using 4D-MR. A sample size of 21 
patients will achieve a 91% power to detect the non-inferiority using a one sided t-test and the 
true difference between the mean is 0.at a type 1 error rate of 0.01. 
5.2 Statistical Considerations for Specific Aim 2
Using a conventional motion reduction technique employing an abdominal compression pillow we 
have found an average motion reduction of 12% with a standard deviation of 13% for lesions 
within the lung [21]. Achievable motion reduction ranged from 3% to 28%, therefore an average 
motion reduction of at least 12% with CPAP is considered clinically meaningful. Using pairwise 
analysis assuming a mean difference of 12% between free breathing and the application of CPAP 
with an associated standard deviation of 13%, and an α=0.01, using a two sided paired t-test we 
find that with 21 patients will have 90% power to detect a motion reduction of at least 12% when 
using CPAP. Assuming an allocation ratio of 1:1 between the two arms of this study we are 
planning to recruit a maximum of 42 patients to this study, however once, 21 patients have been 

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accrued to the CPAP arm no further patients will be enrolled into that part of the study and the 
study will be closed once the necessary patient number for aim 1 has been achieved.
6
EXPECTED ADVERSE EVENTS 
6.1
MRI Scans
MRI Scan:
Anxiety/Stress
Claustrophobia
Discomfort
Gadolinium:
Allergic reaction to contrast agent
Headache
Nausea
Vomiting
Rash
Temporary low blood pressure
Nephrogenic Systemic Fibrosis (NSF)/Nephrogenic Fibrosing Dermopathy (NFD).
NOTE: Precautions should be exercised for patients with a history of grand mal seizures, 
severely impaired renal function or hemolytic anemia. The very unlikely possibility of a reaction, 
including anaphylactic or cardiovascular reactions, should be considered especially for patients 
with a known sensitivity to Gadolinium or history of asthma. Nephrogenic Systemic Fibrosis (NSF) 
or Nephrogenic Fibrosing Dermopathy (NFD) (kidney disorders), may occur in patients with 
moderate to end-stage kidney disease after they have had a MRI scan with gadolinium-based 
contrast agent.
Needle Placement:
Minor discomfort;
Bleeding;
Infection;
Bruising.
6.2
CPAP
CPAP is a safe form of therapy with relatively few recorded major complications. Hypotension, 
local skin irritation, drying of the nasal and pharyngeal membranes, nasal congestion/rhinorrhea, 
gastric distention, vomiting, and eye irritation are the rare adverse events. Nevertheless, minor 
discomfort and complaints regarding the mask interface remain relatively common[15]. 

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7
PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK
7.1
Human Subjects Involvement and Characteristics
We expect to enroll a maximum of 47 subjects (42 patients + 5 healthy volunteer subjects) over a 
24-month period. For each patient participating in the study, the research will involve a
pretreatment MRI and CT scans and treatment CBCT and orthogonal kV/MV images as
described in Section 3. No patients will be excluded based on racial/ethnic or sex/gender.
7.2
Source of Materials
The source of data consists of CT, MRI, CBCT and orthogonal kV/MV images and treatment 
plans as described in Section 3. A data record will be kept in a locked cabinet in the project 
leader’s office, which will be accessible only to the scientific staff involved with this research 
project.
7.3
Potential Risks and Protection against Risks
The MRI scans are minimally invasive. The only contraindications to a MRI scan are the presence 
of any ferrous metal in the body or claustrophobia. Prior to arriving at the MRI facility, all patients 
will be required to complete a standard clinical screening form for any metallic implants or ferrous 
material they may have in their bodies. Any presence of such material will immediately disqualify 
them from the study. 
CPAP is a safe form of therapy with rare complications. Relative contraindications include 
patients with bullous lung disease, fibrotic lung disease, Claustrophobia and recurrent sinus or 
ear infections. The absolute contraindications include obtundation /unconsciousness, chest wall 
trauma, suspected pneumothorax, persistent nausea/vomiting, active upper GI bleeding, history 
of recent gastric surgery, facial anomalies/trauma. All patients will be required to complete a 
screening form for any of these histories. Any presence of these histories will immediately 
disqualify them from Arm 2 protocol. If there is any question about the above history and medical 
problems, the patient will be referred to a pulmonologist for consultation.
7.4
Recruitment and Informed Consent
Drs. Garg, Bodner, Kabarriti, and Ohri will recruit patients for this study, and Dr. Sadoughi will 
evaluate if patients are eligible to be enrolled in Arm 2 CPAP protocol. The patients who 
participate in the study will be screened, educated, and consented. Most imaging protocols 
described in this research proposal are routine clinical imaging protocols in use at our institution. 
Imaging sequences that usually are not used in abdominal scans will be optimized and tested on 
volunteers before using them in patients who participate in the study (Refer to Section 4.3.3).
8
DATA AND SAFETY MONITORING PLAN
Adverse events will be collected and reported according to a DSMP described in Appendix I.

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9
REFERENCES
[1]
Keall PJ, et al. The management of respiratory motion in radiation oncology report of
aapm task group 76. Med Phys 2006;33:3874-3900.
[2]
Lee YK, et al. Radiotherapy treatment planning of prostate cancer using magnetic
resonance imaging alone. Radiotherapy and oncology : journal of the European Society
for Therapeutic Radiology and Oncology 2003;66:203-216.
[3]
Chen L, et al. Magnetic resonance-based treatment planning for prostate intensity-
modulated radiotherapy: Creation of digitally reconstructed radiographs. International 
journal of radiation oncology, biology, physics 2007;68:903-911.
[4]
Jonsson JH, et al. Treatment planning using mri data: An analysis of the dose calculation
accuracy for different treatment regions. Radiation oncology 2010;5:62.
[5]
Lambert J, et al. Mri-guided prostate radiation therapy planning: Investigation of
dosimetric accuracy of mri-based dose planning. Radiotherapy and oncology : journal of 
the European Society for Therapeutic Radiology and Oncology 2011;98:330-334.
[6]
Stanescu T, et al. A study on the magnetic resonance imaging (mri)-based radiation
treatment planning of intracranial lesions. Physics in medicine and biology 2008;53:3579-
3593.
[7]
Greer PB, et al. A magnetic resonance imaging-based workflow for planning radiation
therapy for prostate cancer. The Medical journal of Australia 2011;194:S24-27.
[8]
Dowling JA, et al. An atlas-based electron density mapping method for magnetic
resonance imaging (mri)-alone treatment planning and adaptive mri-based prostate 
radiation therapy. International journal of radiation oncology, biology, physics 2012;83:e5-
11.
[9]
Sjolund J, et al. Generating patient specific pseudo-ct of the head from mr using atlas-
based regression. Physics in medicine and biology 2015;60:825-839.
[10]
Johansson A, Karlsson M Nyholm T. Ct substitute derived from mri sequences with
ultrashort echo time. Med Phys 2011;38:2708-2714.
[11]
Hsu SH, et al. Investigation of a method for generating synthetic ct models from mri
scans of the head and neck for radiation therapy. Physics in medicine and biology 
2013;58:8419-8435.
[12]
Jonsson JH, et al. Treatment planning of intracranial targets on mri derived substitute ct 
data. Radiotherapy and oncology : journal of the European Society for Therapeutic 
Radiology and Oncology 2013;108:118-122.
[13]
Kim J, et al. Implementation of a novel algorithm for generating synthetic ct images from
magnetic resonance imaging data sets for prostate cancer radiation therapy. International 
journal of radiation oncology, biology, physics 2015;91:39-47.
[14]
Su KH, et al. Generation of brain pseudo-cts using an undersampled, single-acquisition
ute-mdixon pulse sequence and unsupervised clustering. Med Phys 2015;42:4974.
[15]
Indications and standards for use of nasal continuous positive airway pressure (cpap) in
sleep apnea syndromes. American thoracic society. Official statement adopted march 
1944. Am J Respir Crit Care Med 1994;150:1738-1745.
[16]
Clini E, et al. The italian multicentre study on noninvasive ventilation in chronic
obstructive pulmonary disease patients. Eur Respir J 2002;20:529-538.
[17]
Ozsancak A, D'Ambrosio C Hill NS. Nocturnal noninvasive ventilation. Chest
2008;133:1275-1286.

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[18]
Goldstein JD, et al. Continuous positive airway pressure for motion management in
stereotactic body radiation therapy to the lung: A controlled pilot study. International
journal of radiation oncology, biology, physics 2015;93:391-399.
[19]
Paradis E, et al. Assessing the dosimetric accuracy of magnetic resonance-generated
synthetic ct images for focal brain vmat radiation therapy. International journal of radiation
oncology, biology, physics 2015;93:1154-1161.
[20]
Ehler ED, Bzdusek K Tome WA. A method to automate the segmentation of the gtv and
itv for lung tumors. Med Dosim 2009;34:145-153.
[21]
Zhang T, Orton NP Tome WA. On the automated definition of mobile target volumes from
4d-ct images for stereotactic body radiotherapy. Med Phys 2005;32:3493-3502.

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APPENDIX I
OVERSIGHT AND MONITORING PLAN
The Albert Einstein College of Medicine/Albert Einstein Cancer Center Data Safety Monitoring 
Committee (DSMC) has the responsibility for ensuring data and safety monitoring along with the 
PI who is ultimately responsible for the ongoing monitoring and safety of clinical protocols.  The 
primary functions of the AECC DSMC are as follows:
1.
To review and ensure protocol compliance with dose escalation in phase I trials
2.
To review/assure protocol compliance for all trials that have two-stage phase II designs,
3.
Reviewing all internal and external serious adverse reports, investigator alerts, action
letters, and other safety reports for trials being performed at AECC-affiliated institutions 
and;
To implement and to determine the adequacy of DSM plans of all approved protocols.
The DSMC is an independent committee and meets on a monthly basis.  During its monthly 
meeting, the DSMC will review serious adverse events from this study.  In the event that the 
DSMC decides that a revision is warranted, the committee will immediately notify the principal 
investigator of this study.  The DSMC has the authority to close trials to patient accrual should the 
risk to patients be excessive or outweigh the potential benefits of the study.  All study 
suspensions and closures will be forwarded to the IRB/CCI and study sponsor from the DSMC.  
MONITORING AND REPORTING GUIDELINES
An adverse event can occur on any clinical trial; it is the responsibility of the PI and the research 
team to identify, review, and report all necessary adverse events to the institutional IRB, the 
sponsor, and governmental agencies (i.e., NCI and/or FDA) as appropriate.  Adverse events 
should be identified through standard, routine protocol review and clinical assessment of each 
subject participating in the clinical trial.  This review should be timely in order to meet the 
requirements for adverse event reporting defined below:
Adverse Event (AE)
An adverse event is defined by the GCP (Good Clinical Practice guidelines) as an undesirable 
experience occurring to a subject during a clinical trial, whether or not considered related to the 
investigational products.
Serious Adverse Event (SAE)
A serious adverse event is an adverse experience that fits one or more of the conditions noted 
below:
1.
Fatal or life threatening
2.
Disabling
3.
Results in hospitalization or prolongation of hospitalization
4.
Results in a congenital anomaly or occurrence of malignancy
All Serious Adverse Events, regardless if they are unrelated to study treatment, should be 
reported to the IRB and sponsors.  These include, but may not be limited to:
1.
All deaths
2.
All SAE associated with study procedures
3.
Any serious problem
4.
Any recurring problem
5.
Any outside AE report
6.
Any unanticipated side effects

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Unexpected Adverse Event
An unexpected AE is an experience not previously reported (in nature, severity, or incidence) in 
the current Investigator’s Brochure or protocol document.
EXPEDITED REPORTING OF ADVERSE EVENTS
Depending on the nature, severity, and attribution of the event an ADR report will be phoned in, 
submitted in writing, or both according to the table below. Telephoned Adverse Events must also 
be reported by email to the AECC DSMC within one working day of the event.  All adverse events 
must also be reported to the Montefiore Medical Center IRB, and any sponsor/funding agency not 
already included in the list.
Telephone reports to:
Study Co-Chair:
Madhur Garg, MD
Phone:  718-920-4140
Fax:  718-531-2064     
Written reports to:
Kathy O’Connor, MMC IRB
Fax:  (718) 515-5217
MMC IRB – Copy of final written report to Sponsor.

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EXPEDITED REPORTING TABLE
Summary of Reporting Requirements for Adverse Events
Expedited Reporting
Unexpected Events
GRADES 2 and 3
Attribution of possible, probably or definite
GRADES 4 and 5
Regardless of attribution
Expedited report within 15 working days to 
FDA
(Grade 1 – Adverse Event Expedited Reporting 
NOT required)
Report by phone to FDA within 24 hours.  
Expedited report to follow within 15 working 
days.
This includes all deaths within 30 days of the 
last dose of treatment with an investigational 
agent regardless of attribution.
Any late death attributed to the agent (possible, 
probable, or definite) should be reported within 
15 working days.
For Hospitalization Only – Any medical event equivalent to the CTC Grade 3, 4, 5 which 
precipitated hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of requirements for phase of study, expected or unexpected and attribution.
Expedited reporting may not be appropriate for specific expected events for certain later phase 2 
and phase 3 protocols. In those situations the adverse events that will not have expedited 
reporting must be specified in the text of the approved protocol.  An expected grade 3 event that 
is using the generic reporting criteria, for instance.  In a trial of investigational agents where grade 
3 diarrhea requiring hospitalization is expected, only diarrhea requiring ICU care (grade 4) might 
be designated for expedited reporting.