Intra-patient Comparison of Active Breathing Coordinator-based vs VisionRT-based Deep Inspiration Breath-hold for Left-chest Wall Irradiation, a Pilot Study for Breast Cancer
Phase: NA
Conditions: Breast Cancer
Sponsor: University of Texas Southwestern Medical Center

 
STU052015-047, Rahimi, FormA-ResearchProtocol, Mod_20, 12-17-19 (1) 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Cancer Center. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
 
Template Updated: 12/2012; 9/2013 
 
 
 
 
NCT02694029 
 
Intra-patient Comparison of Active Breathing Coordinator-based vs VisionRT-based Deep 
Inspiration Breath-hold for Left-chest Wall Irradiation, a Pilot Study for Breast Cancer   
 
 
Responsible Party: Asal Rahimi 
 
 
Dates: 12/3/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
STU052015-047, Rahimi, FormA-ResearchProtocol, Mod_20, 12-17-19 (1) 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Cancer Center. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
 
Template Updated: 12/2012; 9/2013 
 
STU 052015-047  
Intra-patient comparison of Active Breathing Coordinator-based  vs VisionRT-based deep 
inspiration breath-hold for left-chest wall irradiation, A Pilot Study for Breast Cancer 
 
Principal Investigators: 
Asal Rahimi, M.D. 
 
 
 
 
Xuejun Gu, Ph.D. 
 
 
 
 
 
 
 
 
UT Southwestern Medical Center 
 
 
 
 
 
 
5801 Forest Park Ave, Dallas, TX 
 
 
 
 
 
 
Sub-Investigator(s): 
 
Ann Spangler M.D., MS, Radiation Oncology 
 
 
 
 
Kevin Albuquerque, MD, Radiation Oncology 
 
 
 
 
Bo Zhao, Ph.D., Radiation Oncology 
 
 
Biostatistician: 
 
Name: Chul Ahn, Ph.D 
 
 
 
 
Institution: UT Southwestern Medical Center 
 
 
 
 
Email: Chul.Ahn@utsouthwestern.edu 
 
Funding Source:  
Department of Radiation Oncology 
 
 
Version 
Date 
Initial 
09/01/2015 
Amend 1 
12/02/2015 
Amend 2 
3/12/18 
Amend 3 
7/23/18 
Amend 4 
12/03/2019 
 
 
UT Southwestern Medical Center (UTSW) 
Moncrief radiation Oncology Center 
Attn: Clinical Research Office 
5801 Forest Park Rd 
Dallas, Texas 75390-9183 
 

 
STU052015-047, Rahimi, FormA-ResearchProtocol, Mod_20, 12-17-19 (1) 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Cancer Center. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
 
Template Updated: 12/2012; 9/2013 
 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
Amendment # 4 
 
STU 052015-047 
Intra-patient comparison of Active Breathing Coordinator-based  vs VisionRT-based deep 
inspiration breath-hold for left-chest wall irradiation, A Pilot Study for Breast Cancer 
 
 
 
Principal Investigator (PI) Name:_____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date:____________________ 
 

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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS............................................................................................................. 1 
STUDY SCHEMA ............................................................................................................................ 2 
STUDY SUMMARY ......................................................................................................................... 3 
1.0 
BACKGROUND AND RATIONALE ...................................................................................... 4 
1.1 
Disease Background........................................................................................................ 4 
2.0 
STUDY OBJECTIVES ........................................................................................................... 6 
2.1 
Primary Objectives ........................................................................................................... 6 
2.2 
Secondary Objectives ...................................................................................................... 7 
2.3 
Endpoints ......................................................................................................................... 7 
3.0 
PATIENT ELIGIBILITY .......................................................................................................... 7 
3.1 
Inclusion Criteria .............................................................................................................. 7 
3.2 
Exclusion Criteria ............................................................................................................. 8 
4.0 
TREATMENT PLAN .............................................................................................................. 8 
4.1 
Treatment Dosage and Administration ............................................................................ 8 
4.2 
Toxicities and Dosing Delays/Dose Modifications ........................................................... 9 
4.3 
Concomitant Medications/Treatments ........................................................................... 10 
4.4 
Other Modalities or Procedures ..................................................................................... 10 
4.5 
Duration of Therapy ....................................................................................................... 10 
4.6 
Duration of Follow Up .................................................................................................... 10 
4.7 
Removal of Patients from Protocol Therapy .................................................................. 10 
4.8 
Patient Replacement ..................................................................................................... 10 
5.0 
STUDY PROCEDURES ....................................................................................................... 10 
5.1 
Screening/Baseline Procedures .................................................................................... 10 
5.2 
Procedures During Treatment ....................................................................................... 11 

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5.3 
Follow-up Procedures .................................................................................................. 133 
5.4 
Time and Events Table ................................................................................................ 134 
5.5 
Removal of Subjects from Study ................................................................................. 144 
6.0 
ADVERSE EVENTS ........................................................................................................... 155 
6.1 
Adverse Event Monitoring ........................................................................................... 155 
6.2 
Steps to Determine If an Adverse Event Requires Expedited Reporting ...................... 17 
7.0 
STATISTICAL CONSIDERATIONS .................................................................................. 18 
7.1    STUDY DESIGN/STUDY ENDPOINTs ................................................................................ 18 
7.2 
Sample Size and Accrual .............................................................................................. 18 
7.3 
Data Analyses Plans...................................................................................................... 18 
8.0 
STUDY MANAGEMENT .................................................................................................... 19 
8.1 
Conflict of Interest .......................................................................................................... 19 
8.2 
Data Management and Monitoring/Auditing .................................................................. 19 
8.3 
Adherence to the Protocol ........................................................................................... 210 
8.4 
Amendments to the Protocol ....................................................................................... 221 
8.5 
Record Retention ......................................................................................................... 221 
8.6 
Obligations of Investigators ......................................................................................... 221 
9.0 
REFERENCES ................................................................................................................. 231 

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LIST OF ABBREVIATIONS (EXAMPLES) 
AE 
Adverse Event 
ABC                Active Breathing Coordinator 
ALC 
ASCO 
Absolute Lymphocyte Count 
American Society of Clinical Oncology 
BH 
Breath Hold 
BUN 
Blood Urea Nitrogen 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DOT 
Disease Oriented Team 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
IV (or iv) 
Intravenously 
MRI 
Magnetic Resonance Imaging 
MV 
Mega Voltage 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
pCR 
Pathologic Complete Response 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
p.o. 
peros/by mouth/orally 
PR 
Partial Response 
RCB 
Residual Cancer Burden 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SCCC 
Simmons Comprehensive Cancer Center 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
VRT                 Vision RT 
 
 
 

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STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT-sim with ABC 
breath-hold
Monitor VRT breath-hold
 
Signals recorded:
1. Vision RT
2. MV fluoro of Tx fields
Monitor ABC breath-hold
Signals recorded:
1. ABC
2. Vision RT
3. MV fluoro of Tx fields
Export CT surface
Store BH level
ABC
14 Fx
VRT
14 Fx
Setup with ABC
Verify/reposition with ports
Setup with VRT and CT 
surface
Verify/reposition with ports
Analysis
1. Calculate internal translational 
displacement using rigid registration on 
MV fluoro images (e.g., Velocity)
2. Calculate external displacement from 
VRT trace during breath-hold
3. Compute dosimetric impact of  
displacement wrt planned dose for 
organs at risk

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STUDY SUMMARY 
Title 
Intra-patient comparison of Active Breathing Coordinator-based  vs 
VisionRT-based deep inspiration breath-hold for left-chest wall irradiation 
Short Title 
Intra-patient study of ABC vs VisionRT DIBH for left-chest wall irradiation 
Protocol Number 
STU 052015-047  
Phase 
Pilot 
Methodology 
Female patients treated with radiation for left-sided breast malignancy 
will undergo alternate fractions of ABC-assisted and VisionRT-assisted 
DIBH. Residual motion during breath-hold will be quantitatively assessed 
using MV fluoroscopy from the treatment beam itself (i.e., no additional 
radiation dose). The dosimetric impact of residual motion on organs at 
risk (heart and lung) will be assessed by applying rigid and/or 
deformable displacements to the planning CT images, computing the 3D 
dose map and comparing with the original planned dose map.  
Study Duration 
One year 
Study Center(s) 
Single-center UTSW 
Objectives 
1. To quantify residual motion in ABC-assisted vs VRT-assisted 
DIBH 
2. To quantify the dosimetric impact of residual motion on the heart 
and lung. 
Number of Subjects 
10 
Diagnosis and Main 
Inclusion Criteria 
Women with left sided breast malignancy undergoing post-mastectomy 
radiation 
Study Product(s), Dose, 
Route, Regimen 
Left-sided chest wall irradiation; 1.8 Gy x 28 fractions. 
Duration of administration 
28 days 
Statistical Methodology 
As this is a pilot study, we will accrue 10 patients and use descriptive 
statistics. 
 
 
 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
 
Whole breast radiation after lumpectomy is the current standard of care for early stage 
breast cancer. Whole breast radiation is typically delivered with two-four tangential 
radiation beams in order to avoid en-face radiation to the lungs and heart (Fig. 1). 
 
 
 
Figure 1. Standard breast tangents for left-sided breast irradiation 
 
Despite this technique, for left sided breast cancers, the heart and ipsilateral lung still 
receive minimal doses of radiation. Some studies have alluded to long-term survival for 
breast cancer survivors being compromised by late cardiac toxicity such as coronary 
artery disease.1, 2 Darby et al, reported that cardiac risk increases linearly with mean 
heart dose by 7.4%/Gray without a threshold.1  
 
 
             Figure 2. Positions of the heart in the absence (a,c) and presence (b,d) of DIBH.  
 
STANDARD BREAST TANGENTS
Deep Inspiratory Breath Hold

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Deep inspiratory breath hold (DIBH) techniques have been developed to help minimize 
cardiac and lung dose. As a patient takes a deep breath, the lungs fill with air, causing 
the heart to be displaced posteriorly and inferiorly outside of the radiation tangential 
beams. This movement increases the distance between the heart and chest wall. With 
this distance in place, the radiation tangential beams can target the breast or chest wall 
with significantly less cardiac irradiation. Figure 2 demonstrates the position of the heart 
during free breathing in Figures 2a and c and how it is displaced out of the radiation 
portal in Figures 2b and d with a DIBH. 
 
There are several ways to assist in DIBH during radiation treatments. One of the more 
common ways is by using a commercially available system Active Breathing Coordinator 
(ABC; Elekta, Crawley, UK) device. The ABC system has a digital spirometer that records 
real time breathing. When the patient inspires to a preset DIBH level, a balloon valve is 
inflated so as to prevent the patient from breathing out and thereby maintain a consistent 
chest wall expansion with each DIBH. A nose clip prevents air leakage. The therapist 
monitors the respiratory cycle and DIBH on the screen during the radiation delivery. 
When the patient depresses a handheld thumb switch, treatment is stopped and valve 
opens so breathing can resume normally again. Dosimetric advantages of cardiac 
sparing using DIBH ABC technique have been shown.3, 4  
 
 
Active Breathing Control Device
-Digital spirometer- records real time breathing
-Balloon Valve inflated so patient cant breathe air out
-Nose clip prevents air leakage
-Handheld thumb switch
Figure 3. ABC-assisted deep inspiration breath-hold 
Figure 4. The AlignRT system with three ceiling-mounted imaging pods in the treatment 
room (left) and the therapist user interface (right) for real-time position monitoring. 

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A more recent,  competing technology for implementing the DIBH technique is real-time 
surface photogrammetry using the AlignRT system (Vision RT Ltd., London, UK), shown 
in Figure 4. The patient is CT simulated in the DIBH position. The 3D DIBH external 
surface rendering at the time of CT scan serves as a baseline. In the treatment room, a 
speckled optical pattern in the visible red range is projected on the patient’s thoraco-
abdominal surface by each of three ceiling-mounted imaging pods. Once the patient has 
matched the pre-determined DIBH position (with 2 mm accuracy), the radiation beam is 
enabled to be turned on for treatment. The optical pattern is imaged by optical cameras 
(two per pod) at ~25 Hz. The user selects a region-of-interest (ROI) on the surface and 
the software calculates and displays the real-time position in six degrees (3 translations 
and 3 rotations) in real-time (Figure 4 right panel). Since visible light is used for the 
position monitoring, there is no additional (non-therapeutic) ionizing radiation delivered to 
the patient.  
 
Several studies have pointed out potential drawbacks of the ABC system. E.g., even 
though the patient’s tidal volume remains consistent with ABC, different breathing 
maneuvers (abdominal versus thoracic breathing) can cause for variations in breath-
hold.5 They reported that for the same vital capacity, abdominal and thoracic breathing 
led to an average difference of chest wall expansion of 1.9 cm. Remouchamps et al. also 
showed that that overshoot can occur with ABC device where the patient can inhale a 
larger air volume than the pre-determined set limit.3, 6 More recently, Mittauer et al. 
showed through using an optical surface-tracking system to monitor ABC assisted DIBH, 
that large positional variations can occur in some patients due to their different breath 
hold techniques, causing increases in mean heart and coronary artery dose.7 
 
In contrast, the VisionRT system has several potential advantages. First, it monitors 
patient (surface) position which is a more relevant surrogate for internal motion than the 
tidal volume (e.g., the tidal volume can remain the same even if the patient shifts slightly 
on the couch). Thus VRT can monitor residual motion during the breath-hold. Second, 
from a clinical standpoint, the VRT system 
• 
requires no patient training during sim or Tx  
• 
takes approximately half the time for treatment 
• 
Is much more cost effective, as patient tubing needs to be replaced daily for ABC 
The one potential advantage of ABC over VRT is that the former system performs an 
assisted breath-hold (i.e., the patient is actively impeded from inhale/exhale) while the 
VRT system depends entirely on patient compliance.  
 
The purpose of this study is to perform an intra-patient comparison of ABC vs VisionRT 
for DIBH in left-sided chest wall radiotherapy. The primary goals are to record the 
presence and magnitude of residual motion during DIBH and determine the clinical 
impact of motion in terms of changes in heart and lung dose with respect to that 
calculated in the treatment plan.    
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
2.1.1 
To quantify residual motion during deep inspiratory breath-hold using ABC and 
Vision RT during left post-mastectomy chest wall radiotherapy 
 
2.1.2     To determine clinical and dosimetric impact of residual motion, on heart and lung 
dose 
 
 

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2.2 
Secondary Objectives 
 
2.2.1 
To compare time of simulation and daily treatment for DIBH with both ABC and 
Vision RT 
 
2.2.2 
To evaluate DIBH reproducibility of both ABC and vision RT DIBH 
 
2.3 
Endpoints 
To quantify residual motion during DIBH using ABC and VRT, MV fluoro images of 
treatment fields will be acquired during daily radiation fractions. These motions will be 
plotted out, to quantify amount of chest wall motion during daily treatments. The mean, 
and median value of motion obtained for VRT DIBH and ABC DIBH will then be 
translated to axial CT images using deformable registration in Velocity, and dosimetric 
impact of residual motion on critical organs such as the heart and lung will then be 
quantified.  
 
Minutes of daily radiation setup and treatment delivery will be recorded for all daily 
radiation fractions. Mean and median setup and treatment delivery times for ABC versus 
VRT will then be compared. 
 
The DIBH levels will be recorded daily (on both ABC and VRT days) using the VisionRT 
system and the inter-fraction reproducibility of the DIBH level will be calculated for ABC 
and VisionRT.   
 
3.0 
Subject ELIGIBILITY 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria 
to be registered to the study. Study treatment may not begin until a subject is registered. 
3.1 
Inclusion Criteria 
 
3.1.1 
Women with diagnosis of breast malignancy 
3.1.2 
Women whom requires left chest wall post-mastectomy radiation with or without 
bolus 
 
3.1.3 
Age ≥ 18 years. 
 
3.1.4 
Performance status ECOG </=3 
 
3.1.5 
Women of child-bearing potential must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry, and 
during radiation therapy. Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating physician 
immediately. 
 
3.1.5.1 A female of child-bearing potential is any woman (regardless of sexual 
orientation, having undergone a tubal ligation, or remaining celibate by 
choice) who meets the following criteria: 
 
• 
Has not undergone a hysterectomy or bilateral oophorectomy; or 
• 
Has not been naturally postmenopausal for at least 12 consecutive 
months (i.e., has had menses at any time in the preceding 12 
consecutive months). 

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3.1.6 
Ability to understand and the willingness to sign a written informed consent. 
3.1.7 
Patient must be able to maintain a 30 second breath hold. 
3.1.8 
Conventional chest wall radiation delivery dose of 50.4 Gy/ 28 fractions with or 
without a boost (boost will not be evaluated for endpoints) 
 
3.2 
Exclusion Criteria 
 
3.2.1 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
 
3.2.2 
Subjects must not be pregnant or nursing due to the potential for congenital 
abnormalities and the potential of this regimen to harm nursing infants. 
 
 
4.0 
TREATMENT PLAN 
4.1 
Treatment Dosage and Administration 
 
 
Simulation: Patients will be simulated on the breast board supine with arms abducted 
and externally rotated. A vac lok bag will be made to immobilize patient arms. Patients 
head will be turned to the right side to avoid facial irradiation. Wire markers will be placed 
mid-sternum, 2 cm inferior to the inframammary fold, mid-axillary line, and at the level of 
the clavicular head. A wire marker will be placed over the lumpectomy scar. Patient will 
then have a CT scan in the treatment position with normal free breathing. ABC machine 
will then be set up. Nasal clip will be placed on nose to prevent air leakage from nasal 
cavity. Digital spirometer tubing will be placed in patient’s mouth to record real time 
breathing on computer monitor. Patient given hand held thumb switch in order to control 
breathing. Care must be taken to ensure tubing is not over left chest, as same CT 
images will be used to acquire VRT surface rendering. Patient instructed to take in a 
deep breath, while maintaining scapula on table and not arching back. CT scan acquired 
with ABC assisted breath hold.  
 

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Active Breathing Control Device
-Digital spirometer- records real time breathing
-Balloon Valve inflated so patient cant breathe air out
-Nose clip prevents air leakage
-Handheld thumb switch
\ 
 
 
   
After CT simulation, both free breathing and ABC DIBH images transferred to 
pinnacle treatment planning software. Exported DICOM DIBH surface will then 
be used to acquire baseline VRT surface rendering.   
 
Free breathing and breath hold CT simulation images will be visually compared 
to assure there is an advantage to proceed with breath hold technique. 3-D 
Treatment planning on breath hold scan will proceed. Patients will then be 
treated daily with breath hold technique, using only the ABC device every other 
day. The VRT software will be used on a daily basis in conjunction with the ABC 
device, and solely on days when ABC is not used. Results will then be analyzed 
by interpreting the MV images and after determining amount of respiratory 
movement during ABC and VRT, retrospectively re-planning the breast plans. 
 
 
4.2 
Toxicities and Dosing Delays/Dose Modifications 
Any subject who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
table. Toxicity will be assessed according to the NCI Common Toxicity Criteria for 
Adverse Events (CTCAE), version 4.0. Dose adjustments should be made according to 
the system showing the greatest degree of toxicity.  
 
Expected toxicities are those that we would normally consent patients for breast radiation. 
As we are not modifying the dose or treatment volume from standard breast radiation we 
will not have dose modifications. 
Potential breast radiotherapy toxicities include: dermatitis, fatigue, hyperpigmentation, 
brachial plexopathy, radiation pneumonitis, shrinkage of the breast, coronary artery 
disease, pericarditis, rib damage or fracture. 

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4.3 
Duration of Therapy 
End of protocol therapy will be the last day of radiation. Other exceptions may apply: 
• 
Disease progression 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Subject  decides to withdraw from the study, OR 
• 
General or specific changes in the patient’s condition render the subject 
unacceptable for further treatment in the judgment of the investigator”. 
4.4 
Duration of Follow Up 
- 
No follow-up required for this study after radiation completed. F/up per standard of 
care for malignancy per treating radiation oncologist 
 
4.5 
Removal of Subjects from Protocol Therapy 
Subjects will be removed from therapy when any of the criteria listed in Section 5.5 apply. 
The PI will be notified and a Note to File will be written for Removal of Subjects from 
study, when taken off study treatment, withdrawn at their own request or at the discretion 
of the investigator (detailed reasons listed in Section 5.5). The subject should be 
followed-up per protocol.  
4.6 
Subject Replacement 
If a subject is withdrawn from the study prior to completing radiation therapy without 
experiencing a SAE prior to withdrawal, an additional subject may be added.  
 
5.0 
STUDY PROCEDURES 
5.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. 
 
All screening procedures must be performed within 60 days prior to registration unless 
otherwise stated. The screening procedures include: 
5.1.1 Informed Consent 
5.1.2 Medical history 
Complete medical and surgical history 
5.1.3 Demographics 
Age 
5.1.4 Review subject eligibility criteria 
5.1.5 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight 
5.1.6 Performance status 
Performance status evaluated prior to study entry. 

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5.1.7 Adverse event assessment 
See section 6 for Adverse Event monitoring and reporting. 
5.2 
Procedures During Treatment 
5.2.1 
Prior to Radiation Treatment Cycle 
• Physical exam, vital signs 
• Consent 
• Eligibility/ineligibility criteria 
5.2.2 
CT simulation 
• CT Simulation scan in free breathing  
• CT simulation scan with DIBH and ABC machine- must ensure tubing from 
ABC not over chest wall so skin rendering is able to be reproduced 
• Preparation of vac lock bag, coaching for breath hold should not be included 
in timing  
• Planning and contouring- 
• Structures that should be contoured are lumpectomy cavity, heart, left anterior 
descending artery, lungs, and ipsilateral breast tissue 
• Simulation and treatment may be performed with the patient in the supine 
position only 
• Patients should be optimally positioned with alpha cradle casts, breast boards, 
or wing boards and/ or other methods of immobilization at the discretion of the 
treating physician. 
• A treatment planning CT scan in the treatment position will be required to 
define the clinical target volumes (CTV) and planning target volumes (PTV 
• Radio-opaque markers should be placed on external landmarks at the 
acquisition of the CT scan to facilitate contouring segmentation of the CT 
data-set. These markers should identify: 1) The mastectomy incision 2) The 
outline of the palpable chest wall tissue circumferentially at least from 2 
o’clock to 10 o’clock 3) The superior border of the chest wall tissue at 12 
o’clock based on palpation. Additional markers to define the borders of 
“clinical” tangent fields (e.g. based on the palpable chest wall tissue and 
boney landmarks) are often helpful. 
• The CT should extend cephalad to start at or above the mandible and extend 
sufficiently caudally (or inferiorly) to the inframammary fold to encompass the 
entire lung volume. A CT scan image thickness of ≤ 0.5 cm should be 
employed. 
• External skin localizing marks, which may include permanent tattoos, are 
recommended for radiation daily localization and set-up accuracy. 
• CT simulation will likely be around 1 hour in length one time 
 
Treatment Planning/Target Volumes 
 
The definitions for the CTV, PTV and normal structures used in this protocol 
generally conform to the RTOG-endorsed consensus guidelines for delineation of 
target and normal structures for breast cancer 
(http://www.rtog.org/CoreLab/ContouringAtlases/BreastCancerAtlas.aspx) 
and the 1993 ICRU report #50: Prescribing, Recording and Reporting Photon 
Beam Therapy. 
The plans generated using forward-planning methods or segmental techniques 
such as “field-in-field” to meet dose-volume constraints are considered as 
3DCRT 
plans. These forward-planned or segmental treatment techniques are those 

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intended to mainly improve the uniformity of the dose distribution, but not to 
produce steep dose gradients to protect critical structures (e.g., heart or lung). 
3D-CRT should be used for planning.  
 
Chestwall CTV: Includes the Mastectomy Scar CTV, and takes into account the 
radiopaque markers placed at CT identifying clinical extent of chestwall, surgical 
changes visualized by CT, and consensus definitions of anatomical borders of 
chestwall from the RTOG Breast Cancer Atlas 
http://www.rtog.org/CoreLab/ContouringAtlases/BreastCancerAtlas.aspx.  
The Chestwall CTV is limited by the skin anteriorly and should not extend deeper 
than the ribs so that it excludes the lung and heart. Depending on the location of 
the Mastectomy Scar CTV, it should exclude the sternum medially and the axilla 
deep to anterior surface of the pectoralis major muscle laterally. In general, the 
chestwall CTV should not cross midline.  
Expanders, implants or autologous tissue present for reconstruction will be 
included in the Chestwall CTV. The degree of expander expansion present is per 
the treating physician’s discretion. The expander should remain at the same 
expansion through the course of treatment that is present for the CT simulation.  
 
Chestwall PTV: Chestwall CTV + 7 mm 3D expansion (excludes heart and does 
not cross midline).  
 
Chestwall PTV Eval: As a part of the Chestwall PTV often extends outside the 
patient, the Chestwall PTV is then copied to a Chestwall PTV Eval which is 
edited. This Chestwall PTV Eval is limited anteriorly to exclude the part outside 
the patient and the first 3 mm of tissue under the skin (in order to remove some 
of the buildup region for the DVH analysis) and posteriorly is limited to no deeper 
than the posterior rib surface and excludes lung and heart. In general, the 
Chestwall CTV should not cross midline. This Chestwall PTV Eval is the structure 
used for DVH constraints and analysis and not for beam aperture generation. 
 
Ipsilateral lung. This may be contoured with auto-segmentation with manual 
verification. 
 
Contralateral lung. This may be contoured with auto-segmentation with manual 
verification 
 
Heart: This is to be contoured on all cases- not just the left sided cases. The 
heart should be contoured beginning just inferior to the level in which the 
pulmonary trunk branches into the left and right pulmonary arteries (PA). Above 
the PA, none of the heart’s 4 chambers are present. The heart should be 
contoured on every contiguous slice thereafter to its inferior 
most extent near the diaphragm. The following structures if identifiable should be 
excluded from the heart contour: esophagus, great vessels (ascending and 
descending aorta, inferior vena cava). One need not include pericardial fat, if 
present. Contouring along the pericardium itself, when visible, is appropriate. 
Left Anterior Descending Artery: The left anterior descending artery (LAD), 
including the small segment of left coronary artery before bifurcation, was 
contoured, with a 3-mm diameter, from its origin, continued between the left 
ventricle and right ventricle in the interventricular groove, and to the inferior 
border of 
the heart. 
 
Thyroid: The thyroid is easily visible on a non-contrast CT due to its preferential 
absorption of Iodine, rendering it “brighter” or denser than the surrounding neck 
soft tissues. The left and right lobes of the thyroid are somewhat triangular in 

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shape and often do not converge anteriorly at mid-line. All “bright” thyroid tissue 
should be contoured. 
 
Treatment Planning: Treatment Planning CT-based planning with tissue 
inhomogeneity correction is required. 
 The following critical organs dosimetric parameters will be recorded for 
dosimetric comparison: 
 
 
 
 
- Suggested Dose Parameters- at Discretion of treating Radiation Oncologist 
-≥ 95% of the Chestwall PTV Eval will receive ≥ 95% (47.5 Gy) of the chestwall 
dose of 50 Gy  
-</=  5% of the whole heart should receive ≥ 25 Gy for left-sided breast cancers 
-V20 total lung <30%  
 
 
                        5.2.3 Daily Treatment                                                                                                                  
-  First 14 fractions to be set up with ABC for DIBH or Vision RT (patient will be 
randomized as to which starts first) 
-   Last 14 fractions to be set up with Vision RT for DIBH or ABC (patient will be 
randomized as to which starts second) 
-   Each daily fraction should be timed and recorded from moment patient lays on 
treatment table to last radiation beam treated (treatments will be timed and 
recorded per institutional standard). 
-days when portals taken will be recorded to account for longer set up times 
-Weekly Port films will be taken with both ABC and vision RT (this should 
increase time on treatment table by roughly 10 minutes, once weekly and is 
considered standard of care) 
- ABC DIBH and VRT DIBH signals of chest wall motion will both be recorded 
during radiation treatment using Mega Voltage (MV) fluoroscopy (this should not 
increase treatment time as MV radiation fluoroscopy being used is from actual 
radiation treatment) 
-  
 
5.2.4  Post-Radiation Analysis                                                                                                                      
-calculate internal translational displacement using rigid registration on MV   
fluoro images (ie; Velocity) 
-calculate external displacement from VRT trace during DIBH 
-after displacement recorded, dosimetric plans will be rerun taking into account 
displacement (deformable registration), and to determine impact of mean 
displacement on critical organs such as lung and heart 
-Determine the variance of DIBH with ABC and VRT to determine reproducibility 
-Compare mean, median and range for average time of daily radiation set up and 
delivery for ABC and VR  
 
5.3 
Follow-up Procedures 
- 
No follow-up required for this study after radiation completed. F/up per standard of 
care for malignancy per treating radiation oncologist 
 
 
5.4 
Time and Events Table [When appropriate, this may be referenced and included in 
the appendices rather than within the body of the protocol. Consider landscape 
format when necessary to include all of the appropriate procedures and tests.] 
 

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Pre-study 
Daily 
during 
radiation 
Weekly 
during 
radiation 
Assessment 
 
 
 
Informed Consent 
X 
 
 
History and PE 
X 
 
 
Performance 
Status 
X 
 
 
 
 
 
 
Port films 
 
 
X 
Timing 
daily 
radiation set up 
and delivery 
 
X 
 
MV 
flouro 
of 
treatment fields 
 
X 
 
 
 
5.5 
Removal of Subjects from Study 
Subjects can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation will be 
documented and may include: 
5.5.1 
Subject voluntarily withdraws from treatment (follow-up permitted); 
5.5.2 
Subject withdraws consent (termination of treatment and follow-up); 
5.5.3 
Subject is unable to comply with protocol requirements; 
5.5.4 
Subject  demonstrates disease progression (unless continued treatment with 
study drug is deemed appropriate at the discretion of the investigator); 
5.5.5 
Subject experiences toxicity that makes continuation in the protocol unsafe; 
5.5.6 
Treating physician judges continuation on the study would not be in the subject’s 
best interest; 
5.5.7 
Subject becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
5.5.8 
Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study; 
5.5.9 
Lost to follow-up.  
 
 
 
 
5.6 Randomization 
In order to minimize technology-specific bias in this pilot study, ten patients will be 
randomly assigned to two groups of five patients each. The probability of being assigned 
to each group is 0.5. Randomization log will be created. Five patients in group 1 will be 
administered 14 fractions with ABC-assisted DIBH, followed by 14 fractions with VRT-

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assisted DIBH. Five patients in group 2 will be administered 14 fractions with VRT-
assisted DIBH, followed by 14 fractions with ABC-assisted DIBH. 
 
6.0 
ADVERSE EVENTS 
6.1        Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies. Adverse events are reported in a routine manner at 
scheduled times during a trial. Additionally, certain adverse events must be reported in an 
expedited manner to allow for optimal monitoring of subject safety and care.  
 
All subjects experiencing an adverse event, regardless of its relationship to study 
therapy, will be monitored until:  
➢ the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline or is stable in the opinion of the investigator;  
➢ there is a satisfactory explanation other than the study therapy for the changes 
observed; or 
➢ death. 
6.1.1 
Definition  
An adverse event is defined as any untoward or unfavorable medical occurrence in a 
human research study participant, including any abnormal sign (for example, abnormal 
physical exam, imaging finding or clinically significant laboratory finding), symptom, 
clinical event, or disease, temporarily associated with the subject’s participation in the 
research, whether or not it is considered related to the subject’s participation in the 
research. 
Adverse events encompass clinical, physical and psychological harms. Adverse events 
occur most commonly in the context of biomedical research, although on occasion, they 
can occur in the context of social and behavioral research. Adverse events may be 
expected or unexpected. 
Acute Adverse Events  
Adverse events occurring in the time period from the signing of the informed consent, 
through treatment, until the last day, will be considered acute adverse events. 
Severity  
Adverse events will be graded by a numerical score according to the defined NCI 
Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. Adverse 
events not specifically defined in the NCI CTCAE will be scored on the Adverse Event log 
according to the general guidelines provided by the NCI CTCAE and as outlined below.   
• 
Grade 1: Mild  
• 
Grade 2: Moderate 
• 
Grade 3: Severe or medically significant but not immediately life threatening 
• 
Grade 4: Life threatening consequences 
• 
Grade 5: Death related to the adverse event 
 

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Serious Adverse Events  
ICH Guideline E2A and the UTSW IRB define serious adverse events as those events, 
occurring at any dose, which meets any of the following criteria:  
• 
Results in death   
• 
Immediately life-threatening  
• 
Results in inpatient hospitalization1,2 or prolongation of existing hospitalization  
• 
Results in persistent or significant disability/incapacity  
• 
Results in a congenital anomaly/birth defect  
• 
Based upon appropriate medical judgment, may jeopardize the subject’s health 
and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition. 
Note: A “Serious adverse event” is by definition an event that meets any of the above 
criteria. Serious adverse events may or may not be related to the research project. A 
serious adverse event determination does not require the event to be related to the 
research. That is, both events completely unrelated to the condition under study and 
events that are expected in the context of the condition under study may be serious 
adverse events, independent of relatedness to the study itself. As examples, a car 
accident requiring >24 hour inpatient admission to the hospital would be a serious 
adverse event for any research participant; likewise, in a study investigating end-stage 
cancer care, any hospitalization or death which occurs during the protocol-specified 
period of monitoring for adverse and serious adverse events would be a serious adverse 
event, even if the event observed is a primary clinical endpoint of the study. 
1Pre-planned hospitalizations or elective surgeries are not considered SAEs. Note: If 
events occur during a pre-planned hospitalization or surgery, that prolong the existing 
hospitalization, those events should be evaluated and/or reported as SAEs.   
2 NCI defines hospitalization for expedited AE reporting purposes as an inpatient hospital 
stay equal to or greater than 24 hours. Hospitalization is used as an indicator of the 
seriousness of the adverse event and should only be used for situations where the AE 
truly fits this definition and NOT for hospitalizations associated with less serious events. 
For example: a hospital visit where a patient is admitted for observation or minor 
treatment (e.g. hydration) and released in less than 24 hours. Furthermore, 
hospitalization for pharmacokinetic sampling is not an AE and therefore is not to be 
reported either as a routine AE or in an expedited report.  
 
 
 
 
6.1.2 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs): 
The phrase “unanticipated problems involving risks to subjects or others” is found, but not 
defined in the HHS regulations at 45 CFR 46, and the FDA regulations at 21 CFR 
56.108(b)(1) and 21 CFR 312.66. For device studies, part 812 uses the term 
unanticipated adverse device effect, which is defined in 21 CFR 812.3(s). Guidance from 
the regulatory agencies considers unanticipated problems to include any incident, 
experience, or outcome that meets ALL three (3) of the following criteria: 
• 
Unexpected in terms of nature, severity or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied;  

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AND 
• 
Related or possibly related to participation in the research (possibly related means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); 
 
AND  
• 
Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. Note: According to OHRP, if the adverse event is serious, it would always 
suggest a greater risk of harm. 
 
Follow-up  
All adverse events will be followed up according to good medical practices.  
 
6.2 
Steps to Determine If a Serious Adverse Event Requires Expedited Reporting to the 
SCCC DSMC and/or HRPP 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v5).  
 
Step 2: Grade the adverse event using the NCI CTCAE v5. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE may NOT be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur to the end of the acute adverse events reporting 
period as defined in section 6.1. 
 
Step 4: Determine the prior experience of the adverse event. Expected events are those 
that have been previously identified as resulting from administration of the treatment. An 
adverse event is considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in: 
• 
the current known adverse events listed in the Agent Information Section of this 
protocol (if applicable); 
• 
the drug package insert (if applicable); 
• 
the current Investigator’s Brochure (if applicable) 
• 
the Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities 
section of this protocol 
 
6.2.1 
Reporting SAEs and UPIRSOs to the Simmons Comprehensive Cancer Center 
(SCCC) Data Safety Monitoring Committee (DSMC) 
 
All SAE/UPIRSOs at all sites, which occur in research subjects on protocols for which the 
SCCC is the DSMC of record require reporting to the DSMC regardless of whether IRB 
reporting is required. All SAEs/UPIRSOs occurring during the protocol-specified 
monitoring period should be submitted to the SCCC DSMC within 5 business days of the 
PI or delegated study team members awareness of the event(s). In addition, for 
participating centers other than UTSW, local IRB guidance should be followed for local 
reporting of serious adverse events. 

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The UTSW study team is responsible for submitting SAEs/UPIRSOs to the SCCC DSMC 
Coordinator.  Hardcopies or electronic versions of the eIRB Reportable Event report; FDA 
Form #3500A forms, or other sponsor forms, if applicable; and/or any other supporting 
documentation available should be submitted to the DSMC Coordinator.  The DSMC 
Coordinator forwards the information onto the DSMC Chairman who determines if 
immediate action is required.  Follow-up eIRB reports, and all subsequent SAE/UPIRSO 
documentation that is available are also submitted to the DSMC Chair who determines if 
further action is required. (See Appendix III of the SCCC DSMC Plan for a template Serious 
Adverse Event Form which may be utilized when a sponsor form is unavailable and SAE 
submission to the eIRB is not required). 
  
 
If the event occurs on a multi-institutional clinical trial coordinated by the UTSW Simmons 
Comprehensive Cancer Center, the DOT Manager or lead coordinator ensures that all 
participating sites are notified of the event and resulting action, according to FDA 
guidance for expedited reporting. DSMC Chairperson reviews all SAEs/UPIRSOs upon 
receipt from the DSMC Coordinator.  The DSMC Chairperson determines whether action 
is required and either takes action immediately, convenes a special DSMC session 
(physical or electronic), or defers the action until a regularly scheduled DSMC meeting.  
 
 
 
Written reports to: 
Sarmistha Sen 
2280 Inwood Rd 
Dallas, TX 75390 
 
UTSW SCCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-5949 or deliver to BLB.306 
 
UTSW Institutional Review Board (IRB) 
Submit a Reportable Event via eIRB with a copy of the final sponsor report as attached 
supporting documentation 
 
Reporting Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRSOs) to the UTSW HRPP/IRB 
 
UTSW reportable event guidance applies to all research conducted by or on behalf of UT 
Southwestern, its affiliates, and investigators, sites, or institutions relying on the UT 
Southwestern IRB. Additional reporting requirements apply for research relying on a non-
UT Southwestern IRB. 
 
According to UTSW HRPP/IRB policy, UPIRSOs are incidents, experiences, outcomes, 
etc. that meet ALL three (3) of the following criteria: 
1. Unexpected in nature, frequency, or severity (i.e., generally not expected in a 
subject’s underlying condition or not expected as a risk of the study; therefore, not 
included in the investigator’s brochure, protocol, or informed consent document),AND 
2. Probably or definitely related to participation in the research, AND 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized.  Note: According to OHRP, if the adverse event is serious, it 
would always suggest a greater risk of harm. 
 
For purposes of this policy, UPIRSOs include unanticipated adverse device effects 
 

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(UADEs) and death or serious injury related to a humanitarian use device (HUD).  
 
UPIRSOs must be promptly reported to the UTSW IRB within 5 working days of 
PI awareness. 
 
For research relying on a non-UT Southwestern IRB (external, central, or single IRB): 
 
Investigators relying on an external IRB who are conducting research on behalf of UT 
Southwestern or its affiliates are responsible for submitting LOCAL UPIRSOs to the UT 
Southwestern IRB within 5 working days of PI awareness. Investigators must report to 
their relying IRB according to the relying IRB’s policy. In addition, the external IRB’s 
responses or determinations on these local events must be submitted to the UT 
Southwestern IRB within 10 working days of receipt. 
 
Events NOT meeting UPIRSO criteria: 
 
Events that do NOT meet UPIRSO criteria should be tracked, evaluated, summarized, 
and submitted to the UTSW HRPP/IRB at continuing review. 
 
For more information on UTSW HRPP/IRB reportable event policy, see 
https://www.utsouthwestern.edu/research/research-administration/irb/assets/policies-
combined.pdf. 
• 
 
7.0 
STATISTICAL CONSIDERATIONS 
Statistical aspects of this study will be developed in consultation with Dr. Chul Ahn from the 
Department of Clinical Sciences. As this is a pilot study, we will accrue 10 patients and use 
descriptive statistics to characterize the extent of motion during DIBH and its dosimetric impact in 
terms of increased dose to the heart and lung. The findings from these studies will be used to 
inform the sample size for a future larger scale (Phase II) study.  
7.1  Study Design/Study Endpoints 
A single-center prospective pilot study will be conducted according to the schema 
outlined at the beginning of this document. Informed consent will be obtained from ten 
post-mastectomy, left-sided breast cancer patients, each to be treated with 50.4 Gy/ 28 
fx. In order to minimize technology-specific bias, the patients will be divided into two 
groups of five each. Group 1 will be administered 14 fractions with ABC-assisted DIBH, 
followed by 14 fractions with VRT-assisted DIBH. Group 2 will be administered 14 
fractions with VRT-assisted DIBH, followed by 14 fractions with ABC-assisted DIBH. 
(Both ABC and VRT are FDA-approved for clinical use and are used in our clinic as 
standard-of-care.) 
 
In each case, the residual motion during DIBH-assisted dose delivery will be recorded via 
MV fluoroscopy of the exiting beam using an electronic portal imaging device (EPID). 
Note that this procedure does not involve the administration of any additional non-
therapeutic ionizing radiation to the patient (other than the prescribed dose).  
 
7.2  Sample Size and Accrual 
As this is a pilot study, we will accrue 10 patients and use descriptive statistics to 
characterize the extent of motion during DIBH and its dosimetric impact in terms of 
increased dose to the heart and lung. The findings from these studies will be used to 
inform the sample size for a future larger scale (Phase II) study.  

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7.3   Data Analyses Plans 
Individual frames from each MV fluoroscopic series will be imported into Velocity (a 
clinically available medical image processing software) and a rigid registration will be 
performed between successive frames in order to quantify the residual motion during a 
DIBH. The mean, and median value of motion obtained for VRT DIBH and ABC DIBH will 
then be used to translate axial CT images in Velocity and the originally planned beam 
arrangement will be used to recalculate the treatment plan and compute the dose to the 
displaced anatomy. In this manner, the dosimetric impact of residual motion on critical 
organs such as the heart and lung will be quantified.  
8.0 
STUDY MANAGEMENT 
8.1 
Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed by the UTSW COI Committee and IRB according to UTSW Policy 
on Conflicts of Interest.  All investigators will follow the University conflict of interest 
policy. 
8.2 
Data Management and Monitoring/Auditing 
 
REDCap is the UTSW SCCC institutional choice for the electronic data capture of case 
report forms for SCCC Investigator Initiated Trials. REDCap will be used for electronic 
case report forms in accordance with Simmons Comprehensive Cancer Center 
requirements, as appropriate for the project 
 
Trial monitoring will be conducted no less than annually and refers to a regular interval 
review of trial related activity and documentation performed by the DOT and/or the CRO 
Multi-Center IIT Monitor. This review includes but is not limited to accuracy of case report 
forms, protocol compliance, timeless and accuracy of Velos entries and AE/SAE 
management and reporting. Documentation of trial monitoring will be maintained along 
with other protocol related documents and will be reviewed during internal audit.   
 
For further information, refer to the UTSW SCCC IIT Management Manual. 
 
Toxicity and dose escalation reviews will be annually. The reviews will be documented by 
written report saved in the study folder. 
 
The UTSW Simmons Comprehensive Cancer Center (SCCC) Data Safety Monitoring 
Committee (DSMC) is responsible for monitoring data quality and patient safety for all 
UTSW SCCC clinical trials.  As part of that responsibility, the DSMC reviews all local 
serious adverse events and UPIRSOs in real time as they are reported and reviews 
adverse events on a quarterly basis.  The quality assurance activity for the Clinical 
Research Office provides for periodic auditing of clinical research documents to ensure 
data integrity and regulatory compliance.  A copy of the DSMC plan is available upon 
request. 
 
The SCCC DSMC meets quarterly and conducts annual comprehensive reviews of 
ongoing clinical trials, for which it serves as the DSMC of record. The QAC works as part 
of the DSMC to conduct regular audits based on the level of risk. Audit findings are 
reviewed at the next available DSMC meeting.  In this way, frequency of DSMC 
monitoring is dependent upon the level of risk.  Risk level is determined by the DSMC 
Chairman and a number of factors such as the phase of the study; the type of 
investigational agent, device or intervention being studied; and monitoring required to 

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ensure the safety of study subjects based on the associated risks of the study. Protocol-
specific DSMC plans must be consistent with these principles. 
 
 
 
8.3 
Adherence to the Protocol 
Except for an emergency situation, in which proper care for the protection, safety, and 
well-being of the study subject requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.  
8.3.1 
Exceptions (also called single-subject exceptions or single-subject waivers): 
include any departure from IRB-approved research that is not due to an 
emergency and is: 
• intentional on part of the investigator; or 
• in the investigator’s control; or 
• not intended as a systemic change (e.g., single-subject exceptions to eligibility 
[inclusion/exclusion] criteria) 
➢ Reporting requirement: Exceptions are non-emergency deviations that require prospective 
IRB approval before being implemented. Call the IRB if your request is 
urgent. If IRB approval is not obtained beforehand, this constitutes a major 
deviation. 
8.3.2 
Emergency Deviations: include any departure from IRB-approved research that 
is necessary to:  
• avoid immediate apparent harm, or 
• protect the life or physical well-being of subjects or others 
➢ Reporting requirement: Emergency deviations must be promptly reported 
to the IRB within 5 working days of occurrence. 
 
8.3.3 
Major Deviations (also called violations): include any departure from IRB-
approved research that: 
• 
Harmed or placed subject(s) or others at risk of harm (i.e., did or has the 
potential to negatively affect the safety, rights, or welfare of subjects or 
others), or 
• 
Affect data quality (e.g., the completeness, accuracy, reliability, or validity of 
the data) or the science of the research (e.g., the primary outcome/endpoint of 
the study) 
➢ Reporting requirement: Major deviations must be promptly reported to  
the IRB within 5 working days of PI awareness. 
 
8.3.4 
Minor Deviations: include any departure from IRB-approved research that: 
• 
Did not harm or place subject(s) or others at risk of harm (i.e., did not or did 
not have the potential to negatively affect the safety, rights, or welfare of 
subjects or others), or 
• 
Did not affect data quality (e.g., the completeness, accuracy, reliability, or 
validity of the data) or the science of the research (e.g., the primary 
outcome/endpoint of the study) 
➢ Reporting requirement: Minor deviations should be tracked and summarized 
in the progress report at the next IRB continuing review.  
 

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8.4 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator.  A summary of changes document outlining 
proposed changes as well as rationale for changes, when appropriate, is highly 
recommended.  When an amendment to the protocol substantially alters the study design 
or the potential risk to the patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
8.5 
Record Retention 
Study documentation includesdata correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, Note to Files when a 
patient is removed from the study,  and regulatory documents (e.g., protocol and 
amendments, IRB correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator retain 
all study documentation pertaining to the conduct of a clinical trial. In the case of a study 
with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
8.6 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected. . Periodically, monitoring visits may  be conducted and 
the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data.  
 
 

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9.0 
REFERENCES 
 
1 
S.C. Darby, M. Ewertz, P. McGale, A.M. Bennet, U. Blom-Goldman, D. Bronnum, C. Correa, D. 
Cutter, G. Gagliardi, B. Gigante, M.B. Jensen, A. Nisbet, R. Peto, K. Rahimi, C. Taylor, P. Hall, 
"Risk of ischemic heart disease in women after radiotherapy for breast cancer," The New England 
journal of medicine 368, 987-998 (2013). 
2 
G. Gagliardi, L.S. Constine, V. Moiseenko, C. Correa, L.J. Pierce, A.M. Allen, L.B. Marks, 
"Radiation dose-volume effects in the heart," International journal of radiation oncology, biology, 
physics 76, S77-85 (2010). 
3 
V.M. Remouchamps, N. Letts, D. Yan, F.A. Vicini, M. Moreau, J.A. Zielinski, J. Liang, L.L. Kestin, 
A.A. Martinez, J.W. Wong, "Three-dimensional evaluation of intra- and interfraction 
immobilization of lung and chest wall using active breathing control: a reproducibility study with 
breast cancer patients," International journal of radiation oncology, biology, physics 57, 968-978 
(2003). 
4 
K.E. Sixel, M.C. Aznar, Y.C. Ung, "Deep inspiration breath hold to reduce irradiated heart volume 
in breast cancer patients," International journal of radiation oncology, biology, physics 49, 199-
204 (2001). 
5 
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