Pilot Study For Prone Breath Hold Technique to Decrease Cardiac and Pulmonary Doses in Women Receiving Left Breast Radiotherapy
Phase: NA
Conditions: Breast Cancer
Sponsor: University of Arizona

 
 
Official Title: 
Pilot study for Prone Breath Hold Technique to Decrease 
Cardiac and Pulmonary Doses in Women Receiving Left 
Breast Radiotherapy 
NCT number: 
NCT02379988 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
Protocol version 08/17/2015 – IRB approved 08/25/2015 
 
 

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Protocol version 4 8/17/2015 
 
 
 
 
 
Pilot Study For Prone Breath Hold Technique to Decrease Cardiac and 
Pulmonary Doses in Women Receiving Left Breast Radiotherapy 
 
 
Principal Investigator: 
 
 
Victor Gonzalez 
Assistant Professor  
Radiation Oncology 
University of Arizona  
Tucson, AZ  85724 
(520) 626-6724 
 
Study Site 
 
 
 
 
The University of Arizona  
Radiation Oncology 
 
 
 
 
1501 North Campbell Avenue 
 
 
 
 
 
 
Tucson, AZ 85724  
 
 
 
 
 
Co Investigators:  
 
 
Uma Goyal, MD 
 
 
 
 
 
 
Radiation Oncology Resident 
 
 
 
 
 
 
University of Arizona College of Medicine 
 
 
 
 
 
 
Tucson, Arizona  85724 
 
 
 
 
 
 
 
Denise Roe, PhD 
 
 
 
 
 
 
Arizona Cancer Center 
 
 
 
 
 
 
 
 
Tucson, Arizona 85719 
 
 
Protocol Version and Date 
 
 
 
 
 
 
 
Version 4, 8/17/2015 
 
 
 
 
 
 
 
 

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Protocol version 4 8/17/2015 
 
 
 
 
 
 
Investigator Agreement  Version 4  8/17/2015 
 
I have read, understand and will adhere to the protocol as written, that any changes to 
the protocol will be approved by the sponsor or sponsor-investigator and the IRB, 
except changes to eliminate an immediate hazard to study subjects.  
 
I agree to conduct this study in accordance with the current International Conference on 
Harmonization (ICH) guidance, the Good Clinical Practice (GCP) guidance, the 
Declaration of Helsinki, FDA regulations, local IRB and legal requirements.  
 
 
 
 
 
 
__________________________   
 
 
_______________________ 
Signature 
 
 
 
 
 
 
Date (MM/DD/YY) 
 
 
 
 
Victor Gonzalez, MD 
Name of Principal Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol version 4 8/17/2015 
 
 
 
Table of Contents 
 
Section 1:   INTRODUCTION 
Section 2:   STUDY DESIGN 
Section 3:   OBJECTIVES 
Section 4:   BACKGROUND and RATIONALE 
Section 5:   INVESTIGATIONAL PRODUCT 
Section 6:   SUBJECT ELIGIBILITY 
Section 7:   STUDY PLAN 
Section 8:   REQUIREMENTS FOR TREATMENT 
Section 9:   STUDY PROCEDURES 
Section 10: PHARMACOKINETIC STUDIES 
 
Section 11: DATA AND SAFETY MONITOIRING PLAN  
Section 12: ADDITIONAL SAFETY REPORTING 
Section 13: QUALITY ASSURANCE MEASURES 
Section 14: RECIST CRITERIA 
Section 15: REMOVAL OF SUBJECTS 
 
Section 16: STATISTICAL CONSIDERATIONS 
Section 17: ANALYSIS 
Section 18: REGULATORY OBLIGATIONS 
Section 19: ADMINISTRATIVE PROCEDURES 
Section 20: SUBJECT CONFIDENTIALITY 
Section 21: STUDY DOCUMENTATION AND ARCHIVE 
Section 22: DATA 
Section 23: PROTOCOL DEVIATIONS 
Section 24: KARNOFSKY PERFORMANCE STATUS 
Section 25: COMMON TOXICITY CRITERIA 
Section 26: STUDY SCHEDULE 
Section 27: GLOSSARY 
Section 28: DEFINTIONS 
Section 29: REFERENCES 
Section 30: APPENDIX 
 
 
 

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1.   
INTRODUCTION  
 
1.1 
Phase:  
This is a pilot study to determine whether the addition of inspiratory hold (breath 
holding) can decrease the radiation dose that the heart receives for patients 
being treated for left sided breast cancer. 
 
1.2 
Indication:   
Utilizing prone radiation therapy along with inspiratory hold to reduce the 
radiation dose to the heart and lungs. 
 
1.3 
Endpoints: 
 
Primary 
The primary endpoint is the feasibility of the breath-hold technique for women 
treated with radiation for left-sided breast cancer in the prone position.  
 
Secondary 
The secondary endpoint is to evaluate the changes in mean dose to the heart 
and lungs with prone breath hold. Other secondary endpoints include heart 
volume receiving 20 Gy, maximum dose to left ventricle/LAD artery and relative 
volumes of lung receiving 20 Gy. 
 
 
1.4 
Patient population: 
Eligible subjects must be able to understand and sign the study specific subject 
consent form.  They must be patients of Dr. Gonzalez and >18 years of age. 
Eligible subjects must also have node-negative left breast cancer, invasive or 
DCIS breast cancer and have had a prior lumpectomy and deemed appropriate 
for treatment in the prone position by the treating physician.  They must be able 
to tolerate breath-hold in the prone position. 
 
 
2.    STUDY DESIGN 
 
2.1 
Phase:  This is a Pilot Study 
 
2.2 
Number of centers: One  
This study will be performed by The University of Arizona Medical Center 
(UAMC) Radiation Oncology Department at both the University Campus Hospital 
and Orange Grove Clinic. 
 
2.3 
Number of subjects: Approximately 15 
 
2.4 
Subject participation time period:    
Subjects will be enrolled in the study for 15 months, including screening time, 
treatment time, and follow-up at one year post radiation therapy.  
 
Subjects enrolled in this study are undergoing treatment at UAMC Main Campus 
or Orange Grove Clinic as part of standard of care for the treatment of breast 

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cancer.  Typical Radiation treatment schedule is between four and six weeks in 
length with treatments administered Monday through Friday.   
 
 
SCHEMA  
    See Section 9.3 
 
3.   
OBJECTIVES  
 
3.1 
Primary: 
 
The primary endpoint is the feasibility of the breath-hold technique for women 
treated with radiation for left-sided breast cancer in the prone position.  
 
3.2 
Secondary: 
To determine whether cardiac dose and lung dose can be reduced in women 
receiving prone breast radiotherapy when inspiratory gating is added. To 
evaluate the changes in mean dose to the heart and lungs with prone breath 
hold. Other secondary endpoints include heart volume receiving 20 Gy, 
maximum dose to left ventricle/LAD artery and relative volumes of lung receiving 
20 Gy. 
  
4. BACKGROUND and RATIONALE 
 
4.1 
Disease 
4.2 
There are currently estimated to be more than 2.8 million breast cancer survivors 
alive in the United States. Among these women, approximately 50% have 
received radiotherapy as part of their primary treatment. Adjuvant radiotherapy 
following lumpectomy improves both local control as well as overall survival. As 
such, whole breast radiotherapy following lumpectomy is the standard of care for 
women under 70. With advances in treatment, cure rates for early stage breast 
cancer now frequently exceed 95%. For these reasons, interventions aimed at 
reducing the long-term risks of radiotherapy are critical in this population as more 
survivors are living longer. 
 
Late cardiac toxicity from breast radiotherapy is well documented. Early 
randomized studies from the 1970s and 80s comparing lumpectomy alone to 
lumpectomy plus radiotherapy demonstrated improved cause specific survival 
with the addition of radiotherapy. However, this cancer-specific survival benefit 
was negated by an increased risk of cardiac mortality 10-20 years following 
radiotherapy (Clarke et al 2005).  While technical improvements in radiotherapy 
have dramatically reduced the risk of cardiac injury, recent studies have 
continued to demonstrate a small but significant increased risk of cardiovascular 
events following breast radiotherapy. Darby et al recently demonstrated that the 
risk of cardiac events following radiotherapy is directly proportional to the mean 
heart dose (Darby et al 2013). Thus, methods for reducing cardiac dose will be 
anticipated to reduce the long term risk of cardiac disease. 
 
The two methods most frequently used to reduce cardiac dose during breast 
radiotherapy are prone positioning on a breast-board and inspiratory gated breath-

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hold treatment. Lymberis et al prospectively studied 100 patients with CT 
simulation scans for RT planning in the prone and supine setups. It was found that 
prone position decreased the volume of lung within the radiation field in all patients 
and for left sided breast cancers 87% of patients had a decrease in irradiated 
volume of the heart. Formenti et al published their abstract of 200 patients with 
left-sided breast cancer who underwent radiotherapy treatment planning in both 
the prone and supine position. Radiation treatment plans for each position were 
compared specifically looking at doses to heart and lung volumes. Their results 
showed that prone positioning was associated with a 91.1% reduction in lung 
radiation dose and 85.7% reduction of in-field heart volume. A critique of the prone 
position is that due to gravity not only does the breast tissue fall away from the 
chest wall but the heart falls anteriorly towards the chest wall. 
 
Remouchamp et al evaluated moderate deep-inspiration breath hold (DIBH) in 
external beam radiation treatment of left sided breast cancer. The treatment plans 
from the breath hold and free breathing CTs were compared showing a mean 
decrease of 3.6% of heart volume that received 30Gy. This would translate into a 
1.5% decrease in the rate of heart normal tissue complication probability (NTCP). 
However, the absolute lung volume seeing higher doses of radiation is increased 
with DIBH but relative lung percentages receiving significant radiation doses may 
be improved. A retrospective study (Nissen et al 2013) reviewed 144 left-sided 
breast cancer patients treated with DIBH and 83 left-sided patients treated free 
breathing. The heart mean dose was decreased from 5.2 to 2.7Gy.  
 
While both methods have independently been demonstrated to reduce cardiac 
dose and pulmonary dose,  the combination of the two have not been reported. 
This study seeks to evaluate whether cardiac dose and pulmonary dose can further 
be reduced in women receiving prone breast radiotherapy with the addition of 
inspiratory gating. We anticipate that prone breath hold can further reduce 
radiation doses to these organs at risk, and potentially reduce the risk of late 
cardiovascular and pulmonary complications from breast radiotherapy.  
 
If this study shows feasibility and potential for lowering cardiac and pulmonary 
dose for patients treated in the prone position with the addition of breath-hold then 
a larger randomized trial looking at optimal patient characteristics for this combined 
technique, further examining dose reductions using this experimental technique 
versus standard of care, and possible late toxicities, including cardiovascular and 
pulmonary, can be considered in the future. 
 
 
4.2  
Investigational Product:  
 
Not applicable 
 
 
 
4.3      Pre-clinical Experience 
 
Not applicable 
 

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4.4   Clinical Experience 
 
The two methods most frequently used to reduce cardiac dose during breast 
radiotherapy are prone positioning on a breast-board and inspiratory gated breath-
hold treatment. Lymberis et al prospectively studied 100 patients with CT simulation 
scans for RT planning in the prone and supine setups. It was found that prone 
position decreased the volume of lung within the radiation field in all patients and for 
left sided breast cancers 87% of patients had a decrease in irradiated volume of the 
heart. Formenti et al published their abstract of 200 patients with left-sided breast 
cancer who underwent radiotherapy treatment planning in both the prone and supine 
position. Radiation treatment plans for each position were compared specifically 
looking at doses to heart and lung volumes. Their results showed that prone 
positioning was associated with a 91.1% reduction in lung radiation dose and 85.7% 
reduction of in-field heart volume. A critique of the prone position is that due to 
gravity not only does the breast tissue fall away from the chest wall but the heart 
falls anteriorly towards the chest wall. 
 
Remouchamp et al evaluated moderate deep-inspiration breath hold (DIBH) in 
external beam radiation treatment of left sided breast cancer. The treatment plans 
from the breath hold and free breathing CTs were compared showing a mean 
decrease of 3.6% of heart volume that received 30Gy. This would translate into a 
1.5% decrease in the rate of heart normal tissue complication probability (NTCP). 
However, the absolute lung volume seeing higher doses of radiation is increased 
with DIBH but relative lung percentages receiving significant radiation doses may be 
improved. A retrospective study (Nissen et al 2013) reviewed 144 left-sided breast 
cancer patients treated with DIBH and 83 left-sided patients treated free breathing. 
The heart mean dose was decreased from 5.2 to 2.7Gy.  
 
While both methods have independently been demonstrated to reduce cardiac and 
lung dose, the combination of the two has not been reported. This study seeks to 
evaluate whether cardiac and lung dose can further be reduced in women receiving 
prone breast radiotherapy with the addition of inspiratory gating. We anticipate that 
prone breath hold can further reduce radiation doses to these organs at risk, and 
potentially reduce the risk of late cardiovascular and pulmonary complications from 
breast radiotherapy.  
 
5.   
INVESTIGATIONAL PRODUCT 
 
5.1 
Investigational Product (IP)   
Not Applicable  
 
5.2 
Investigational Product Supply 
Not Applicable 
 
  
5.3  
Investigational Product Accountability 
Not Applicable  
 
5.4 
Storage 
Not Applicable  
 

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5.5 
Preparation 
Not Applicable  
 
5.6 
Handling 
Not Applicable  
 
 
6.    SUBJECT  ELIGIBILITY 
 
Investigators will maintain an electronic subject log in the UACC OnCore and RedCao 
system of all potential (i.e. consented) study subjects, which will include as applicable 
(demographics, informed consent, eligibility, treatment assignment, on treatment, off 
treatment, follow up and off study dates).  
 
6.1    Inclusion Criteria 
1. Patients of Dr. Gonzalez 
2. ≥18 years of age 
3. Node-negative left breast cancer 
4. Invasive or DCIS breast cancer 
5. Prior lumpectomy 
6. Deemed appropriate for treatment in the prone position by the treating 
physician 
7. Able to tolerate prone position and breath hold during CT simulation 
8. Patient must be English speaking. 
6.2   
Exclusion Criteria 
1. <18 years of age  
2. Patients requiring treatment in supine position  
 
6.3    Enrollment  
 
The source of subjects is the patient population at the Banner – University 
Medical Center Tucson/Arizona Cancer Center. Patients who are scheduled as 
part of their routine care to consult with the radiation oncologist for treatment of 
left sided breast cancer will be provided with information regarding this study. 
See attached list for our website, newsletter and Front Desk Poster. 
 
 
 
Subjects will be consented at an already scheduled appointment with the 
radiation oncologist. This could be either at their initial consult visit or prior to 
their CT simulation appointment. Subjects will have the opportunity to take their 
time in making a decision, and will be encouraged to take the Informed Consent 
Form home and discuss it with whomever they would like. The treating physician 
will explain to the subjects the risks and benefits. They will be informed that their 
participation is voluntary, and lack of participation will not affect the subject’s 
relationship with the treating staff or our facility. Subjects will be consented by 
either the PI, Co –PI, or the Research Staff of the Radiation Oncology 
department. Subjects will also be made aware that should they consent, they can 
withdraw their consent at any time. When new information becomes available, it 

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will be given to the patient as soon as possible, either at their next visit, or if that 
is more than 30 days away, by phone call. Once an approved revised consent 
form is submitted and approved by the IRB, the subject will be asked to sign the 
new consent and the subject will be notified of the change to the consent form. 
The AZCC Verification of Consent form will be completed at the time the subject 
is consented. This form includes information pertaining to who is present at 
consenting, that the consent form was reviewed with the subject, the subject 
understood the consent form, and the date and the time of the consent. Also 
documented will be the version of the Subject Consent form and the HIPAA form.  
Only English speaking patients will be enrolled. 
 
7.   
STUDY PLAN  
 
7.1   Treatment Regimen 
Subjects will be recruited by Dr. Gonzalez and Dr. Goyal (or covering physician) 
at their standard of care appointment prior to the radiation planning appointment. 
Patients will be asked by Dr. Gonzalez and Dr. Goyal (or covering physician) if 
they are interested in participating in the study. If they are, a member of the 
research staff will review the study with the patient and complete the consent 
process. Subjects will be enrolled prior to their radiation therapy panning 
simulation (CT simulation).  
 
During the radiation planning appointment, patients undergo CT scans used to 
plan the radiation doses and delivery. The number of images taken during the CT 
simulation is the same is if they were not treated on this research study. A CT  
scan will be performed in the prone position using coached voluntary inspiratory 
breath-holding using the RPM visual feedback system. Prone breath hold will be 
conducted using a monitor in the headrest of the prone breastboard that the 
subject will watch. This monitor allows the subjects to see their respiratory cycle 
which is a sinusoidal curve. Therapists coach the patient to hold their breath for 
approximately 15 seconds in order to maintain inspiration within a threshold bar 
set by the simulation therapists that is seen via the patient monitor. The purpose 
of the breath hold technique is to allow for optimal heart positioning for this study. 
This is the same method used for breath hold in the supine position which is 
considered standard of care.  The reason this study is unique is because it is 
using the combination of prone positioning and inspiratory gated breath hold 
versus individually. 
 
After the subject completes the radiation planning simulation, the physician will 
generate two radiation treatment plans: one for the free-breathing scan (standard 
of care) and one for the breath-hold scan (using inspiratory gating). For each 
plan, the heart, left ventricle/LAD artery and lungs will be contoured on each CT 
scan with radiation fields placed on both CT scans to dosimetrically determine 
heart, left ventricle/LAD artery and lung radiation doses and coverage of the 
affected breast. The doses to the heart, left ventricle/LAD artery and lungs will be 
compared to determine the plan with the lower cardiac and lung doses.  
 
At the discretion of the treating physician, the plan with the lower cardiac and 
lung doses will be used to treat the subject. Inspiratory breath hold will only be 
used if it results in lower cardiac and lung doses. If the free breathing plan shows 

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lower cardiac and lung doses, the patient will be treated per standard of care 
(prone without inspiratory breath hold). If the plan involves inspiratory breath 
hold, the subject will be notified by the research staff prior to the first day of 
treatment. Reasoning for treating a patient prone only versus prone and breath-
hold will be documented by the treating physician.  If the plan with inspiratory 
breath hold resulted in the lower cardiac and lung dose, inspiratory gating will be 
performed during each daily treatment. Treatment with breath hold adds 
approximately 5 minutes to the overall setup and treatment time of each daily 
treatment. During daily radiation, prone breath hold will be conducted using a 
monitor below the prone headrest that the patient will watch. This monitor allows 
the patient to see their respiratory cycle and indicates the amount of inhalation 
that would be required (threshold bar represented as a blue box) in order to allow 
for treatment that is representative each day of their initial simulation CT scan. 
This monitor allows the subjects to see their respiratory cycle which is somewhat 
of a sinusoidal curve. Therapists coach the patient to hold their breath for 
approximately 15 seconds in order to maintain inspiration within a threshold bar 
(blue box) set by the simulation therapists that is seen via the patient monitor. 
During treatment, the radiation beam is only active when the patient breath hold 
is within the threshold bar on the monitor. The radiation treatment machine is set 
to turn off when the breath hold is outside of this threshold bar (blue box).  
 
The physician will complete an evaluation form (RTOG CF form attached) 
regarding cardiac co-morbidities. The form will be completed at baseline 
(radiation planning session) and at 6 months post RT, and then at 1 year. This 
will not require any additional time for the subject and will be based on the 
information gathered by the physician at the standard of care appointment.  
 
In addition to the intervention, data from the subjects medical record will also be 
collected (please see attached data collection sheet). Details regarding the 
subject’s treatment, imaging studies, medical history and follow up visits will be 
collected. The research staff has access to the medical record as part of their 
position with UA/UAMC.  
 
7.2  
Pre-medications: 
Not Applicable 
 
7.3   
Rescue medications:  
Not Applicable 
 
7.4  
Excluded medications: 
Not Applicable 
 
8.   
REQUIREMENTS FOR TREATMENT  
 
8.1  
Standard dose/treatment 
Not applicable 
 
8.2  
Dose/treatment modification 
Not applicable   
 

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8.3   Investigational Product Dose Delay  
Not Applicable 
 
8.4   Definition of a Dose Limiting Toxicity (DLT) 
Not Applicable 
 
 
9. 
STUDY PROCEDURES (the actual procedures need to be entered below 
 
and/or in a study schema/calendar – see my note in section # 26) 
 
9.1  
Screening 
Potential subjects will enter the screening period of the study after completely 
executing a study specific informed consent form. 
 
9.2  
Registration/Randomization 
Once this study is approved by all internal regulatory agencies to enroll subjects, 
study enrollment will begin. Subjects will be entered into the study.  Subjects will 
be identified by their initials (First, Middle if available, Last) and a study number. 
Study numbers will begin with GO-B-001and continue sequentially. 
The subject CT Simulation will be scheduled.  
 
9.3  
On  Intervention:  Subjects will undergo the standard of care CT simulation, 
which includes an additional breath hold CT. Inspiratory gated breath-hold will be 
used.  Two radiation plans will be generated:   one for the CT scan performed 
free breathing, and one for the scan performed with inspiratory gated breath hold.  
The cardiac and lung doses will be determined.  At the discretion of the treating 
physician, the plan with the lower cardiac and lung dose may be used to treat the 
patient.   
 
9.4  
End of Intervention:  The intervention will be considered complete at the time the 
patient’s treatment plan has been generated.  
 
9.5   Follow up 
Subjects will be seen for one 30 day [±10 days] follow-up visit after the end of RT 
then at 6 months (+ 30 days) and then at one year (+ 30 days) from the end of 
radiation therapy.   These visits are part of RT standard of care.  During each of 
these  visits, patients will be asked about any cardiac or pulmonary changes, 
including any cardiac or pulmonary symptoms [i.e. shortness of breath, rapid 
heart beat, chest pain, and whether or not they have had any cardiac or 
pulmonary testing (i.e. ECG, echo, muga or PFTs)].  
 
9.6   Early intervention termination 
Not Applicable  
 
9.7   
Off study 
 
Subjects will be considered off study after completing their one year (+/- 30 days)                       
post RT follow-up visit.  Subjects will also be considered off study if they chose to 
voluntarily withdraw from the study.  They will be asked to be seen for a final end 

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of study follow-up that would include the same procedures as the follow-up appt. 
described in Section 9.5.  
 
10. 
PHARMACOKINETIC STUDIES 
Not applicable 
 
11.  
DATA AND SAFETY MONITORING PLAN  
 
11.1 Identification of the DSMB obligated for oversight responsibilities: 
The Arizona Cancer Center Data and Safety Monitoring Board (DSMB) will 
provide ongoing oversight for this trial. 
 
 
11.2 Identification of the entity obligated for routine monitoring duties: 
Routine monitoring will be provided by the Quality Assurance/Quality Control 
(QA/QC) Program to ensure that the investigation is conducted according to 
protocol design and regulatory requirements.  
 
11.3 Monitoring progress and data review process: 
Routine monitoring of subject data will be conducted at least annually.   
The first routine monitoring visit will include at a minimum: 
• Informed consent – 50% of cases enrolled;  
• Subject eligibility - 10% of cases, up to two subjects; 
• Data review - 10% of cases, up to two subjects. 
 
All subsequent monitoring visits will consist of randomly selected subject cases 
based on current enrollment and include continuing review of previously selected 
cases, as applicable. 
 
A monitoring visit report and follow-up letter will be completed approximately two 
weeks after the routine monitoring visit; a copy will be maintained in the study 
file. A query/finding form or an electronic record will also be completed by the 
monitor to request additional source documentation, clarification, information or 
corrections to the CRF and/or regulatory records. The Clinical Research 
Coordinator or other applicable staff responsible for the study will be given a 
copy of this form, or will be notified of the electronic record for resolution of 
queries/findings. The query/finding form will be maintained with a copy of the visit 
report for follow-up at the next monitoring visit. Electronic records will be 
available in the institutional database or provided by the QA/QC Program staff.  
 
The Principal Investigator will ensure the accuracy, completeness, legibility and 
timeliness of the data reported in the Case Report Form (CRF), or other 
acceptable data formats. Source documentation supporting the study data should 
indicate the subject’s participation in the trial and should document the dates and 
details of study procedures, adverse events, and patient status.  
 
Case report forms, which include the inclusion/exclusion criteria form, adverse 
event forms and serious adverse event forms [other forms, depending on study] 
should be completed via the institution database or other acceptable data 

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formats. Trials using paper CRFs will have the data entered with a black ball-
point pen or typed. Corrections to the forms should not obscure the original entry 
and should be made by striking the incorrect information with a single line. Each 
strike should be accompanied by the initials of the corrector and the correction 
date. All subject forms and study files will be stored in a secure area limited to 
authorized staff. 
 
Note: Routine monitoring of regulatory documents and test article will be 
conducted at least annually. 
 
11.4 Process to implement study closure when significant risks or benefits are 
identified: 
There are no plans for early study closure for this study, since the intervention 
used will actually reduce the side effects patients experience.                                                      
 
 
11.5 Description of adverse events and reporting procedures: 
 
ADVERSE EVENTS  
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and that does not 
necessarily have a casual relationship with this treatment. An AE can therefore 
be any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product.  
 
Any and all adverse events will be recorded on the UMC adverse events record 
form and reviewed by the Principal Investigator. 
 
All adverse events will be classified using either the MedDRA term or NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 or 4.0 
and will address: 
• Grade 
• Relationship to study drug(not related, unlikely, possible, probable, definitely)  
• Causality other than study drug (disease related, concomitant medication 
related, intercurrent illness, other)   
• Date of onset, date of resolution 
• Frequency of event (single, intermittent, continuous) 
• Event outcome (resolved, ongoing, death) 
• Action taken (none, held, dose reduced, discontinued, medication given) 
 
 
SERIOUS ADVERSE EVENTS 
 
A serious adverse event (SAE) is any untoward medical occurrence that at 
 
any dose:  
 
1) Results in death;  
 
2) Is life-threatening; 
3) Requires in-patient hospitalization or prolongation of an existing hospital stay;  
 
4) Results in disability persistent or significant disability/incapacity, or: 
 
5) Is a congenital anomaly/birth defect.  
 

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Note: A SAE may also be an important medical event, in the view of the 
investigator that requires medical or surgical intervention to prevent one of the 
outcomes listed above.  
 
All serious adverse events, regardless of attribution, and any deaths will be 
reported within 24 hours of notification of the event to the sponsor and DSMB 
Coordinator. All serious adverse events, regardless of attribution, and any deaths 
will be reported within 5 days of notification of the event to the University of 
Arizona Human Subjects Protection Program.  
 
All serious adverse events will be processed by the DSMB Coordinator monthly 
for initial trend analysis and fully reviewed by the DSMB, every six months. The 
DSMB Coordinator will review the SAE reporting process to confirm reporting 
requirements are met. 
 
11.6  Plan for assuring data accuracy and protocol compliance: 
Routine study activity and safety information will be reported to the DSMB on an 
annual basis, or more frequently if requested. These reports will include: 
• Study activity, cumulative and for the period under review; 
• Safety (narrative description on non-serious and serious adverse events, 
protocol pre-determined early stopping rules for safety or treatment-emergent 
adverse events); 
• Predetermined protocol early stopping rules for efficacy/futility;  
• Status of study in relationship to stopping rules;   
• Current dose level of study agent;  
• Routine monitoring and protocol compliance (describe the monitoring process 
and identify the status of the monitoring); 
• Comments;  
• Attachments (AE data reviewed by the PI to compile the report, SAE letters 
and reports, results of any review(s), applicable correspondence with the IRB 
or other regulatory agencies 
 
 
Data, safety and study progress will be reported to: 
• Human Subjects Protection Program (IRB) at least annually; 
• Sponsor (if applicable) at least annually. 
 
. 
Identification of the sponsor or funding agency, as applicable: 
The PI will immediately notify; in writing, the funding agency, if applicable, any 
action resulting in a temporary or permanent suspension of the study.  
A copy of this correspondence will also be forwarded to the DSMB and the SRC.  
 
11.7 Process to implement study closure when significant risks or benefits are 
identified: 
 
Not applicable. 
 
 
12.  
ADDITIONAL SAFETY REPORTING 
 
Serious adverse events will be reported to the Data Safety Monitoring Board as 
well as the institutional IRB within 24 hours of notification of the event to the PI.  

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Serious adverse events will be reported using the FDA MedWatch form to inform 
the DSMB, and using the F224 (Reportable Local New Information that is 
Potentially Problematic) form to inform the IRB. 
 
13.    QUALITY ASSURANCE MEASURES 
 
Not applicable 
 
14.    RECIST CRITERIA 
 
Not Applicable 
 
15. 
REMOVAL OF SUBJECTS 
 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
If this occurs, the investigator, or designee, is to discuss with the subject the safe 
and appropriate processes for discontinuation from the investigational  
intervention. 
 
The investigator or designee must document the change in status of the subject’s 
participation in the study and as applicable, the level of follow up that is agreed to 
by the subject (i.e. agrees to follow up exams, adverse event review, phone 
contact, but not to further treatment and/or procedures).  
 
Subject withdrawal of consent for a study indicates that the subject does not wish 
to receive further protocol required therapies or procedures, and the subject does 
not wish to, or is unable to continue further study participation. Subject data only 
up to the time when consent is withdrawn will be included in the analysis of the 
study.  
  
 16. 
STASTISITICAL CONSIDERATIONS  
 
Statistical analysis will be performed in collaboration with Dr. Denise Roe, the 
Director of the University of Arizona Cancer Center Biometry Shared Service.   
 
The primary endpoint of the study is the feasibility of the breath-hold technique 
for women treated with radiation for left-sided breast cancer in the prone position.  
Although it is expected that the number of women who are unable to master the 
breath-hold technique will be small, the proportion of women who cannot master 
the technique will be estimated with the appropriate exact 95% confidence 
interval. 
 
The secondary endpoint is to evaluate the changes in the mean dose to the heart 
and lungs with prone breath hold.  Each woman enrolled in the study will have 
two radiation plans generated in the prone position:  one for the free-breathing 
scan and one for the breath-hold scan.  The mean difference between the 
dosimetrically determined heart and lung radiation doses will be computed with 
the associated 95% confidence interval.  A paired t test will be used to assess 

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whether the mean difference is statistically significant.  The other secondary 
endpoints will be analyzed in a similar fashion.  
 
Ten women will give 80% statistical power to detect a difference of 1 standard 
deviation unit in the mean dose between the two conditions. Note that since 
paired data will be generated, the number of women required is less than if two 
independent samples of women were to be used. Additionally, the percentage of 
women in which adding the breath-hold results in a lower cardiac and lung dose 
will be estimated with standard error of 16% or less. The estimated mean 
difference (and its standard error) will be used to generate the sample size 
required for a larger study to statically assess the benefit of adding the breath-
hold in reducing the cardiac and lung radiation dose.   
 
 
17.  
ANALYSIS  
 
17.1  Safety Analysis 
Not applicable 
 
17.2  Efficacy Analysis 
 
Efficacy analysis will be conducted at the completion of the study.  
 
17.3   Interim Analysis 
 
Not applicable 
 
18. 
REGULATORY OBLIGATIONS 
 
18.1  Informed consent  
Before a subject’s participation in the clinical study, the investigators or identified 
designee is responsible for obtaining written informed consent from the subject or 
legally authorized representative after adequate explanation of the aims, 
methods, anticipated benefits, and potential hazards of the study and before any 
protocol specified procedures, investigational product, intervention or device are 
administered or initiated.  
 
18.2 Institutional Review Board 
A copy of the protocol, proposed ICF, and all other applicable subject information 
will be submitted to the IRB for written approval. A copy of the written approval of 
the protocol and ICF must be on file at the institution before recruitment of 
subjects into the study.   
 
The investigator is responsible for obtaining IRB approval/renewal at least 
annually throughout the duration of the study. Copies of the investigator’s reports 
and the IRB continuance of approval must be on file at the institution.  
 
The investigator must submit study information to the IRB as required by all 
applicable guidelines and requirements. The investigator will obtain IRB approval 
for subsequent protocol amendments; except changes to eliminate an immediate 
hazard to study subjects, and changes to the informed consent document from 
the IRB prior to implementation.  

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The investigator will notify the IRB of deviations from the protocol or serious 
adverse events occurring at the site and other serious adverse event reports 
occurring at or received from participating centers as applicable for multi-center 
trials following the IRB policies and procedures. 
 
19.   ADMINISTRATIVE PROCEDURES 
  
 
19.1  Investigator responsibilities 
The PI will conduct this study in accordance with the current International 
Conference on Harmonization (ICH) guidance, the Good Clinical Practice (GCP) 
guidance, the Declaration of Helsinki, FDA regulations, local IRB and legal 
requirements.  
 
 
19.2  Data and Safety Monitoring Board protocol review 
Initial DSMB protocol review will be conducted prior to SRC and IRB 
submissions.  
 
Any protocol revision or amendment that includes a potential change to any 
section of data and safety monitoring plan must be reviewed and approved by 
the DSMB prior to the protocol amendment submission to the IRB. 
  
 
19.3  Multicenter Trials 
 
Not Applicable 
 
 
19.3.1 UACC DSMB and QA/QC Monitoring 
The UACC QA/QC Program will be responsible for routine monitoring of local 
study data for the coordinating center.  
 
19.3.2  Alternate DSMB Oversight  
 
 Not Applicable 
 
20.   SUBJECT CONFIDENTIALITY  
 
The principal investigator will ensure that the subject’s confidentiality is 
maintained in compliance with Federal regulations, the International Conference 
on Harmonization (ICH), and Good Clinical Practice (GCP) Guidelines.  
 
Oversight entities and/or regulatory authorities will be permitted direct access to 
review the subject’s original medical records, electronic medical records or 
certified copies for verification of study-related procedures and data. Direct 
access includes examining, analyzing, verifying, and reproducing any records 
and reports that are important to the evaluation of the study.  
 
 21.  STUDY DOCUMENTATION AND ARCHIVE  
 
The investigator will maintain a list of appropriately qualified persons to whom he 
has delegated study duties. All persons authorized to make entries and/or 

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corrections on case report forms (CRF) will be included on the Delegation of 
Responsibilities Form.  
 
Source documents, data, and records from which the subject’s CRF data are 
obtained include, but are not limited to, hospital records, clinical/office/research 
charts, laboratory and pharmacy records, diaries, microfiches, radiographs, and 
correspondence. Source data will include information necessary for the 
reconstruction and evaluation of the trial.  
 
The principal investigator or sponsor-investigator is responsible for maintaining a 
comprehensive and centralized filing system of all study-related (essential) 
documentation as required per ICH Guidelines. This can be accomplished by the 
PI, through the site’s standard operating procedures and/or the institutions 
infrastructure. 
 
The investigator will follow ICH Good Clinical Practice Guidelines and the Code 
of Federal Regulations for records and record retention.  
 
22.   DATA  
 
Applicable data as specified as required in the protocol will be reported/submitted 
in the CRF. Data reported in the case report forms that are derived from source 
documents must be consistent with the source documents or the discrepancies 
must be explained. CRFs will be completed via the OnCore system and RedCap. 
which is currently being used by many UMC departments for their study data 
bases.   
 
Additional procedures and assessments may be performed as the institution’s 
standard of care; however these data should remain in the medical records and 
should not be provided as part of the clinical study data unless it pertains to a 
serious adverse event.  
 
The investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation 
on each individual administered the investigational intervention. 
 
23.   PROTOCOL DEVIATIONS   
 
The investigator will conduct the study in conformance with this protocol, 
generally accepted standards of Good Clinical Practice and all applicable federal, 
state and local laws, rules, and regulations.  
 
Approvals or waivers for protocol deviations will be obtained from the investigator 
prior to occurring, except changes to eliminate an immediate hazard to study 
subjects. If immediate verbal approval is obtained, it will be documented by the 
research staff obtaining the approval and followed by a written protocol deviation 
form per the site standard operating procedures. The investigator will sign the 
Protocol Deviation (Waiver) Approval Form or other similar document. The 
original will be filed in the regulatory binder and a copy will be placed in the 
subject’s research file.  

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24.   KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS 
Not Applicable  
 
25.   COMMON TOXICITY CRITERIA 
 
CTCAE version 4.0 
  
26. 
STUDY SCHEDULE 
See Section 9  
 
27.  
GLOSSARY:  
Not Applicable 
 
28.  
DEFINITIONS:  
Not Applicable 
 
29.   REFERENCES  
 
1) Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans E, Godwin J, Gray R, 
Hicks C, James S, MacKinnon E, McGale P, McHugh T, Peto R, Taylor C, Wang Y; 
Early Breast Cancer Trialists' Collaborative Group (EBCTCG). (2005) Effects of 
radiotherapy and of differences in the extent of surgery for early breast cancer on 
local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 
366(9503):2087-106. 
2) Darby SC, Ewertz M, Hall P. (2013). Ischemic heart disease after breast cancer 
radiotherapy. N Engl J Med. Jun 27;368(26):2527 
3) Formenti SC, DeWyngaert JK, Jozsef G, Goldberg JD. (2012) Prone vs supine 
positioning for breast cancer radiotherapy. JAMA. 308(9):861-3 
4) Lymberis, SC, et al (2012). Prospective assessment of optimal individual position 
(prone versus supine) for breast radiotherapy: volumetric and dosimetric correlations 
in 100 patients. IJROBP. 84(4): 902-909. 
5) Remouchamps VM, Huyskens DP, Mertens I, Destine M, Van Esch A, Salamon E, 
De Neve W. (2007) The use of magnetic sensors to monitor moderate deep 
inspiration breath hold during breast irradiation with dynamic MLC compensators. 
Radiother Oncol. 82(3):341-8.  
6) Remouchamps VM, Letts N, Vicini FA, Sharpe MB, Kestin LL, Chen PY, Martinez 
AA, Wong JW. (2003). Initial clinical experience with moderate deep-inspiration 
breath hold using an active breathing control device in the treatment of patients with 
left-sided breast cancer using external beam radiation therapy. Int J Radiat Oncol 
Biol Phys. 56(3):704-15.  
 
30.  
APPENDIX 
 
30.1 CF Form 
30.2 Data Collection Form