A Phase II Study of Preoperative Boost Radiotherapy in Patients With Breast With Biomarker Analysis
Phase: NA
Conditions: Breast Cancer
Sponsor: Duke University

A Radiation Therapy Study 
A Phase II Study of Preoperative Boost Radiotherapy in 
Patients with Breast Cancer with Biomarker Analysis 
Sponsor: 
Funding Source: 
Protocol Source: 
Duke IRB#: 
clinicaltrials.gov
Dr. Janet Horton – Duke Cancer 
Institute 
Gateway for Cancer Research 
Dr. Janet Horton – Duke Cancer 
Institute 
Pro00063936
NCT02482389 
Principal Investigator 
Rachel Blitzblau, M.D., Ph.D. 
Department of Radiation Oncology 
DUMC Box 3085 Durham, NC 27710 
Original version: 
09/02/2015 
Version5:  
09/20/2018 

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1 Table of Contents 
2 
LIST OF ABBREVIATIONS ...............................................................................................................4 
3 
PROTOCOL SYNOPSIS ...................................................................................................................6 
3.1 
Purpose .........................................................................................................................................6 
3.2 
Background and Significance ........................................................................................................6 
3.3 
Rationale .......................................................................................................................................6 
3.4 
Selection of Subjects and Sample Size ..........................................................................................8 
4 
SUBJECT ELIGIBILITY .....................................................................................................................8 
4.1 
Inclusion Criteria ...........................................................................................................................8 
4.2 
Exclusion Criteria ..........................................................................................................................8 
4.3 
Inclusion of Women and Minorities……………………………………………………………………………………..….9 
5 
TREATMENT PLAN ........................................................................................................................9 
5.1 
Surgery ..........................................................................................................................................9 
5.2 
Radiotherapy ................................................................................................................................9 
5.3 
Supportive Care ..........................................................................................................................11 
5.4 
 Early Study Termination .............................................................................................................11 
6 
PATIENT ASSESSMENTS ..............................................................................................................11 
6.1 
Pretreatment Evaluations/Management ....................................................................................11 
6.2 
Screening Examination ...............................................................................................................12 
6.3 
End of Treatment/Follow-up Period ...........................................................................................12 
6.4 
Early Withdrawal of Subject(s) ...................................................................................................12 
6.4.1 
Criteria for Early Withdrawal ..............................................................................................12 
6.4.2 
Follow-up Requirements for Early Withdrawal ..................................................................12 
7 
Statistical Considerations ...........................................................................................................12 
    7.1     Statistical Analysis of Cosmetic Outcome………………………………………………………………………………12 
    7.2 Statistical Analyses of the Secondary Objectives…………………………………………............................13 
8 
SAFETY MONITORING AND REPORTING .....................................................................................13 
8.1 
Adverse Events ...........................................................................................................................13 
8.1.1 
AEs of Special Interest ........................................................................................................13 
8.1.2 
Reporting of AEs .................................................................................................................14 

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8.2  
Serious Adverse Events ..............................................................................................................14 
8.3 
Safety Oversight Committee (SOC)…………………………………………………………………………………………14 
9 
QUALITY CONTROL AND QUALITY ASSURANCE ..........................................................................14 
9.1  
Monitoring ..................................................................................................................................14 
 9.2 
Audits…………………………………………………………………………………………………………………………………….14 
10 
ADMINISTRATIVE AND ETHICAL CONSIDERATIONS ...................................................................15 
10.1   
Regulatory and Ethical Compliance ........................................................................................15 
10.2   
DUHS Institutional Review Board and DCI Cancer Protocol Committee .................................15 
10.3   
Informed Consent ...................................................................................................................15 
10.4   
Study Documentation .............................................................................................................16 
10.5   
Privacy, Confidentiality, and Data Storage .............................................................................16 
10.6   
Data and Safety Monitoring ....................................................................................................17 
10.7   
Protocol Amendments ............................................................................................................17 
10.8   
Records Retention ..................................................................................................................17 
11 
REFERENCES ...............................................................................................................................18 
12 
APPENDICES ...............................................................................................................................20 
APPENDIX I:  Blood Processing ................................................................................................................20 
APPENDIX II: NRG Cosmesis Scale ...........................................................................................................21 
APPENDIX III: Patient Self-Assessment ....................................................................................................22 
APPENDIX IV:  Quality of Life ...................................................................................................................23 
APPENDIX V: Digital Photographs ...........................................................................................................25 
 
 
 

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2 LIST OF ABBREVIATIONS 
 
 
3D                  3 Dimensional 
5-FU              5 fluoro-uracil 
AE                 Adverse events 
ANC              Absolute Neutrophil Count 
AP/PA           Anterior to Posterior, Posterior to Anterior 
APC               Argon Plasma Coagulation 
BED               Biologically Equivalent Dose 
BID                Twice Daily 
CBC               Complete Blood Count 
CBCT            Cone Beam Computed Tomography 
CDDP            Cisplatin 
Chemo           Chemotherapy 
CPC               Cancer Protocol Committee 
CRT              Chemoradiotherapy 
CT                Computed Tomography 
CTCAE        
Common Terminology Criteria for Adverse Events 
CTEP           
Cancer Therapy Evaluation Program 
CTV             
Clinical Tumor Volume 
D10cc           Minimum dose to the 10 milliliters of any volume receiving the highest dose 
D2cc             Minimum dose to the 2 milliliters of any volume receiving the highest dose 
DCI              
Duke Cancer Institute 
DCIS 
Ductal Carcinoma in situ 
DLT             
Dose Limiting Toxicity 
Dmax            Maximum dose to any voxel within a volume 
DUHS           Duke University Health System 
DWI 
Diffusion weighted imaging 
ECOG           Eastern Cooperative Oncology Group 
EFRT            Extended Field Radiotherapy 
EQD2           Equivalent dose at 2 Gray per fraction 
FIGO            International Federation of Gynecology and Obstetrics 
G3 or G4      Grade 3 or Grade 4 toxicity 
GCP              Good Clinical Practice 
GOG             Gynecologic Oncology Group 
GTV             Gross Tumor Volume 
GU               Genitourinary 
GY               
Gray 
HDR            
High Dose Rate 
ICRU            International Commission on Radiation Units and Measurement 
ID                 Identification  
IMRT           Intensity Modulated Radiation Therapy (including Volumetric Modulated Arc Therapy) 
IRB              
Institutional Review Board 
KPS             
Karnofsky Performance Scale 
LDR             
Low Dose Rate 
LINAC         
Linear Accelerator 
LRC             
Loco-regional control 
MRI             
Magnetic Resonance Imaging. 
MTD            Maximum Tolerated Dose 
MV              
Megavoltage 
NCI             
National Cancer Institute 

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NRG 
National Surgical Adjuvant Breast and Bowel Project (NSABP), the Radiation Therapy Oncology Group 
(RTOG), and the Gynecologic Oncology Group (GOG) 
OBI 
On board-imaging 
OS               
Overall Survival 
PA               
Para-aortic 
PET             
Positron Emission Tomography 
PI                
Primary Investigator 
PTV            
Planning Target Volume 
SAE 
Serious adverse event 
SOC           
Safety Oversight Committee 
TD5/5         
Toxic dose of 5% at 5 years 
V18             
Partial volume receiving greater than or equal to 18 Gray 
WAI            
Whole abdominal irradiation 
WPRT         
Whole Pelvic Radiotherapy 
 
 

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3 PROTOCOL SYNOPSIS  
3.1 
Purpose 
This protocol seeks to utilize a novel method of tumor bed boost delivery and to better understand breast 
cancer radiation response through the analysis of pre-and post-radiation samples. 
 
Primary Objective: 
1. 
Determine physician and patient-reported rates of good/excellent cosmesis at baseline and 6 months, 1, 
2, and 3 years post-treatment as measured by the NRG cosmesis scale.  
 
Secondary Objective: 
1. 
Evaluate changes in circulating free DNA pre and post-radiation in order to identify potential blood based 
radiation response biomarkers.   
2. 
Assess patient-reported Quality of Life (FACT-B) and patient satisfaction at the same time points as above 
(primary objective). 
3. 
Assess local control in the treated breast relative to historical controls. 
4. 
To review treatment plans, evaluate delivery techniques, and assess positioning verification images. 
 
Hypotheses 
We hypothesize that the boost can be delivered preoperatively to the intact breast tumor with acceptable 
cosmetic outcomes. Furthermore, we anticipate that pre- and post-radiation blood samples will provide an 
avenue for understanding breast cancer radiation response. 
 
3.2 
Background and Significance 
In 1990, the National Institutes of Health concluded that breast conservation, conservative surgery followed 
by radiotherapy, was the preferred treatment for women with early stage breast cancer as no survival 
advantage was seen in women receiving a more radical and disfiguring mastectomy.  As a result, breast 
conservation consisting of lumpectomy followed by 6 weeks of daily external beam radiotherapy became the 
standard of care in the United States (US).  Treatment typically consisted of 4.5-5 weeks of whole breast 
treatment followed by a 1-1.5 week boost to the surgical resection cavity.  Unfortunately, some women 
electing to receive breast conserving surgery struggled to complete the recommended radiotherapy.  Patterns 
of care studies demonstrated that older women, and those living in low-income regions or far from 
radiotherapy centers, often omitted radiotherapy altogether1-3.  Numerous studies have demonstrated that 
the local recurrence rates in these women receiving conservative surgery alone are unacceptably high4,5.   
 
As a result, there has been much interest in development of a more convenient alternative to standard 
radiotherapy.  Recently, robust data has documented that a 3 week course of whole breast radiotherapy is an 
efficacious and safe alternative6,7 to standard therapy.  Much additional work has been done on partial breast 
irradiation, rapid treatment of the tumor bed plus a small margin of normal tissue, delivered in 1 to 5 days.  
Randomized data for this approach is beginning to be reported.  Preliminary data suggest comparable rates of 
local control.  However, early results are mixed in regards to normal tissue toxicity8,9 and may be technique 
dependent.  Finally, numerous investigators have explored the concept of concurrent or intra-operative tumor 
bed boost, thus eliminating the final 1 to 1.5 weeks of treatment.   
 
 
3.3 
Rationale 
A. Rationale for tumor bed boost 
Radiotherapy significantly decreases the rate of local recurrence in women receiving conservative surgery10-13.  
A boost to the surgical resection cavity provides a small additional local control benefit at the cost of increased 
fibrosis and an extra 1 to 1.5 weeks of treatment.  Two randomized trials have established the benefit of a 
tumor bed boost with a consistent relative risk reduction which extends across all subgroups14,15.  However, 
higher risk women clearly derive a much larger absolute benefit from the boost.  NCCN guidelines recommend 
boost treatment in women deemed to be at higher risk of locoregional recurrence.  Many radiation 

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oncologists routinely deliver a boost to all subjects undergoing breast-conserving therapy.  In this proposal, 
women judged as deriving a benefit from a tumor bed boost by the treating investigator based on clinical 
stage will be eligible for inclusion. 
 
B. Rationale for alternative boost delivery 
Radiation has historically involved 6 weeks of daily therapy at a radiation oncology facility.  For many women, 
particularly those who are older, poor, or live in rural areas, this presents a significant hardship.  Surveillance, 
Epidemiology, and End Results (SEER) registry data has noted in the past that many women were not receiving 
appropriate breast conservation therapy1-3.  Inadequate breast conserving therapy (i.e., no radiotherapy, no 
axillary node evaluation or neither) increased from 10% of women in 1989 to 19% in 1995 attributable in 
approximately equal amounts to omission of axillary nodal evaluation and radiotherapy.  As a result, 
numerous investigators spent the following decade proposing techniques to shorten the course of radiation.   
 
Two such techniques were the delivery of a concurrent boost and the delivery of the boost at the time of 
surgical resection.  These techniques were evolving simultaneously with partial breast irradiation, but 
captured a much larger population of women for whom partial breast treatment was not felt to be 
appropriate.  There are now numerous early-phase trials16,17 demonstrating favorable outcomes with the 
concurrent boost technique.  In fact, this approach is currently the subject of a recently completed NRG phase 
III trial.   Women felt to be at higher risk of locoregional recurrence were enrolled and randomized to receive a 
standard course of 4-6 weeks of radiation or a shortened 3 week course of treatment with a concurrent boost. 
 
Intra-operative boost is another technique that has been investigated by a number of groups18-21.  Doses of 9 
to 12 Gy have been utilized in a single fraction.  In general, this approach has been well-tolerated with no clear 
indications of increased toxicity.  The key limitation for this technique is the costly intra-operative linear 
accelerator which is not widely available to many oncologists or subjects. 
 
C. Rationale for single-fraction preoperative technique  
We propose in this trial to build on the favorable results of the intraoperative boost trials but using a 
preoperative delivery approach.  We have demonstrated the feasibility of the preoperative approach22 and 
successfully completed a Phase I dose-finding partial breast trial.  The preoperative approach has several 
advantages: 1) expensive intra-operative equipment is unnecessary, 2) a small intact breast tumor results in 
significantly less uninvolved breast tissue receiving high radiation doses which likely decreases toxicity; 3) 
more accurate targeting of the high-risk areas of subclinical disease surrounding the tumor is possible, 4) 
smaller treatment volumes are amenable to dose escalation which can further accelerate treatment and 
improve accessibility for subjects, and 5) the pre-operative approach provides a novel opportunity to study 
breast cancer radiation response.  
  
While delivery of intra-operative treatment is likely to remain limited in its availability, nearly all radiation 
oncology facilities have the capability of delivering focused external beam radiotherapy.   Significant 
technological advances have been made in recent years that support sophisticated treatment delivery and the 
ability to modulate the dose as needed to minimize toxicity. 
 
D. Rationale for magnetic resonance imaging (MRI) treatment planning 
Target delineation has always been highly subjective in the post-lumpectomy setting.  The tumor bed is 
currently defined as the area of architectural distortion plus surgical clips.  Defining this area is subject to 
inherent variability depending on the bias of the treating physician.  Pre-operative assessment of the tumor 
should certainly improve delineation of the target and the surrounding area at risk.  However, the typical tools 
used for defining breast tumors, mammography and ultrasound, cannot currently be used in conjunction with 
radiation planning software.  MRI, on the other hand, has a growing role in breast imaging and can be used for 
radiation treatment planning.   
 
 
E. 
Rationale for endpoints 

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Numerous investigators have documented limited toxicity in studies evaluating an intraoperative boost.  In 
addition, we noted no acute dose-limiting toxicities in our Phase I trial delivering preoperative doses greater 
than the one planned in this study.  Therefore, we feel that there is conceptual support from the existing 
literature for this approach.   
 
Radiotherapy to the intact tumor is a relatively rare event in breast cancer irradiation, particularly in the 
setting of early stage breast cancer. Tumor and normal tissue radiation response remain relatively poorly 
understood.  Markers capable of predicting radiation response are rare indeed.   
 
3.4 
Selection of Subjects and Sample Size 
Women judged by clinical stage as someone to whom a tumor bed boost would be offered during 
conventional radiation therapy will be eligible.  As a general guideline, this typically includes women with 
invasive cancer that are eligible for and electing breast-conserving therapy under the age of 60.  Selected 
women greater than 60 may also be offered a boost at the discretion of the treating investigator.  For 
example, known nodal involvement may prompt a boost in this scenario.  Women with in situ cancers <50 are 
also typically offered a boost though again, certain women greater than 60 may also be included at the 
discretion of the treating physician. 
 
The final sample size is 40 subjects.  Given the broad eligibility criteria and the more than 400 new subjects 
with invasive breast cancer seen in Radiation Oncology at Duke each year, accrual is anticipated to be 
complete in 3 years once the first patient is enrolled. 
 
4 SUBJECT ELIGIBILITY 
4.1 
Inclusion Criteria 
1. 
Women with a biopsy proven diagnosis of ductal carcinoma in situ or invasive carcinoma of the breast. 
Biopsy tissue (either slides or block) from outside institutions will be reviewed to confirm diagnosis.  
2. 
Breast preservation candidates (no prior breast or nodal radiotherapy, no imaging evidence of 
multicentric disease preventing resection through a single incision, no pregnant women, and no comorbid 
conditions precluding surgery)  
3. 
cTis-T3 cancer judged to benefit (by treating radiation oncologist) from a tumor bed boost  
4. 
Women of child-bearing potential must consent to use adequate contraception during the course of the 
study: (1) surgical sterilization (such as a tubal ligation or hysterectomy), (3) barrier methods (such as a 
condom or diaphragm) used with a spermicide, or (4) an intrauterine device (IUD). Contraceptive 
measures such as Plan B (TM), sold for emergency use after unprotected sex, are not acceptable methods 
for routine use.  
5. 
WBC > 3000, Hgb > 10, platelets >100000 within 30 days of consent 
6. 
Eligible for contrasted MRI on initial evaluation with GFR≥ 60 ml/min.  A diagnostic MRI ordered within 60 
days of diagnosis will be considered an acceptable alternative and will not be repeated.   
7. 
Outside breast imaging will be reviewed at Duke to confirm that findings are consistent with trial eligibility 
 
4.2 
Exclusion Criteria 
1. 
Breast implant in the breast to be treated (contralateral breast implant is acceptable) 
2. 
Medical conditions that may increase risk for poor cosmetic outcome (i.e.  Lupus, rheumatoid arthritis, 
scleroderma) 
3. 
Subjects unable to receive study treatment planning secondary to body habitus or inability to lie flat on 
the stomach for at least 1 hour 
4. 
Positive serum pregnancy test 
5. 
Insufficient breast imaging to judge clinical stage 
6. 
Subjects without placement of a biopsy clip at the diagnostic procedure who are unwilling to undergo clip 
placement. 
7. 
Subjects in whom treatment planning constraints cannot be met 

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4.3  
Inclusion of Women and Minorities 
Only women will be eligible for this study.  Minority groups will also be eligible and accrual is expected to 
reflect the population of subjects seen in the Duke Multi-disciplinary Breast Cancer Clinic.   
 
5 TREATMENT PLAN 
5.1  
Surgery  
Surgical tumor resection will be completed 2-4 days after RT delivery (though up to 7 days will be allowed for 
logistical constraints without considering this a protocol deviation).  Subjects will undergo intraoperative 
lymphatic mapping and sentinel lymphadenectomy as is standard at our institution.  Standard axillary nodal 
dissection is acceptable if there is a contraindication to the sentinel node procedure or if felt to be clinically 
indicated based on nodal involvement.  Negative margins, defined as no tumor on ink, are the institutional 
standard.   Standard pathologic assessment will follow.   
 
5.2  
Radiotherapy 
Target Volume:  
Prior to treatment, a biopsy clip fiducial marker will be placed in the region of the tumor to provide 
localization for radiotherapy delivery. Kilovoltage on-board-imaging (OBI) and/or cone beam CT (CBCT) will be 
used for localization as described in the section on target localization.     
 
The patient will then undergo a research magnetic resonance (MR) for radiation treatment planning.  The 
patient will be placed on the MR table with the breast pendant in a dedicated breast surface coil with arms 
raised overhead.  Alternatively, the patient will be placed supine and specialized thoracic coils will be utilized 
in order to keep the breast in the same shape for the MR, CT, and radiation treatment to the extent possible.  
MR/CT compatible surface markers will be used to assist in this effort.  T1-weighted imaging, T2-weighted 
imaging, inversion-recovery imaging, diffusion weighted imaging (DWI), and Dynamic contrast enhanced (DCE) 
MRI of the breast will be performed on the 1.5 Tesla GE Signa scanner in the Department of Radiation 
Oncology, equipped with a research key.   
 
More specifically, T1 weighted MRI will be acquired with a 3D gradient-echo with spoiler (SPGR) sequence to 
achieve spatial resolution of sub-millimeter; T2 weighted MRI will be acquired with a 2D fast spin-echo (FSE) 
sequence; inversion recovery MRI will be acquired by a 2D axial short-T1 inversion-recovery (STIR) sequence; 
DCE-MRI will be acquired with a 3D SPGR sequence.  Before DCE-MRI acquisition, a MedRad Power Injector 
will be used to administer weight appropriate dose of gadolinium at 2cc/second after a 30 second inject delay.   
 
Axial T1, axial short-T1 inversion-recovery (STIR), and dynamic VIBRANT images will be required for the 
delineation of the enhancing tumor, the gross tumor volume (GTV).  A planning CT scan will also be acquired in 
order to generate dose calculations.   
 
Treatment Planning and Dose: 
The MR images will be used to define the GTV.  A 1.5 cm uniform expansion will be applied around the GTV to 
create the clinical target volume (CTV).  MRI images will be fused to the CT images for further identification of 
normal structures and target volumes.  The first 5mm of subcutaneous tissue and any chest wall (pectoralis 
muscle and deeper) if >1 cm from the GTV will be excluded from this volume.  The first 5mm of tissue is in the 
photon “build-up” region and to include this area would skew the dose calculations.  The chest wall is 
considered an anatomic boundary to tumor that is separate from the chest wall.  An additional 0.5 cm margin 
to beam edge, will be used to generate the planning target volume (PTV) in order to account for set-up 
uncertainty.  A PTV eval will be utilized for analysis of dose coverage.  The PTV eval will include the same 
volume as the PTV with the exception of the first 5mm of skin. The CTV will be utilized for target dose-volume 
analysis.   
 

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The skin, ipsilateral and contralateral lung, ipsilateral and contralateral breast tissue, spinal cord and heart will 
be segmented as per institutional standard and analyzed for dose.  The skin will be defined as a 3 mm layer 
from the external body surface.  The ipsilateral and contralateral breast tissue will be segmented utilizing the 
guidelines from ongoing phase III NRG trials.  In short, the breast tissue typically included in standard breast 
tangents minus the lungs and chest wall will be designated the breast volume with hand modification as 
needed by the principal investigator or designee. 
 
The skin, spinal cord, and lungs will be auto-contoured in standard fashion.   The heart should be contoured 
from the apex to the root of the great vessels.  The thyroid and brachial plexus will also be contoured as 
appropriate depending on tumor location.  The thyroid should be easily visible and contoured at the base of 
the neck.  The brachial plexus should be visible on MRI and will be contoured with the assistance of radiology 
as indicated.  Alternatively, the axillary vessels will be used as a surrogate for the brachial plexus23.   
 
A treatment plan utilizing arc therapy, or multiple conformal beams, or intensity-modulated therapy, or a 
combination of these techniques will then be designed.  The beam arrangement can be organized in any 
fashion provided that the dose constraints listed below are met.  The dose will be normalized to provide a 
desired coverage (95% to 98%) to the CTV. Subjects will receive a single fraction of 7 Gy.   
 
Dose coverage (taken with some modifications to account for the single-dose preoperative delivery technique 
from the ongoing NRG phase III trial evaluating concurrent boost) will be considered appropriate as follows:  
 
Target volume (CTV): prescribed dose covers >90% of the CTV without exceeding maximum dose of 110% 
of prescribed dose 
Normal breast:  <30% of the whole breast reference volume should receive 50% or more of the 
prescribed dose and <15% of the whole breast reference volume should receive the prescribed dose 
Contralateral breast:  the contralateral whole breast reference volume should receive <10% of the 
prescribed dose to any point 
Lungs: Mean lung dose <3.6Gy, V5<10% 
Heart:  Mean should not exceed 50cGy, no point should receive greater than 4Gy, Dose to 1cc <2Gy 
Thyroid:  maximum point dose < 10% of the prescribed dose 
Brachial plexus:  no point in the brachial plexus should receive more than 10% (1Gy maximum) of the 
prescribed dose.   
Skin dose:  1) Maximum dose will not exceed prescription dose.  2) Dose to 1cc:  <6Gy (85% prescription) 
Cord: maximum dose to 1 cc should be 1 Gy. 
 
In addition, a low dose survey will be performed to ensure no unanticipated regions are receiving 
inappropriate dose. 
 
Target Localization and Treatment Delivery: 
Subjects will be taken to the treatment machine and positioned comfortably as they were at the time of CT 
simulation.  Image-guidance will be used to localize the treatment volume, including on-board radiographic 
imaging and cone-beam CT.  Cone-beam CT will always be completed except in cases where this is not 
technically feasible due to machine technical constraints.   Positioning correction will be performed as 
necessary, verified and documented. Implanted marker may be considered as surrogates for effective target 
localization.  The target localization procedure will be documented and adjustments will be made as 
appropriate.  Treatment will be delivered to the target volume in one fraction.  Each treatment plan will be 
checked for quality assurance in both calculation and dosimetry.  All treatment will be recorded and verified 
through ARIA information system. 
 
Post-operative Radiation:  
Following pre-operative boost subjects will proceed to surgical resection.  Systemic therapy will then be 
delivered as indicated and radiation will resume following systemic therapy in standard fashion.  Alternatively, 
women will return following surgical resection and initiate conventional whole breast radiation +/- regional 

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nodal treatment as per standard procedures.  Hypofractionated breast treatment will be considered an 
acceptable alternative to standard therapy (46-50Gy) when clinically appropriate.   
 
Cosmesis, recurrence and late RT toxicities outcomes will be gathered and recorded separately for subjects 
deemed to require mastectomy based on unexpected findings at the time of surgical resection.  It would not 
be accurate to compare the secondary endpoints of these subjects to those receiving breast conservation.   
 
5.3    Supportive Care 
Standard supportive therapies at the discretion of the treating radiation oncologist. 
 
5.4  
Early Study Termination 
This study can be terminated at any time for any reason by the PI-sponsor.  If this occurs, all subjects on study 
should be notified as soon as possible.  Additional procedures and/or follow up should occur in accordance 
with Section 10.7, which describes procedures and process for prematurely withdrawn subjects. 
 
6 
PATIENT ASSESSMENTS 
Assessment 
Pre-Tx. 
Follow-up 
Consent 
X 
 
History/Physical 
X 
Xa 
Complete Blood Count (no differential)/CMP 
X 
 
Breast imaging (mammogram minimum) 
Xg 
Xa 
Core Biopsy/Fiducial Markers 
Xb 
 
Planning MRI 
X 
 
Surgical Excision 
 
Xc 
Acute Toxicity Evaluation 
 
Xd 
Cosmetic Evaluation Form/Digital Photographs/QOL 
Xe 
Xe 
Clinical Outcomes 
 
Xa 
Serum Collection 
Xf 
Xf 
 
a.  Physical exam by member of oncology team recommended every 4-6 months for 2 years, every 6 months 
through year 5 and annually years 5-10.  Bilateral mammogram recommended at least annually.   
b.  Verify placement of a biopsy clip at diagnostic procedure. 
c.  Within 2-4 days following radiation (up to 7 allowed if needed – see below).   
d.  Appointment by a radiation oncology physician/mid-level provider 1-2 months post-radiation.   
e.  At baseline (prior to treatment), six months and one year after treatment and then annually for 2 additional 
years.  To be filled out by both patient and physician/mid-level provider.  Digital photographs at the same time 
points and at investigator’s discretion.  
f.  2 lavender tubes drawn prior to radiation therapy and post radiation therapy (before surgery) 
g.  Mammogram will not be repeated if one has been obtained within 6 months of signed study consent.  
Mammography does not need to be repeated unless clinically indicated. 
 
 
6.1  
Pretreatment Evaluations/Management 
Prior to treatment each patient will be required to have a complete history and physical including signed 
informed consent, basic clinical laboratory studies, staging and a biopsy demonstrating ductal carcinoma in 
situ or invasive breast carcinoma.  

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Assessment of the tumor by physical exam and mammogram (further imaging at radiologist/physician 
discretion) should include tumor measurements.  Each patient will complete a baseline cosmetic evaluation as 
will her physician/mid-level provider.  QOL measures will also be assessed.  Prior to study treatment, 
placement of a biopsy clip at the time of diagnostic biopsy will be verified as this will serve as a fiducial marker 
(described in section 8.2) to assist in radiotherapy localization.  MRI and CT of the affected breast will then be 
completed in Radiation Oncology for radiation treatment planning. 
 
6.2  
Screening Examination 
The screening examination will take place up to 45 days before study treatment.  An informed consent must 
be signed by the patient before any screening procedure takes place. If however, standard of care evaluation 
procedures have been obtained and are within the screening evaluation time points, the SOC procedures do 
not need to be repeated and may be included in the screening examination. 
 
6.3  
End of Treatment/Follow-up Period 
Lumpectomy will be completed 2-4 days (though up to 7 days will be allowed for logistical constraints without 
considering this a protocol deviation) following RT delivery.  Tissue will be processed as described below in 
section 8.1.  A surgical margin will be considered negative if there is no ink on tumor.  The patient will be 
assessed by a Radiation Oncology physician/mid-level provider within 2 months after preoperative treatment, 
to evaluate for treatment toxicity.  Subjects will then go on to complete systemic therapy as indicated or 
proceed to conventional radiation.   
 
Subjects will be seen weekly during conventional treatment as is standard procedure in our department.  
Follow-up after conventional radiation will follow national guidelines and includes a history and physical every 
4-6 months for the 1st 2 years, every 6 months to a year through year 5 and annually through year 10.  
Mammograms will be obtained at least annually.  Other laboratory or radiographic studies will be obtained as 
directed by patient symptoms or physical exam.  Quality of life and cosmetic assessments, physician/mid-level 
provider and patient, will be performed at 6 month, 1 year, and then annually through 3 years of follow-up as 
will digital photographs.  Locoregional recurrence will be monitored on protocol at each follow-up visit.   
 
6.4       Early Withdrawal of Subject(s) 
        6.4.1      Criteria for Early Withdrawal 
Subjects may voluntarily withdraw from the study at any time.  The PI may also withdraw a subject 
from the study at any time based on his/her discretion.  Reasons for PI-initiated withdrawal may 
include, but is not limited to the following: 
- 
Adverse events 
- 
Abnormal laboratory values 
- 
Abnormal test procedure results 
- 
Protocol deviation 
- 
Administrative issues 
- 
Disease progression 
- 
Pregnancy 
 
6.4.2      Follow-up Requirements for Early Withdrawal 
Standard of care follow up will adhered to. 
7 Statistical Considerations 
 
7.1  
Statistical Analysis of Cosmetic Outcome 

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This trial will accrue a total of 40 patients over 3 years. The rate of physician-reported good/excellent cosmetic 
outcome will be estimated at baseline and at the following four follow-up time points: 6, 12, 24, and 36 months.  A 
true rate of good/excellent cosmetic outcome rate of ≥ 0.80 would be considered acceptable, while a true rate of 
≤0.60 would be unacceptable. The cosmetic outcome rate at 6-months will be monitored with the following rules. 
 
 
 
Sample 
size 
Review patient data if and 
when the number of 
patients with fair/poor 
cosmetic outcome at 6 
months is: 
20 
≥ 8  
40 
≥ 12  
 
Specifically, if and when 8 or more of the first 20 patients (40%) have a fair/poor outcome, or if and when 12 or 
more of the 40 patients (30%) have a fair/poor outcome, the data will be reviewed and a decision will be made 
whether to close the trial. In other words, least 29 of the 40 patients (0.725) must have a good/excellent cosmetic 
outcome in order to consider the cosmetic outcome rate acceptable. If the true cosmetic rate is 0.60 and 0.80, 
then the probability that the rules above will call for a review is 0.93 and 0.10, respectively.  Assuming an observed 
good/excellent cosmesis rate of 0.75, a sample size of 40 will provide a 95% CI’s of 0.62
0.88. 
‒
 
 
7.2 
Statistical Analyses of the Secondary Objectives 
(a) To identify potential blood-based radiation response biomarkers, we will estimate mean (with 95% CI) and 
median change in circulating free DNA from pre- to post-RT, by level of biomarker.  
(b) Quality of life (FACT-B) and patient satisfaction will be measured at baseline and at 6, 12, 24, and 36 months.  
For each scale, the mean and its 95% CI’s will be estimated at each time point; boxplots will be used to estimate 
the distribution of these scales at each time point.  
(c) Time to local or regional failure will be defined as the time from start of treatment to date of local or regional 
failure, whichever comes first; distant failures will be ignored; deaths will be censored. Time to distant failure will 
be defined as the time from start of treatment to date of distant failure; local and regional failures will be ignored; 
deaths will be censored. The Kaplan Meier method will be used to estimate both of these distributions.   
 
8 
SAFETY MONITORING AND REPORTING 
The PI is responsible for the identification and documentation of adverse events and serious adverse events, as 
defined below.  At each study visit, the PI or designee must assess, through non-suggestive inquiries of the subject 
or evaluation of study assessments, whether an AE or SAE has occurred. 
 
8.1  
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a subject receiving study therapy and which 
does not necessarily have a causal relationship with this treatment.  For this protocol, the definition of AE also 
includes worsening of any pre-existing medical condition.  An AE can therefore be any unfavorable and 
unintended or worsening sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of radiation therapy, whether or not related to use of the radiation therapy.  
Abnormal laboratory findings without clinical significance (based on the PI’s judgment) should not be recorded 
as AEs.  But laboratory value changes that require therapy or adjustment in prior therapy are considered 
adverse events.  All acute toxicities will be captured from time of preoperative boost therapy to 1 month post 
conventional radiation therapy.  Chronic toxicities to be captured include breast pain, fibrosis, skin induration, 
hyperpigmentation, lymphedema, breast atrophy and swelling, infection, seroma, and wound healing. 
 

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From the time the subject signs the informed consent form through the End of Study visit (as defined in 
Section 10.4), all AEs must be recorded in the subject medical record and adverse events case report form. 
 
AEs will be assessed according to the CTCAE version 4.0.  If CTCAE grading does not exist for an AE, the severity 
of the AE will be graded as mild (1), moderate (2), severe (3), life-threatening (4), or fatal (5). 
 
Attribution of AEs will be indicated as follows: 
  
Definite:  The AE is clearly related to the study therapy 
  
Probably:  The AE is likely related to the study therapy 
  
Possible:  The AE may be related to the study therapy 
  
Unlikely:  The AE is doubtfully related to the study therapy 
  
Unrelated:  The AE is clearly NOT related to the study therapy 
 
8.1.1 
AEs of Special Interest 
All possible treatment related adverse events/toxicities reported or observed, the information should 
be recorded in the patient’s medical record and on the study’s Toxicity Evaluation Form or in the 
study’s toxicity database.  This should include a description of the event, its severity grade, the 
relationship to the study treatment and the onset date.  
 
8.1.2 
Reporting of AEs 
All grade 4 or higher unexpected and possibly related toxicity will be reviewed by the PI and study 
team and reported to the Duke University Health System IRB via the eIRB system. 
 
8.2  
Serious Adverse Events 
An AE is considered “serious” if in the opinion of the investigator it is one of the following outcomes: 
  
Fatal 
  
Life-threatening 
  
Constitutes a congenital anomaly or birth defect 
  
A medically significant condition (defined as an event that compromises subject safety or may require 
medical or surgical intervention to prevent one of the three outcomes above) 
  
Requires inpatient hospitalization or prolongation of existing hospitalization 
  
Results in persistent or significant incapacity or substantial disruption to conduct normal life functions 
 
 
8.3   
Safety Oversight Committee (SOC) 
The Duke Cancer Institute SOC is responsible for annual data and safety monitoring of DUHS sponsor-
investigator phase I and II, therapeutic interventional studies that do not have an independent Data Safety 
Monitoring Board (DSMB). The primary focus of the SOC is review of safety data, toxicities and new 
information that may affect subject safety or efficacy. Annual safety reviews includes but may not be limited 
to review of safety data, enrollment status, stopping rules if applicable, accrual, toxicities, reference literature, 
and interim analyses as provided by the sponsor-investigator.  The SOC in concert with the DCI Monitoring 
Team (see Section 12.1 for Monitoring Team description) oversees the conduct of DUHS cancer-related, 
sponsor-investigator greater-than-minimal-risk intervention studies that do not have an external monitoring 
plan, ensuring subject safety and that the protocol is conducted, recorded and reported in accordance with 
the protocol, standing operating procedures (SOPs), Good Clinical Practice (GCP), and applicable regulatory 
requirements. The DCI Safety Oversight Committee (SOC) will perform annual reviews on findings from the DCI 
Monitoring Team visit and additional safety and toxicity data submitted by the Principal Investigator. 
 
9  
QUALITY CONTROL AND QUALITY ASSURANCE 
9.1  
Monitoring 
The Duke Cancer Institute (DCI) Monitoring Team will conduct monitoring visits to ensure subject safety and to 
ensure that the protocol is conducted, recorded, and reported in accordance with the protocol, standard 

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operating procedures, good clinical practice, and applicable regulatory requirements.  As specified in the DCI 
Data and Safety Monitoring Plan, the DCI Monitoring Team will conduct routine monitoring after the third 
subject is enrolled, followed by annual monitoring of 1 – 3 subjects until the study is closed to enrollment and 
subjects are no longer receiving study interventions that are more than minimal risk.   
 
Additional monitoring may be prompted by findings from monitoring visits, unexpected frequency of serious 
and/or unexpected toxicities, or other concerns and may be initiated upon request of DUHS and DCI 
leadership, the DCI Cancer Protocol Committee, the Safety Oversight Committee (SOC), the sponsor, the 
Principal Investigator, or the IRB.  All study documents must be made available upon request to the DCI 
Monitoring Team and other authorized regulatory authorities, including but not limited to the National 
Institute of Health, National Cancer Institute, and the FDA.  Every reasonable effort will be made to maintain 
confidentiality during study monitoring. 
 
9.2  
Audits 
The Duke School of Medicine Clinical Trials Quality Assurance (CTQA) office may conduct confidential audits to 
evaluate compliance with the protocol and the principles of GCP.  The PI agrees to allow the CTQA auditor(s) 
direct access to all relevant documents and to allocate his/her time and the time of the study team to the 
CTQA auditor(s) in order to discuss findings and any relevant issues. 
 
CTQA audits are designed to protect the rights and well-being of human research subjects. CTQA audits may 
be routine or directed (for cause). Routine audits are selected based upon risk metrics generally geared 
towards high subject enrollment, studies with limited oversight or monitoring, Investigator initiated 
Investigational Drugs or Devices, federally-funded studies, high degree of risk (based upon adverse events, 
type of study, or vulnerable populations), Phase I studies, or studies that involve Medicare populations. 
Directed audits occur at the directive of the IRB or an authorized Institutional Official. 
 
CTQA audits examine research studies/clinical trials methodology, processes and systems to assess whether 
the research is conducted according to the protocol approved by the DUHS IRB. The primary purpose of the 
audit/review is to verify that the standards for safety of human subjects in clinical trials and the quality of data 
produced by the clinical trial research are met. The audit/review will serve as a quality assurance measure, 
internal to the institution. Additional goals of such audits are to detect both random and systemic errors 
occurring during the conduct of clinical research and to emphasize “best practices” in the research/clinical 
trials environment. 
 
10  
ADMINISTRATIVE AND ETHICAL CONSIDERATIONS 
10.1   Regulatory and Ethical Compliance 
This protocol was designed and will be conducted and reported in accordance with the International 
Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice, the 
Declaration of Helsinki, and applicable federal, state, and local regulations. 
 
10.2   DUHS Institutional Review Board and DCI Cancer Protocol Committee 
The protocol, informed consent form, advertising material, and additional protocol-related documents must 
be submitted to the DUHS Institutional Review Board (IRB) and DCI Cancer Protocol Committee (CPC) for 
review.  The study may be initiated only after the Principal Investigator has received written and dated 
approval from the CPC and IRB. 
 
The Principal Investigator must submit and obtain approval from the IRB for all subsequent protocol 
amendments and changes to the informed consent form.  The CPC should be informed about any protocol 
amendments that potentially affect research design or data analysis (i.e. amendments affecting subject 
population, inclusion/exclusion criteria, agent administration, statistical analysis, etc.).  
 

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The Principal Investigator must obtain protocol re-approval from the IRB within 1 year of the most recent IRB 
approval.  The Principal Investigator must also obtain protocol re-approval from the CPC within 1 year of the 
most recent IRB approval, for as long as the protocol remains open to subject enrollment. 
 
10.3   Informed Consent 
The informed consent form must be written in a manner that is understandable to the subject population.  
Prior to its use, the informed consent form must be approved by the IRB. 
 
The Principal Investigator or authorized key personnel will discuss with the potential subject the purpose of 
the research, methods, potential risks and benefits, subject concerns, and other study-related matters.  This 
discussion will occur in a location that ensures subject privacy and in a manner that minimizes the possibility 
of coercion.  Appropriate accommodations will be made available for potential subjects who cannot read or 
understand English or are visually impaired.  Potential subjects will have the opportunity to contact the 
Principal investigator or authorized key personnel with questions, and will be given as much time as needed to 
make an informed decision about participation in the study. 
 
Before conducting any study-specific procedures, the Principal Investigator or authorized key personnel, must 
obtain written informed consent from the subject or a legally acceptable representative.  The original 
informed consent form will be stored with the subject’s study records, and a copy of the informed consent 
form will be provided to the subject.   
10.4   Study Documentation 
Study documentation includes but is not limited to source documents, case report forms (CRFs), monitoring 
logs, appointment schedules, study team correspondence with sponsors or regulatory bodies/committees, 
and regulatory documents that can be found in the DCI-mandated “Regulatory Binder”, which includes but is 
not limited to signed protocol and amendments, approved and signed informed consent forms, FDA Form 
1572, CAP and CLIA laboratory certifications, and clinical supplies receipts and distribution records. 
 
Source documents are original records that contain source data, which is all information in original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial.  Source documents include but are not limited to hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after verification as being 
accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical 
trial.  When possible, the original record should be retained as the source document.  However, a photocopy is 
acceptable provided that it is a clear, legible, and an exact duplication of the original document. 
 
Electronic case report forms (eCRF) in REDCap will be the primary data collection document for the study.  The 
CRFs will be updated within two weeks of acquisition of new source data.  Only approved study staff will be 
permitted to make entries, changes, or corrections in the CRF.  For paper CRFs, errors will crossed out with a 
single line, and this line will not obscure the original entry.  Changes or corrections will be dated, initialed, and 
explained (if necessary).  The Principal Investigator or authorized key personnel will maintain a record of the 
changes and corrections.  For electronic CRFs, an audit trail will be maintained by REDCap. 
 
10.5   Privacy, Confidentiality, and Data Storage 
The Principal Investigator will ensure that subject privacy and confidentiality of the subject’s data will be 
maintained.  Research Data Security Plans (RDSPs) will be approved by the appropriate institutional Site Based 
Research group. 
 
To protect privacy, every reasonable effort will be made to prevent undue access to subjects during the course 
of the study.  Prospective participants will be consented in an exam room where it is just the research staff, 

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the patient and his family, if desired. For all future visits, interactions with research staff (study doctor and 
study coordinators) regarding research activities will take place in a private exam room. All research related 
interactions with the participant will be conducted by qualified research staff who are directly involved in the 
conduct of the research study. 
 
To protect confidentiality, subject files in paper format will be stored in secure cabinets under lock and key 
accessible only by the research staff. Subjects will be identified only by a unique study number and subject 
initials.  Electronic records of subject data will be maintained using a secure online REDCap database. Access 
to the REDCap database will be limited to essential study personnel. Subject data may be stored temporarily 
on encrypted and password-protected portable memory devices such as flash drives and external hard drives, 
but only when absolutely necessary.  Data stored on portable memory devices will be de-identified.  Subject 
data will be deleted from the portable memory device at the earliest opportunity.  The security and viability of 
the IT infrastructure will be managed by the DCI and/or Duke Medicine.   
 
Upon completion of the study, research records will be archived and handled per DUHS HRPP policy.     
 
Subject names or identifiers will not be used in reports, presentations at scientific meetings, or publications in 
scientific journals. 
 
10.6   Data and Safety Monitoring 
This clinical research study will be monitored both internally by the PI and institutionally by the Duke Cancer 
Institute (DCI).  In terms of internal review the PI will continuously monitor and tabulate adverse events.  
Appropriate reporting to the Duke University Medical Center IRB will be made.  If an unexpected frequency of 
Grade III or IV events occur, depending on their nature, action appropriate to the nature and frequency of 
these adverse events will be taken.  This may require a protocol amendment, dose de-escalation, or 
potentially closure of the study.  The PI of this study will also continuously monitor the conduct, data, and 
safety of this study to ensure that: 
 
Stopping rules for toxicity and/or response are met; 
Risk/benefit ratio is not altered to the detriment of the subjects; 
Appropriate internal monitoring of AEs and outcomes is done; 
Over-accrual does not occur; 
Under-accrual is addressed with appropriate amendments or actions; 
Data are being appropriately collected in a reasonably timely manner. 
 
DCI review and monitoring of this protocol occurs in accordance with the NCI-approved Data and Safety 
Monitoring Plan.  Briefly, protocol review begins with an initial review by the Cancer Protocol Committee 
(CPC), which assesses the ethics and safety of the protocol.  Documentation of these assessments will be 
maintained.  Formal, independent monitoring will be conducted by the DCI Monitoring Team after the first 3 
subjects are enrolled, followed by annual monitoring of 1-3 subjects until the study is closed to enrollment and 
subjects are no longer receiving study interventions that are more than minimal risk.  DCI Monitoring Team 
reports and additional data/safety/toxicity reports submitted by the PI will be reviewed by the Safety 
Oversight Committee (SOC) on an annual basis.  Additional monitoring may be prompted by findings from 
monitoring visits, unexpected frequency of serious and/or unexpected toxicities, or other concerns.  
Monitoring visits may also be initiated upon request by DUHS and DCI Leadership, CPC, SOC, a sponsor, an 
investigator, or the IRB.     
 
10.7   Protocol Amendments 
All protocol amendments must be initiated by the Principal Investigator and approved by the IRB prior to 
implementation.  IRB approval is not required for protocol changes that occur to protect the safety of a 
subject from an immediate hazard.  However, the Principal Investigator must inform the IRB and all other 
applicable regulatory agencies of such action immediately. 

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10.8   Records Retention 
The Principal Investigator will maintain study-related records for the longer of a period of at least six years 
after study completion, per Duke policy. 
 
 
 

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11  REFERENCES 
 
1. 
Morrow M, White J, Moughan J, et al: Factors predicting the use of breast-conserving therapy in 
stage I and II breast carcinoma. J Clin Oncol 19:2254-62, 2001 
 
2. 
Nattinger AB, Hoffmann RG, Kneusel RT, et al: Relation between appropriateness of primary 
therapy for early-stage breast carcinoma and increased use of breast-conserving surgery. Lancet 356:1148-53, 
2000 
 
3. 
Nattinger AB, Kneusel RT, Hoffmann RG, et al: Relationship of distance from a radiotherapy 
facility and initial breast cancer treatment. J Natl Cancer Inst 93:1344-6, 2001 
 
4. 
Foley KL, Kimmick G, Camacho F, et al: Survival disadvantage among Medicaid-insured breast 
cancer subjects treated with breast conserving surgery without radiation therapy. Breast Cancer Res Treat 
101:207-14, 2007 
 
5. 
Darby S, McGale P, Correa C, et al: Effect of radiotherapy after breast-conserving surgery on 10-
year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 
randomised trials. Lancet 378:1707-16, 2011 
 
6. 
Whelan TJ, Pignol JP, Levine MN, et al: Long-term results of hypofractionated radiation therapy 
for breast cancer. N Engl J Med 362:513-20, 2010 
 
7. 
Haviland J, Agrawal R, Aird E, et al: The UK START (Standardisation of Breast Radiotherapy) Trials:  
10-year follow-up results. Cancer Research 72, Supplement 3 (abs), 2012 
 
8. 
Olivotto IA, Whelan TJ, Parpia S, et al: Interim cosmetic and toxicity results from RAPID: a 
randomized trial of accelerated partial breast irradiation using three-dimensional conformal external beam 
radiation therapy. J Clin Oncol 31:4038-45, 2013 
 
9. 
Vaidya JS, Wenz F, Bulsara M, et al: Risk-adapted targeted intraoperative radiotherapy versus 
whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A 
randomised trial. Lancet 383:603-13, 2014 
 
10. 
Fisher B, Anderson S, Bryant J, et al: Twenty-year follow-up of a randomized trial comparing total 
mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J 
Med 347:1233-41, 2002 
 
11. 
Veronesi U, Marubini E, Mariani L, et al: Radiotherapy after breast-conserving surgery in small 
breast carcinoma: long-term results of a randomized trial. Ann Oncol 12:997-1003, 2001 
 
12. 
Clark RM, Whelan T, Levine M, et al: Randomized clinical trial of breast irradiation following 
lumpectomy and axillary dissection for node-negative breast cancer: an update. Ontario Clinical Oncology Group. J 
Natl Cancer Inst 88:1659-64, 1996 
 
13. 
Liljegren G, Holmberg L, Bergh J, et al: 10-Year results after sector resection with or without 
postoperative radiotherapy for stage I breast cancer: a randomized trial. J Clin Oncol 17:2326-33, 1999 
 
14. 
Bartelink H, Horiot JC, Poortmans PM, et al: Impact of a higher radiation dose on local control 
and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no 
boost EORTC 22881-10882 trial. J Clin Oncol 25:3259-65, 2007 
 
15. 
Romestaing P, Lehingue Y, Carrie C, et al: Role of a 10-Gy boost in the conservative treatment of 
early breast cancer: results of a randomized clinical trial in Lyon, France. J Clin Oncol 15:963-8, 1997 
 
16. 
Freedman GM, White JR, Arthur DW, et al: Accelerated fractionation with a concurrent boost for 
early stage breast cancer. Radiother Oncol 106:15-20, 2013 
 
17. 
Osa EO, DeWyngaert K, Roses D, et al: Prone Breast Intensity Modulated Radiation Therapy: 5-
Year Results. Int J Radiat Oncol Biol Phys, 2014 
 
18. 
Forouzannia A, Harness JK, Carpenter MM, et al: Intraoperative electron radiotherapy boost as a 
component of adjuvant radiation for breast cancer in the community setting. Am Surg 78:1071-4, 2012 
 
19. 
Ivaldi GB, Leonardi MC, Orecchia R, et al: Preliminary results of electron intraoperative therapy 
boost and hypofractionated external beam radiotherapy after breast-conserving surgery in premenopausal 
women. Int J Radiat Oncol Biol Phys 72:485-93, 2008 
 
20. 
Lemanski C, Azria D, Thezenas S, et al: Intraoperative radiotherapy given as a boost for early 
breast cancer: long-term clinical and cosmetic results. Int J Radiat Oncol Biol Phys 64:1410-5, 2006 

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21. 
Reitsamer R, Peintinger F, Kopp M, et al: Local recurrence rates in breast cancer subjects treated 
with intraoperative electron-boost radiotherapy versus postoperative external-beam electron-boost irradiation. A 
sequential intervention study. Strahlenther Onkol 180:38-44, 2004 
 
22. 
Palta M, Yoo S, Adamson JD, et al: Preoperative single fraction partial breast radiotherapy for 
early-stage breast cancer. Int J Radiat Oncol Biol Phys 82:37-42, 2012 
 
23. 
Hall WH, Guiou M, Lee NY, et al: Development and validation of a standardized method for 
contouring the brachial plexus: preliminary dosimetric analysis among subjects treated with IMRT for head-and-
neck cancer. Int J Radiat Oncol Biol Phys 72:1362-7, 2008 
 
24. 
DeRose YS, Gligorich KM, Wang G, et al: Patient-derived models of human breast cancer: 
protocols for in vitro and in vivo applications in tumor biology and translational medicine. Curr Protoc Pharmacol 
Chapter 14:Unit14 23, 2013 
 
 
 

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12 APPENDICES 
 
APPENDIX I:  Blood Processing 
Blood collected pre and post treatment will be used to explore the biologic response to radiotherapy by comparing 
changes in circulating cell-free DNA expression pre and post-radiotherapy:   
 
cfDNA 
 
2 EDTA tubes will be collected prior to radiation and following radiation.  Following collection, plasma will 
be isolated with the following protocol.   
 
1. Spin blood at 3200xg for 12 minutes at room temperature. 
2. Pipette off plasma using a plastic pasteur pipette. Transfer into tube. 
3. Spin NEW plasma tube at 2000xg for 10 minutes at 4°C. 
4. Aliquot into 1ml aliquots in labelled cryovials. 
5. Store at -80°C. 
 
Plasma isolation will be performed in the Clinical Cancer Research Lab and stored as above for future biomarker 
analysis.   
 
 
 
 
 
 

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APPENDIX II: NRG Cosmesis Scale 
 
1. ____-____-_____DATE EVALUATION DONE 
 
2. PLEASE ASSESS THE COSMETIC RESULTS OF BREAST CONSERVATION THERAPY AT THIS TIME. 
(Circle the number next to the word that best describes the cosmetic results.) 
 
1   EXCELLENT: when compared to the untreated breast or the original appearance of the treated breast, there is 
minimal or no difference in the size or shape of the treated breast. The way the breast feels (its texture) is the 
same or slightly different. There may be thickening, scar tissue, or seroma within the breast but not enough to 
change the appearance. 
 
2   GOOD: there is mild asymmetry between the breasts, which means that there is some acceptable difference in 
the size or shape of the treated breast as compared to the opposite breast or the appearance of the breast before 
treatment. There may be some mild reddening or darkening of the breast. The thickening or scar tissue within the 
breast causes a mild change in its shape or size. 
 
3   FAIR: moderate deformity of the breast, with an obvious difference in the shape and size of the treated breast. 
This change involves 1/4 or less of the breast. There can be moderate thickening or scar tissue of the skin and the 
breast and there may be obvious color changes. 
 
4   POOR: marked change in the appearance of the treated breast involving more than 1/4 of the breast tissue. The 
skin change may be obvious and detract from the appearance. Severe scarring and thickening of the breast which 
clearly alters its appearance may be present. In retrospect, the breast may have been better treated by a 
mastectomy. 
 
Please circle one (1) number for each of the following treatment effects. 
 
 
None 
Yes, present but does not 
affect cosmesis 
Yes, present and 
affects cosmesis 
Skin telangiectasia 
0 
1 
2 
Skin atrophy 
0 
1 
2 
Pigment change 
0 
1 
2 
Erythema 
0 
1 
2 
Fat necrosis 
0 
1 
2 
Fibrosis 
0 
1 
2 
Retraction or contour defect 
0 
1 
2 
Volume loss 
0 
1 
2 
Other significant tx effects 
Specify: _______________ 
0 
1 
2 
 
 
 
 
 
 
 
 
 
 

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APPENDIX III: Patient Self-Assessment 
 
1.  Please assess the cosmetic outcome of your treatment.  (Circle the number next to the word that best 
describes the appearance of the breast.) 
 
1     Excellent - when compared to the untreated breast, there is minimal or no difference in the size, shape or 
texture of the treated breast. There may be mild thickening or scar tissue within the breast or skin, but not enough 
to change the appearance.  
 
2     Good - there is mild asymmetry in the size or shape of the treated breast as compared to the normal breast. 
The thickening or scar tissue within the breast causes only a mild change in the shape.  
 
3     Fair - there is obvious difference in the size and shape of the treated breast. This change involves 1/4 or less of 
the breast.  
 
4     Poor - marked change in the appearance of the treated breast involving more than ¼ of the breast tissue.  
 
  
2.   How satisfied with your treatment are you?   
Extremely satisfied 
 
Very Satisfied 
 
Satisfied  
Unsatisfied 
 
 
3.  Would you choose this treatment again?    
Yes  
 
 
No 
 
 

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APPENDIX IV:  Quality of Life 
 
Below is a list of statements that other people with breast cancer have said are important to their quality of life. 
Please indicate the extent to which you have experienced each of the following statements during the past 7 days 
by circling the appropriate number using the following scale.  
 
During the past week: 
                                                                                                                                    Not at    A little    Some-     Quite     Very 
PHYSICAL WELL-BEING                                                                                              all           bit         what       a bit      much 
 
1. I have a lack of energy 
0 
1 
2 
3 
4 
 
2. I have nausea 
 
0 
 
1 
 
2 
 
3 
 
4 
 
3. Because of my physical condition, I have trouble meeting                             
the needs of my family 
 
 
 
0 
 
 
1 
 
 
2 
 
 
3 
 
 
4 
4. I have pain 
0 
1 
2 
3 
4 
 
5. I am bothered by side effects of treatment 
 
0 
 
1 
 
2 
 
3 
 
4 
 
6. I feel sick 
 
0 
 
1 
 
2 
 
3 
 
4 
 
7. I am forced to spend time in bed 
 
0 
 
1 
 
2 
 
3 
 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
 
 
 
 
 
8. I feel close to my friends 
 
0 
 
1 
 
2 
 
3 
 
4 
 
9. I get emotional support from my family 
 
0 
 
1 
 
2 
 
3 
 
4 
 
10. I get support from my friends  
 
0 
 
1 
 
2 
 
3 
 
4 
 
11. My family has accepted my illness 
 
0 
 
1 
 
2 
 
3 
 
4 
 
12. I am satisfied with family communication about my                                     
illness 
 
 
0 
 
 
1 
 
 
2 
 
 
3 
 
 
4 
 
13. I feel close to my partner (or the person who is my main support) 
0 
1 
2 
3 
4 
 
14. I am satisfied with my sex life 
 
0 
 
1 
 
2 
 
3 
 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PT-RT P II/III-v03.06.2018 
Duke Cancer Institute 
Page 25 of 26 
CONFIDENTIAL 
 
During the past week:  
 
 
 
 
 
 
 
 
    Not at    A little    Some-     Quite     Very 
EMOTIONAL WELL-BEING                                                                                         all           bit         what       a bit      much 
 
15. I feel sad 
0 
1 
2 
3 
4 
 
16. I am proud of how I am coping with my illness 
 
0 
 
1 
 
2 
 
3 
 
4 
 
17. I am losing hope in the fight against my illness 
 
0 
 
1 
 
2 
 
3 
 
4 
 
18. I feel nervous 
 
0 
 
1 
 
2 
 
3 
 
4 
 
19. I worry about dying 
 
0 
 
1 
 
2 
 
3 
 
4 
 
20. I worry that my condition will get worse 
 
0 
 
1 
 
2 
 
3 
 
4 
 
 
FUNCTIONAL WELL-BEING 
 
 
 
 
 
 
21. I am able to work (include work at home) 
 
0 
 
1 
 
2 
 
3 
 
4 
 
22. My work is fulfilling (include work at home) 
 
0 
 
1 
 
2 
 
3 
 
4 
 
23. I am able to enjoy life 
 
0 
 
1 
 
2 
 
3 
 
4 
 
24. I have accepted my illness 
 
0 
 
1 
 
2 
 
3 
 
4 
 
25. I am sleeping well 
 
0 
 
1 
 
2 
 
3 
 
4 
 
26. I am enjoying the things I usually do for fun 
 
0 
 
1 
 
2 
 
3 
 
4 
 
27. I am content with the quality of my life right now 
 
0 
 
1 
 
2 
 
3 
 
4 
 
 
ADDITIONAL CONCERNS 
 
 
 
 
 
 
28. I have been short of breath 
 
0 
 
1 
 
2 
 
3 
 
4 
 
29. I am self-conscious about the way I dress 
 
0 
 
1 
 
2 
 
3 
 
4 
 
30. My arms are swollen or tender 
 
0 
 
1 
 
2 
 
3 
 
4 
 
31. I feel sexually attractive 
 
0 
 
1 
 
2 
 
3 
 
4 
 
32. I have been bothered by hair loss 
 
0 
 
1 
 
2 
 
3 
 
4 
 
33. I worry about the effect of stress on my illness 
 
0 
 
1 
 
2 
 
3 
 
4 
 
34. I am bothered by a change in weight 
 
0 
 
1 
 
2 
 
3 
 
4 
 
35. I am able to feel like a woman 
 
0 
 
1 
 
2 
 
3 
 
4 
 
 
 
 
 
 
 
 
 
 

PT-RT P II/III-v03.06.2018 
Duke Cancer Institute 
Page 26 of 26 
CONFIDENTIAL 
 
APPENDIX V: Digital Photographs 
 
The first photograph should be a close-up encompassing only the treated breast at a 45 degree oblique with arms 
elevated over the head. The second photograph should be a straight frontal view of both breasts taken in either a 
standing or seated position with the patient’s hands symmetrically placed on her hips, taking care to exclude her 
face and framing or focusing on both the treated and untreated breast to allow optimal comparison of the breasts 
for symmetry.