Evaluation of Single Fraction High-Gradient Partial Breast Irradiation as the Sole Method of Radiation Therapy for Low-Risk Stage 0 and I Breast Carcinoma
Phase: NA
Conditions: Breast Neoplasms
Sponsor: Washington University School of Medicine

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page 1 of 41 
 
 
 
Evaluation of Single Fraction High-gradient Partial Breast Irradiation as the Sole Method 
of Radiation Therapy for Low-risk Stage 0 and I Breast Carcinoma 
 
Washington University School of Medicine 
Department of Radiation Oncology 
660 South Euclid Avenue, Campus Box 8224 
St. Louis, MO  63110 
 
Protocol#: 201401160 
Version Date: 11/26/19 
 
Principal Investigator: 
Imran Zoberi, M.D. 
Phone: (314) 362-8610 
Email: izoberi@radonc.wustl.edu 
 
Sub-Investigators 
 
 
 
Modality 
Maria Thomas, M.D., Ph.D.  
 
Radiation Oncology 
Laura Ochoa, ANP, Ph.D. 
 
 
Radiation Oncology 
Rojano Kashani, Ph.D. 
 
 
Radiation Oncology 
Julie Margenthaler, M.D. 
 
 
Surgery 
Souzan Sanati, M.D.  
 
 
Anatomic & Molecular Pathology 
Todd DeWees, Ph.D.  
 
 
Biostatistics 
 
 
ClinicalTrials.gov #: NCT02076074 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to obtain 
informed consent, may not be disclosed to another party unless law or regulations require such disclosure.  Persons 
to whom the information is disclosed must be informed that the information is confidential and may not be further 
disclosed by them 
 
 

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Evaluation of Single Fraction High-gradient Partial Breast Irradiation as the Sole Method 
of Radiation Therapy for Low-risk Stage 0 and I Breast Carcinoma 
 
Protocol Revision History 
 
Initial Approval Version 
01/31/2014 
Amendment #1 
04/01/2014 
Amendment #2 
05/18/2015 
Amendment #3 
11/03/2015 
Amendment #4 
 
 
 
 
 
 
 
01/05/2016 
Amendment #5 
 
 
 
 
 
 
 
03/20/2017 
Amendment #6 
 
 
 
 
 
 
 
11/26/2019 

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Evaluation of Single Fraction High-gradient Partial Breast Irradiation as the Sole Method 
of Radiation Therapy for Low-risk Stage 0 and I Breast Carcinoma 
 
SCHEMA 
 
Study Summary 
This is a phase I/II study which will evaluate the complication rates, local control, cosmetic results, and 
quality of life of single fraction high gradient partial breast irradiation (HG-PBI) when used as the sole 
method of radiation therapy for patients with pathologic stage 0 (≤ 2 cm) or I carcinoma of the breast treated 
with partial mastectomy with histologically assessed negative surgical margins.  Time to event parameters 
that will be collected are IBTR, mastectomy-free survival, regional recurrence rate, distant disease free 
survival, and overall survival. 
 
  
 
 
 
 
  
 
 
 
Systemic Therapy  
Cytotoxic chemotherapy, hormonal, or biologic therapies are not to be started until at least 4 weeks 
after radiation therapy. 
 
Eligibility (see Section 3.0 for details) 
- 
Ductal carcinoma in situ (lesions ≤ 2 cm) 
- 
Invasive ductal, lobular, medullary, papillary, colloid (mucinous), tubular histologies, or 
mixed histologies (lesions ≤ 2 cm) that are estrogen or progesterone receptor positive and 
do not exhibit HER2/neu gene amplification 
- 
Stages TisN0M0 or T1N0M0  
- 
Postmenopausal 
- 
Age ≥ 50 years 
- 
No prior ipsilateral breast cancer 
- 
No neoadjuvant systemic therapy 
- 
Negative surgical margins after partial mastectomy  
- 
No systemic lupus erythematosis, scleroderma, or dermatomyositis 
- 
Time interval from final definitive breast surgical procedure to HG-PBI less than 8 weeks 
- 
Signed study-specific consent form  
 
Required Sample Size 
50 evaluable patients, with target accrual of 55 patients (expected drop-out rate = 10%) 
 
Radiotherapy 
1. Single Fraction of High Gradient 
Stereotactic Partial Breast 
Irradiation 
2. 20 Gy to cavity surface  7 Gy 
to 1 cm from cavity surface in one 
fraction 
 
 
E
V
A
L
U
A
T
I
O
N 
Cancer Evaluation 
1. Routine History & Physical 
2. Routine Mammography 
 
Cosmetic Evaluation 
1. Qualitative by patient & physician 
2. Quantitative by physician 
 
Quality of Life Evaluation 
1. EORTC Questionnaires 

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Glossary of Abbreviations 
 
3D-CRT 
Three dimensional treatment planning 
AE 
 
Adverse event 
AJCC 
 
American Joint Committee on Cancer 
APBI 
 
Accelerated partial breast irradiation 
ATC 
 
Advanced Technology Consortium 
BCT 
 
Breast conserving therapy 
BID 
 
Bis in die (twice a day) 
BRA 
 
Breast Retraction Assessment 
CRF 
 
Case report form 
CT 
 
Computed tomography 
CTCAE  
Common Terminology Criteria for Adverse Events 
CTV 
 
Clinical target volume 
DCIS 
 
Ductal carcinoma in situ 
DOB 
 
Date of birth 
DSM 
 
Data and safety monitoring 
DVH 
 
Dose volume histogram 
EORTC  
European Organization for Research and Treatment of Cancer 
HDR 
 
High dose rate 
HG-PBI  
High gradient partial breast irradiation 
HRPO  
Human Research Protection Office 
IBTR 
 
Ipsilateral breast tumor recurrence 
IMRT 
 
Intensity modulated radiation therapy 
IRB 
 
Institutional review board 
LCIS 
 
Lobular carcinoma in situ 
NCI 
 
National Cancer Institute 
NSABP  
National Surgical Adjuvant Breast and Bowel Project 
OHRP  
Office for Human Research Protections 
PTV 
 
Planned treatment volume 
QA 
 
Quality assurance 
QASMC 
Quality Assurance and Safety Monitoring Committee 
QOL 
 
Quality of Life 
RT 
 
Radiation therapy 
RTOG  
Radiation Therapy Oncology Group 
SAE 
 
Serious adverse event 
SBRT 
 
Stereotactic body radiotherapy 
SCC 
 
Siteman Cancer Center 
TARGIT 
Targeted intraoperative radiotherapy 
UPN 
 
Unique patient number 
WBI 
 
Whole breast irradiation 
 

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Table of Contents 
SCHEMA ........................................................................................................................................ 3 
1.0 
INTRODUCTION ............................................................................................................... 7 
1.1 
Introduction to Accelerated Partial Breast Irradiation ..................................................... 7 
1.2 
Targeted Intraoperative Radiotherapy (TARGIT) ........................................................... 8 
1.3 
Single Fraction High Gradient APBI (HG-PBI) ............................................................ 10 
1.4 
Cosmetic Analysis in BCT ............................................................................................. 12 
1.5 
Quality of Life Analysis in Breast Cancer ..................................................................... 13 
2.0 
OBJECTIVES .................................................................................................................... 13 
2.1 
Primary Objectives ......................................................................................................... 13 
2.2 
Secondary Objectives ..................................................................................................... 13 
3.0 
PATIENT SELECTION .................................................................................................... 14 
3.1 
Inclusion Criteria ............................................................................................................ 14 
3.2 
Exclusion Criteria ........................................................................................................... 14 
3.3 
Inclusion of Women and Minorities............................................................................... 15 
4.0 
REGISTRATION PROCEDURES ................................................................................... 15 
4.1 
Confirmation of Patient Eligibility ................................................................................. 16 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 16 
4.3 
Assignment of UPN ....................................................................................................... 16 
5.0 
TREATMENT PLAN ........................................................................................................ 16 
5.1 
Pre-Treatment Evaluations ............................................................................................. 16 
5.2 
Radiation Therapy .......................................................................................................... 16 
5.3 
General Concomitant Medication and Supportive Care Guidelines .............................. 19 
5.4 
Duration of Therapy ....................................................................................................... 19 
5.5 
Duration of Follow-up .................................................................................................... 20 
6.0 
DISEASE RESPONSE CRITERIA ................................................................................... 20 
6.1 
Mastectomy Free Survival ............................................................................................. 20 
6.2 
Recurrence of Breast Cancer .......................................................................................... 20 
6.3 
Cosmesis......................................................................................................................... 20 
7.0 
STUDY CALENDAR ....................................................................................................... 22 
8.0 
DATA SUBMISSION SCHEDULE ................................................................................. 23 
9.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 23 
9.2 
Reporting to the Human Research Protection Office (HRPO) at Washington University
 
25 
9.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 

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Washington University .............................................................................................................. 25 
9.4 
Timeframe for Reporting Required Events .................................................................... 26 
10.0 DATA AND SAFETY MONITORING ............................................................................ 26 
11.0 STATISTICAL CONSIDERATIONS............................................................................... 26 
11.1 
Specific Aims ................................................................................................................. 26 
11.2 
Study Endpoints ............................................................................................................. 27 
11.3 
Study Design and Analysis Plan .................................................................................... 27 
11.4 
Sample Size and Study Power ........................................................................................ 28 
11.5 
Treatment Failure ........................................................................................................... 28 
11.6 
Accrual ........................................................................................................................... 29 
12.0 REFERENCES .................................................................................................................. 29 
APPENDIX I: Patient Evaluation of the Treated Breast .............................................................. 33 
APPENDIX II: Physician Evaluation of the Treated Breast ........................................................ 34 
APPENDIX III: Quantitative Cosmetic Analysis ......................................................................... 36 
APPENDIX IV: EORTC QLQ-C30 and BR23 ............................................................................ 37 
APPENDIX V: Brief Pain Assessment......................................................................................... 41 
 
 
 

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1.0 
INTRODUCTION 
 
1.1 
Introduction to Accelerated Partial Breast Irradiation 
 
Prospective, randomized, controlled trials have established that breast conservation therapy (BCT), 
consisting of partial mastectomy and adjuvant radiation therapy, offers equivalent disease control 
in women with Stage I and II breast cancer as compared to mastectomy, and it offers significantly 
superior disease control when compared to partial mastectomy alone [1-3]. BCT offers patients 
better cosmetic outcomes with less emotional trauma than mastectomy [4]. In the setting of ductal 
carcinoma in situ, adjuvant radiation therapy has been shown to increase local control when 
delivered as a part of breast conservation surgery [5-7].  
 
The standard method for administering breast irradiation as a part of BCT is whole breast irradiation 
(WBI), where the entire breast is treated with external beam radiation delivered in five daily 
fractions per week for several weeks, often followed by a boost to the partial mastectomy site. 
Typical whole breast doses range from 40-50 Gy and boost doses range from 10-16 Gy.  WBI can 
present a host of challenges for patients involving work schedules, commuting time, transportation 
expenses, and difficulties with mobility. Previous studies have suggested that some women may 
decline breast conservation therapy due to the time commitment required to complete therapy, and 
some women may simply elect to forgo the radiation therapy component resulting in suboptimal 
care [8-10].  
 
Accelerated partial breast irradiation (APBI) techniques were developed in part to improve breast 
conserving surgery rates and compliance with adjuvant radiation therapy. APBI challenges the 
paradigm that the entire breast should be subjected to adjuvant radiation therapy by treating a 
volume of breast tissue around the partial mastectomy site.  APBI is based on both pathologic [11] 
and empiric [12] data that demonstrates that the greatest site for an ipsilateral breast tumor 
recurrence (IBTR) is near the partial mastectomy surgical bed in patients who are at an overall low 
risk for multicentric foci of disease.  As most commonly practiced, APBI delivers a total dose of 
34 Gy in 10 BID fractions over five treatment days via high dose rate (HDR) brachytherapy.  APBI 
began by using multicatheter interstitial brachytherapy with early reports from a number of others, 
including the Oschner Clinic, [13] William Beaumont Hospital[14], and the Radiation Therapy 
Oncology Group (RTOG) 95-17[15] trial which all described excellent outcomes.   Unfortunately, 
multicatheter interstitial implants proved technically challenging and never achieved widespread 
popularity.  This led a number of companies to develop intracavity brachytherapy applicators such 
as the Mammosite (Holologic, Bedford, MA), Contura (Bard Biopsy Systems, Tempe, AZ), and 
SAVI (Cianna Medical, Aliso Viejo, CA).   Although there are a number of technical differences 
between these devices, they are all inserted into the partial mastectomy cavity and serve as 
applicators for HDR brachytherapy.  The largest series of intracavitary APBI is the Mammosite 
registry trial that reports a less than 4% five-year IBTR[16].   
 
To avoid the attendant risks of pain, bleeding, and infection that are associated with intracavity 
APBI applicator placement, investigators have developed external beam methods of treating a 
limited breast volume.  External beam APBI uses three dimensional treatment planning (3D-CRT) 
to develop a complex, patient-specific beam arrangement to treat the target volume to a dose of 
38.5 Gy in 10 BID fractions over five treatment days.  Typically, three to six beams are used and 
there is the occasional need for intensity modulated beams.  3D-CRT has been studied by the RTOG 
0319 trial [17] and by institutions such as the William Beaumont Hospital [18], with low IBTR in 
both publications.  In general 3D-CRT avoids the applicator placement issues of intracavitary APBI 

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at the expense of greater radiation exposure to breast tissue, chest wall, lungs, and, for left sided 
cancers, heart. 
 
At Washington University, multicatheter interstitial brachytherapy represents our earliest APBI 
technique and was practiced from 2002-2009. We have completed a phase I/II trial of multicatheter 
APBI that was designed to quantify five year IBTR with a narrow 95% confidence interval (HRPO# 
03-1205).  We have demonstrated low IBTR[19] while maintaining excellent cosmetic results[20] 
with low toxicity[21].  Since then, we have initiated both intracavitary and external beam APBI 
programs.  We have completed a dose escalation study utilizing 3D-CRT APBI (HRPO# 05-1053).  
At present we offer APBI or WBI therapy as treatment options for early-stage breast cancer in 
appropriately selected patients.  An exhaustive list of APBI studies using a variety of techniques is 
reported in Smith et al [22]. 
 
1.2 
Targeted Intraoperative Radiotherapy (TARGIT) 
 
APBI minimizes the irradiated volume and shortens the treatment time for adjuvant radiation 
therapy all while maintaining low IBTR.  The ultimate extrapolation of APBI is to reduce the 
fractionation to one and the treatment time to several minutes after partial mastectomy.  TARGIT 
is such a method.  Although TARGIT will be described for the necessary context, it is important to 
note from the outset that this proposed clinical trial involves replicating the TARGIT radiation dose 
distribution but does not use the TARGIT device or involve delivering radiation dose 
intraoperatively.  Adjuvant radiation in the TARGIT method is generated from the Intrabeam 
device (Carl Zeiss, Oberkochen, Germany).  This FDA-approved device provides a point source of 
low energy x-rays (50 kV maximum) at the tip of a 3.2 mm diameter tube that is placed at the center 
of a spherical applicator (Figure 1).  After a standard partial mastectomy an appropriate applicator 
is selected and placed in the tumor bed.  The Intrabeam device is switched on for 20-35 minutes 
which typically delivers a surface dose of 20 Gy that attenuates to 5-7 Gy at 1 cm depth.  If 
necessary the underlying chest wall and/or the skin can be protected by radiopaque tungsten-filled 
polyurethane caps. 
 
Figure 1. Intrabeam device (left) and schematic (right) of 
applicator in the partial mastectomy cavity 
Applicator Shank 

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The safety and tolerability of the TARGIT was evaluated in a pilot study of 25 breast cancer 
patients[23] where it was used to replace the boost component of whole breast radiation therapy.  
There were no major complications and no IBTR at 24 months.  This was followed by a larger 
phase II study of 301 patients who again received TARGIT as a boost followed by whole breast 
radiation therapy[24].  The five year IBTR was 2.6% and complications remained acceptable.  The 
finding that the TARGIT method was feasible along with the separate, coincident development of 
APBI methods led to the design of a prospective, randomized, non-inferiority phase III trial that 
compared standard whole breast radiation therapy with TARGIT-alone APBI (Figure 2).   
 
Eligible patients included women at least 45 years of age with unifocal invasive breast cancers 
suitable for surgical resection via partial mastectomy. The control arm received conventional whole 
breast radiotherapy of 40-56 Gy with or without a boost of 10-16 Gy.  This study has completed 
planned accrual and is in follow-up [25].  Median age was 63 years, 86% of tumors were ≤ 2 cm, 
83% of patients had node negative disease, and 90% of patients had estrogen receptor-positive 
disease.  Early results showed a 4-year IBTR of 1.2% in the control arm and 0.95% in the TARGIT 
arm. In the TARGIT arm the infection rate was 1.8% and 3.3% had skin breakdown or delayed 
wound healing.  Further publications from this study are planned when the median follow-up is 
greater. 
 
Figure 2. TARGIT-A Trial Schema  
 
The major shortcoming of the TARGIT approach is the need to administer radiation therapy before 
the true pathologic extent of disease is known.  In the TARGIT-A study, 15% of patients in the 
TARGIT arm had unexpected pathologic findings that resulted in them requiring an additional 25 

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treatments of daily external beam radiation therapy to achieve the desired outcome, negating the 
positive benefit intended of receiving a solitary treatment. Some patients in the TARGIT-A study 
did have TARGIT treatment as a separate procedure several weeks after the initial partial 
mastectomy.  While this approach avoids the risk of unexpected pathologic findings, it does require 
a reopening in the partial mastectomy incision, and extensive manipulation of breast tissue after 
some healing has occurred negating some of the benefits of a single treatment.  Finally TARGIT 
involves considerable expense as it requires purchase of dedicated equipment that has few other 
uses. 
 
1.3 
Single Fraction High Gradient APBI (HG-PBI) 
 
The proposed clinical trial arose from discussion regarding the numerous merits of TARGIT 
treatment along with its significant limitations.  Clearly a single treatment that is well tolerated and 
effective has enormous appeal.  It has the potential to minimize the impact of local breast cancer 
treatment on the lives of thousands of women each year.  And yet the fact that TARGIT is 
insufficient treatment due to a margin issue, lymph node metastasis, or some other pathologic 
finding in at least 15% of patients (and the frequency is likely to be greater in clinical practice than 
it was in a clinical trial) is clearly unsatisfying.  A review of the radiation dose distributions 
generated in TARGIT demonstrates that they are very similar to those achieved by stereotactic 
body radiosurgery (SBRT).  SBRT is a relative recent method of delivering highly conformal 
radiation dose distributions via external beam radiation therapy; it is commonly used in the 
radiotherapeutic management of small tumors in the lung, liver, and vertebral bodies[26]. In SBRT, 
typically patients receive one to five radiation treatments.  SBRT utilizes special patient 
immobilization devices and requires image guided radiation therapy, but it has become well 
established in most large radiation oncology clinics. 
 
As a preliminary work, we examined the radiation therapy CT data sets of several patients who 
were treated with 3D-CRT APBI.  We sought to determine the feasibility of generating 
dosimetrically acceptable plans with external beam. Our main dosimetric goal was to deliver 7 Gy 
to an irregular surface 1 cm away from the surgical cavity while achieving a dose of at least 15 Gy 
but no more than 20 Gy at the cavity surface.  We sought to limit the skin dose to less than 5 Gy 
and minimize low dose exposure to the surrounding breast tissue and to the nearby chest, lung, and 
heart.  These plans which included IMRT plans using the flattening filter free mode on TrueBeam 
(Varian Medical Systems Inc., Palo Alto, CA) as well as Smart Arc (Philips, Amersterdam, NL) 
plans, showed good conformality and coverage with minimal exposure to normal tissue.  An 
example of a 5 field IMRT plan is shown in Figure 3a and 3b below. 
 
 
Figure 3a (Left): Isodose distribution for a 5 
field IMRT plan using the 10 MV flattening 
filter free mode from TrueBeam.  The dark 
blue target is the surgical bed with a 
prescription Dose of 20 Gy (Magenta line). 
The cyan target is a 1cm expansion of the 
surgical bed which is expected to be covered 
by 7 Gy (shown in blue). Dose to the lungs 
should be less than 5Gy (green line).  The 
yellow line represents the 3 Gy isodose.  
 
Figure 3b (below): Isodose distribution for a 
SmartArc Plan on a different patient.  Again 
the dark blue target is the surgical bed while 
the cyan is a 1 cm expansion. 

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We have demonstrated that it is feasible to generate these plans in several patients who received 
conventional APBI (Table 1).  This dose distribution has been shown to be well tolerated and 
effective in the TARGIT studies.  We believe that this will also be the case when external beam 
radiation therapy is used.  Our proposed approach allows us to avoid administering radiation before 
the pathologic extent of disease is known and without the purchase of specialized intraoperative 
radiation equipment.  If successful this has the potential to revolutionize partial breast irradiation 
by allowing it to take place at many radiation oncology centers with minimal specialized equipment 
beyond that available with modern linear accelerators.  Our first step is this proposed single 
institution phase I/II study designed primarily to evaluate the tolerance of this approach which we 
are choosing to call Single Fraction High Gradient APBI (HG-PBI). 
 
 

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Table 1.  HG-PBI parameters averaged over 9 patients  
Skin structure is from skin to skin-3 mm in the region of the target 
PTV Cavity 
V20 (Rx) 
93.77 
% 
V19 (95% Rx) 
97.87 
% 
Min  
16.622 
Gy 
Max 
26.828 
Gy 
Mean 
23.1 
Gy 
PTV + 1 cm 
V7 (Rx) 
97.448 
% 
V6.65 (95% Rx) 
97.962 
% 
Min 
4.482 
Gy 
Max 
26.828 
Gy 
Mean 
14.972 
Gy 
Contralateral Lung 
Max 
1.824 
Gy 
V5 
0 
% 
Ipsilateral Lung  
Lung_Ipsi_DMax_Gy 
6.164 
Gy 
Lung_Ipsi_V5Gy_% 
2.05 
% 
Heart 
Heart_V5Gy_% 
0.268 
% 
Skin  
Max 
8.7575 
Gy 
V7 
0.9425 
cc 
V5 
4.185 
cc 
V3 
14.6975 
cc 
 
1.4 
Cosmetic Analysis in BCT 
 
The cosmetic result after BCT is an important outcome.  Unfortunately, there is no standard method 
for cosmetic evaluation.  Harris described a four category qualitative scoring system whereby 
cosmesis was classified as excellent, good, fair, or poor.[27] Although this method provided for 
easy patient assessment of their own cosmesis, Pezner demonstrated that consensus between 
observers could only be attained if the four categories were reduced to excellent/good versus 
fair/poor.[28] Aaronson expanded the Harris scale to include global cosmetic result, appearance of 
the surgical scar, breast size, breast shape, nipple position, shape of the areola, and skin color as 
categories to be evaluated by the Harris rating system.[29] (See Appendix I) Whelan et al recently 
reported the cosmetic results in BCT using Aaronson’s scale in the setting of a large phase III 
National Cancer Institute of Canada trial testing two radiotherapy fractionation schedules.[30] At 
five years, 76-77% of patients had an excellent or good cosmetic outcome.  A more quantitative 
cosmetic assessment is the Breast Retraction Assessment (BRA) originally proposed by Pezner[31] 
(See Appendix III).  This tool attempts to quantify the retraction in the treated breast versus the 
contralateral, untreated breast.  The European Organization for Research and Treatment of Cancer 
(EORTC) has published a validation study of the Aaronson scale and the BRA using 731 patients 
with Stage I or II breast cancer involved in a much larger trial.[32, 33] The investigators describe 
moderate intraobserver agreement for the qualitative scoring system with a simple Kappa of 0.42 
and a fair interobserver agreement with a multiple Kappa of 0.27.  The BRA had a mean value of 
30 mm with an intraobserver deviation from average of 2.3 mm (7.7%) and an interobserver 
deviation from the mean of 2.6 mm (8.7%).  The BRA and the qualitative score were significantly 
correlated; however, some treatment sequelae such as scars or skin changes were best measured 

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qualitatively.   This study will use both the Aaronson qualitative cosmetic assessment method used 
in the EORTC trial and the quantitative BRA for cosmetic evaluation. 
 
1.5 
Quality of Life Analysis in Breast Cancer 
 
Quality of Life (QoL) has emerged as an important endpoint in therapeutic clinical trials.  This has 
been particularly true in the study of diseases that have excellent overall survival and/or equivalent 
alternative therapies.  Measures of QoL have evolved from qualitative descriptions such as 
performance status assigned by medical professionals to more quantitative data obtained from 
questionnaires filled out by patients.  The EORTC Study Group on QoL has developed and 
validated a general cancer QoL questionnaire with several site-specific modules.  The general 
cancer QoL questionnaire (QLQ-C30 shown in Appendix VI) contains thirty questions that assess 
the impact of disease and treatment on the daily life of cancer patients and is optimally used in 
conjunction with the appropriate disease site module.[34] The QLQ-C30 is scored using algorithms 
developed by the EORTC.[35] Groenvold reported high agreement between the QLQ-C30 and 
observer rating of patients response to open-ended responses to the same questions.[36] McLahlan 
showed that the QLQ-C30 questionnaire showed expected divergent validity for breast cancer 
patients who were expected to have different QoL based on such differences as performance status 
or treatment with chemotherapy.[37] The same study also demonstrated convergent validity 
between the QLQ-C30 and several widely used QoL scales such as the Psychosocial Adjustment 
to Illness Scale (PAIS) and the Profile of Mood Status (POMS).  Spangers has described the 
development and validity analysis of a breast cancer specific module, the QLQ-BR23, that 
measures QoL issues more specific to breast cancer than the general QoL issues assessed by the 
QLQ-C30.[38] The QLQ-BR23 (See Appendix IV) is a twenty-three-item questionnaire that takes 
an average of 9.2 minutes (SD, 4.7 min) to complete.  It has been found to be reliable and clinically 
valid in American women with breast cancer.[38] This study will use the QLQ-C30 and the QLQ-
BR23 to assess QoL before, during, and after brachytherapy.  Permission to use these copyrighted 
instruments for this study has been obtained.  A standard Visual Analog Scale for Pain will be used 
for general pain assessment. 
 
 
2.0 
OBJECTIVES  
 
2.1 
Primary Objectives 
 
1. To quantify the tolerance of HG-PBI by estimating the rate of acute and late treatment-related 
grade 3 or higher toxicity (per CTCAE, v.4.0) or any other grade 4 or 5 toxicity attributed to 
the therapy.  Toxicities of concern include breast pain, delayed wound healing, persistent 
seroma fluid accumulation, breast fibrosis and fat necrosis in the treated breast.  Rare toxicities 
include radiation pneumonitis and pericarditis. 
2. To estimate the ipsilateral breast tumor recurrence rate at 5 years after HG-PBI as the sole 
radiation therapy technique following partial mastectomy. 
 
2.2 
Secondary Objectives 
 
1. To quantify the proportion of patients who are free of breast cancer recurrence in the regional 
lymph nodes (defined as the ipsilateral axilla, infraclavicular, supraclavicular, and internal 
mammary groups) at five years after HG-PBI. 
2. To quantify the proportion of patients who are free of breast cancer distance metastases at five 
years after HG-PBI. 

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3. To describe quality of life over time as measured by the EORTC QLQ-30 AND QLQ-BR23 
questionnaires. 
4. To measure cosmesis over time quantitatively by the BRA and pBRA and qualitatively by the 
Aronson modified Harris scale. 
5. To describe the presence of any other complications using CTCAE v4.0 criteria. 
6. To quantify the proportion of patients undergoing mastectomy on the treated side at 5 years 
after HG-PBI. 
7. To describe the frequency of any CTCAE v4.0 grade 3-4 toxicities. 
 
 
3.0 
PATIENT SELECTION  
 
3.1 
Inclusion Criteria 
 
1. AJCC 7th Edition stage 0 or I (TisN0 ≤ 2 cm or T1N0) histologically confirmed carcinoma of 
the breast, treated with partial mastectomy.  Axillary sampling is required only for cases of 
invasive cancers. Tumor size is determined by the pathologist (Section 6.2). Clinical size may 
be used if the pathologic size is indeterminate.  Patients with invasive cancer must have no 
positive axillary lymph nodes with at least 6 axillary lymph nodes sampled or a negative 
sentinel node. 
 
2. Negative histologic margins of partial mastectomy or re-excision specimen.  Margins generally 
are positive if there is invasive or noninvasive tumor at the inked resection margin, close but 
negative if the tumor is within 2 mm of the inked margin and negative if the tumor is at least 2 
mm away from the inked edge.[41] 
 
3. Invasive ductal, lobular, medullary, papillary, colloid (mucinous), tubular histologies, or mixed 
histologies (lesions ≤ 2 cm) that are estrogen or progesterone receptor positive and do not 
exhibit HER2/neu gene amplification OR ductal carcinoma in situ (lesions ≤ 2 cm). 
 
4. Systemic therapy, if planned, must be adjuvant in nature and not be scheduled to begin for at 
least 4 weeks after completion of HG-PBI. 
 
5. Good candidate for treatment per protocol in the judgment of the PI and/or treating physician 
following simulation. 
 
6. Postmenopausal status. 
 
7. Age ≥ 50 years at diagnosis. 
 
8. Able to understand and willing to sign IRB-approved written informed consent document. 
 
9. English speaker. 
 
3.2 
Exclusion Criteria 
 
1. Presence of distant metastases.  
 
2. In situ lobular carcinoma or nonepithelial breast malignancies such as sarcoma or lymphoma.  
 

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3. Proven multicentric carcinoma (tumors in different quadrants of the breast, or tumors 
separated by at least 4 cm) with other clinically or radiographically suspicious areas in the 
ipsilateral breast unless confirmed to be negative for malignancy by biopsy.  
 
4. Premenopausal status.  
 
5. Histologically confirmed positive axillary nodes in the ipsilateral axilla. Palpable or 
radiographically suspicious contralateral axillary, supraclavicular, infraclavicular, or internal 
mammary nodes, unless there is histologic confirmation that these nodes are negative for 
tumor.    
 
6. Prior non-hormonal therapy for the present breast cancer, including radiation therapy or 
chemotherapy. 
 
7. Diagnosis of systemic lupus erythematosis, scleroderma, or dermatomyositis.  
 
8. Diagnosis of a coexisting medical condition which limits life expectancy to < 2 years.  
 
9. Diagnosis of psychiatric or addictive disorders that would preclude obtaining informed consent.  
 
10. History of other malignancy ≤ 5 years previous with the exception of basal cell or squamous 
cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of 
the cervix. 
 
11. Paget's disease of the nipple.  
 
12. Skin involvement, regardless of tumor size.  
 
13. Unsatisfactory breast for HG-PBI as determined by the treating physician. For example, if there 
is little breast tissue remaining between the skin and pectoralis muscle after surgery, treatment 
with HG-PBI is technically problematic.  
 
14. Partial mastectomy so extensive that the cosmetic result is fair or poor prior to HG-PBI as 
determined by the treating physician. 
 
15. Surgical margins which cannot be microscopically assessed or are positive at pathological 
evaluation. 
 
16. Time between final definitive breast procedure to HG-PBI simulation is greater than 8 weeks.  
 
3.3 
Inclusion of Women and Minorities 
 
Women and members of all races and ethnic groups are eligible for this trial.  Because breast cancer 
occurs rarely in men, men will not be recruited for participation. 
 
 
4.0 
REGISTRATION PROCEDURES  
 
Patients must not start any protocol intervention prior to registration through the Siteman Cancer 
Center. 
 

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The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center OnCore database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. The registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data will be 
recorded with this identification number on the appropriate CRFs. 
 
 
5.0 
TREATMENT PLAN  
 
5.1 
Pre-Treatment Evaluations 
 
These evaluations must take place no more than 28 days prior to initiation of treatment. 
• 
History and physical exam by team radiation oncologist. 
• 
Pre-implant cosmesis assessment by qualitative means and BRA (See Appendix III)  
• 
Completion of the EORTC QLQ-30 and BR23 questionnaire 
 
5.2 
Radiation Therapy 
 
5.2.1 Timing 
 
HG-PBI must take place no more than 8 weeks from final definitive breast surgery. 
 
5.2.2 Dose Specifications 
 
PTV Cavity: total dose of 15-20 Gy in one fraction. 
PTV Cavity + 1 cm Surface: minimum dose of 5-7 Gy in one fraction. 
 
 
 
5.2.3 Technical Factors 

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The guidelines for IMRT in this trial will conform to the policies set by the Advanced 
Technology Consortium (ATC) and the National Cancer Institute (NCI), which may be 
found at: http://atc.wustl.edu/home/NCI/NCI_IMRT_Guidelines.html.  Each of the target 
volumes and normal structures listed below must be delineated on each slice from the 3D 
planning CT in which that structure exists.  Megavoltage photon beams with energies ≥ 6 
MV and megavoltage electron beams are required. Proton beams are allowed. Co-60 
teletherapy is allowed. 
 
5.2.4 Localization, Simulation, and Immobilization 
 
Simulation and treatment may be performed with the patient in the supine or prone position.  
Patients should be optimally positioned with alpha cradle casts or other methods of 
immobilization at the discretion of the treating physician. 
 
Methods to minimize the cardiac exposure to RT like heart block, gating or breathhold are 
allowed at the discretion of the treating physician.  For large-breasted patients, including 
those with a large inframammary skin fold, devices to improve positioning of the breast 
are permissible. 
 
A treatment planning CT scan in the treatment position will be required to define the 
clinical target volumes (CTV) and planning target volumes (PTV).  The CT required for 
generation of a virtual plan with 3DCRT or IMRT must be post-lumpectomy.  Radio-
opaque markers must be placed on external landmarks at the acquisition of the CT scan to 
facilitate contouring segmentation of the CT data-set. These markers should identify: 
1. The lumpectomy incision 
2. The outline of the palpable breast tissue circumferentially at least from 2 o’clock 
to 10 o’clock 
3. The superior border of the breast tissue at 12 o’clock based on palpation 
 
The CT should extend cephalad to start at or above the mandible and extend sufficiently 
caudally (or inferiorly) to the inframammary fold to encompass the entire lung volume. A 
CT scan image thickness of ≤ 0.5 cm should be employed.  External skin localizing marks, 
which may include permanent tattoos, are allowed. 
 
5.2.5 Treatment Planning/Target Volumes  
 
The definitions for the CTV, PTV and normal structures used in this protocol generally 
conform to the 1993 ICRU report #50 titled Prescribing, Recording and Reporting Photon 
Beam Therapy and the RTOG-endorsed consensus guidelines for delineation of target and 
normal structures for breast cancer found at: 
http://www.rtog.org/CoreLab/ContouringAtlases/BreastCancerAtlas.aspx. 
 
5.2.5.1 Target Volumes and Normal Structures 
 
Partial Mastectomy Volumes 
PTV Cavity: Contour using all available clinical and radiographic information 
including the excision cavity volume, architectural distortion, lumpectomy 
scar, seroma and/or extent of surgical clips. Limit the PTV Cavity posteriorly 
at anterior surface of the pectoralis major and anterolaterally 5 mm from skin 

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and should not cross midline. In general, the pectoralis and/or serratus anterior 
muscles are excluded from the PTV Cavity. 
 
PTV Cavity + 1 cm: PTV Cavity + 1 cm 3D expansion limited to exclude the 
part outside the ipsilateral breast and the first 5 mm of tissue under the skin (in 
order to remove most of the build up region for the DVH analysis) and 
excluding beyond the posterior extent of breast tissue (chest wall, pectoralis 
muscles and lung) when pertinent. The PTV Cavity + 1 cm should not cross 
midline. This PTV Cavity + 1 cm is the structure used for DVH constraints 
and analysis. 
 
Breast Volumes 
Breast CTV: Includes the palpable breast tissue demarcated with radio-opaque 
markers at CT simulation (see Section 5.2.3), the apparent CT glandular breast 
tissue visualized by CT, consensus definitions of anatomical borders, and the 
Lumpectomy CTV from the breast cancer atlas (see Partial Mastectomy 
Volumes above). The breast CTV is limited anteriorly within 5 mm from the 
skin and posteriorly to the anterior surface of the pectoralis, serratous anterior 
muscle excluding chest wall, boney thorax and lung. In general, the pectoralis 
and/or serratous anterior muscles are excluded from the breast CTV unless 
clinically warranted by the patient’s pathology. The breast CTV should 
generally follow consensus guidelines found at: 
http://www.rtog.org/CoreLab/ContouringAtlases/BreastCancerAtlas.aspx 
 
Contralateral Breast 
Includes the apparent CT glandular breast tissue visualized by CT and 
consensus definitions of anatomical borders from the RTOG Breast Atlas. In 
general the borders are: 
Posterior border: At the anterior surface of the pectoralis, serratous anterior 
muscles excluding chest wall, ribs, boney thorax and lung/heart; 
Medial border: The sternal-costal junction, 
Lateral border: Varies based on the size of the breast but typically is at the 
mid-axillary line and excludes the ipsilateral lattismus dorsi muscle. 
Cephald border: Should be similar to that of the ipsilateral breast CTV 
Caudal:border: Inframammry fold and should be similar to that of the 
ipsilateral breast CTV. 
Anterior border: Skin minus 5 mm to minimize inaccuracy of dose calculation 
at the skin surface. 
 
Refer to breast contouring atlas found at: 
http://www.rtog.org/CoreLab/ContouringAtlases/BreastCancerAtlas.aspx 
 
Ipsilateral Lung 
This may be contoured with auto-segmentation with manual verification. 
 
Contralateral Lung 
This may be contoured with auto-segmentation with manual verification 
 
 
Heart 
This is to be contoured on all cases, not just the left sided cases. The heart 

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should be contoured beginning just inferior to the level in which the pulmonary 
trunk branches into the left and right pulmonary arteries (PA). Above the PA, 
none of the heart’s 4 chambers are present. The heart should be contoured on 
every contiguous slice thereafter to its inferior most extent near the diaphragm. 
The following structures, if identifiable, should be excluded from the heart 
contour: esophagus, great vessels (ascending and descending aorta, inferior 
vena cava). One need not include pericardial fat, if present. Contouring along 
the pericardium itself, when visible, is appropriate. 
 
Thyroid 
The thyroid is easily visible on a non-contrast CT due to its preferential 
absorption of iodine, rendering it “brighter” or denser than the surrounding 
neck soft tissues. The left and right lobes of the thyroid are somewhat 
triangular in shape and often do not converge anteriorly at mid-line. All 
“bright” thyroid tissue should be contoured. 
 
5.2.5.2 Treatment Planning 
 
CT-based planning with tissue inhomogeneity correction is required. 
 
IMRT or 3D-CRT are permitted; arc based delivery is allowed; Co-60 
teletherapy is allowed. 
 
PTV Cavity should have a minimum dose of 15 Gy and maximum of 22 Gy.  
PTV Cavity + 1 cm should have a minimum dose of 5 Gy.  With these goals a 
high dose gradient is achieved. 
 
Normal tissue constraints: Skin structure is from skin to skin-3 in the region of 
the target Dmax ≤ 22 Gy, V20 ≤ 10mL, V10 ≤ 15mL, V3 ≤ 20 mL.  
Contralateral Lung Dmax ≤ 3 Gy, V5 ≤ 5%; Ipsilateral Lung Dmax ≤ 7 Gy, 
V5 ≤ 5%; Heart V5 ≤ 2%; Thyroid V5 ≤ 10%. 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
 
Hormone therapy, chemotherapy, or biologic therapy is not allowed prior to HG-PBI, but may be 
started at least 4 weeks after the completion of HG-PBI. 
 
5.4 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the patient’s health 
and/or the patient no longer wishes to continue protocol therapy, the protocol therapy should be 
discontinued and the reason(s) for discontinuation documented in the case report forms. 
 
Treatment will consist of a partial mastectomy and single fraction of HG-PBI which will take place 
no more than 8 weeks after final definitive surgical procedure.  Treatment will be discontinued if 
one of the following criteria applies: 
 
• 
Documented and confirmed disease progression 
• 
Death 

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• 
Adverse event(s) that, in the judgment of the investigator, may cause severe or permanent 
harm or which rule out continuation of study drug 
• 
General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
• 
Suspected pregnancy 
• 
Serious noncompliance with the study protocol 
• 
Lost to follow-up 
• 
Patient withdraws consent 
• 
Investigator removes the patient from study 
• 
The Siteman Cancer Center decides to close the study 
 
5.5 
Duration of Follow-up 
 
Patients will be followed according to the scheduled described in the study calendar for 5 years or 
until death, whichever occurs first.  Patients removed from study for unacceptable adverse events 
will be followed until resolution or stabilization of the adverse event. 
 
 
6.0 
DISEASE RESPONSE CRITERIA 
 
6.1 
Mastectomy Free Survival 
 
Any form of mastectomy to the treated breast for any reason is a failure for mastectomy-free 
survival. 
 
6.2 
Recurrence of Breast Cancer 
 
Recurrence of breast cancer in the treated breast is an ipsilateral breast tumor recurrence (IBTR).   
Recurrence in a regional lymph node is a regional failure.  The regional lymph nodes are defined 
as the axillary, supraclavicular, infraclavicular and internal mammary lymph nodes.  The definition 
of recurrence of breast cancer is: histologic evidence of recurrent carcinoma, either invasive or non-
invasive (except LCIS) in the ipsilateral breast. 
 
Clinical evidence of recurrent carcinoma by physical examination and/or mammogram will not be 
construed as evidence of treatment failure without biopsy proof, but will be considered as 
suspicious for recurrence.  Ipsilateral breast recurrences will be categorized as local (infield) if they 
occur within the prescription isodose volume, peripheral if between the prescription isodose volume 
and a volume 2 cm outside of the prescription isodose volume, and non-contiguous or extrafield if 
they are beyond the peripheral volume described above.  
 
6.3 
Cosmesis 
 
At a minimum, cosmesis will be graded by the patient and the radiation oncologist before treatment, 
6-10 weeks after HG-PBI, at 4-8 month follow-up, at 10-14 month follow-up, and at yearly 
intervals thereafter for a total of 5 years following HG-PBI.  Cosmesis will be graded on qualitative 
and quantitative scales. 
 
 
 
6.3.1 Qualitative Evaluation 

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The Aaronson modification of the Harris scale will be used to qualitatively evaluate 
cosmesis.  The patient and physician forms are included in Appendix I and II.  The 
following general descriptors will be used: 
• 
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.  
• 
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.  
• 
Fair - there is obvious difference in the size and shape of the treated breast. This 
change involves 1/4 or less of the breast.  
• 
Poor - marked change in the appearance of the treated breast involving more than 
1/4 of the breast tissue.  
 
6.3.2 Quantitative Evaluation 
 
BRA will be calculated by the radiation oncologist or NP at each follow up assessment.  
See Appendix III for BRA calculation. 
 

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7.0 
STUDY CALENDAR 
 
Baseline assessments should be performed no more than 28 days before initiation of treatment. 
 
Surgery 
Baseline 
No more 
than 8 wks 
post-surgery 
2 wksa 8 wksb 6 moc 
12 moc 
18 moc 
24 moc 
36 moc 
Yr 4 
Yr 5 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
Physical exam 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Mammogram 
 
Xf 
 
 
 
Yearly 
Simulation 
 
X 
 
 
 
 
 
 
 
 
 
 
Partial mastectomy 
X 
 
 
 
 
 
 
 
 
 
 
 
HG-PBI 
 
 
X 
 
 
 
 
 
 
 
 
 
EORTC-QLQ30 and  BR23, 
Brief Pain Assessment 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Aronson modified Harris 
scale 
 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
BRA calculation 
 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
Adverse events 
 
X 
 
X 
Xd 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
a: after HG-PBI 
b: +/- 2 weeks 
c: +/- 2 months 
d: monitoring for acute toxicities 
e: monitoring for late toxicities 
f: baseline mammogram is not required within 28 days before initiation of treatment 
g: EORTC-QLQ30 and BR23attached as appendix IV, Brief Pain Assessment attached as appendix V 
 

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8.0 
DATA SUBMISSION SCHEDULE 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
Registration Form 
Eligibility Form 
Demographics Form 
On-Study Form 
Prior to starting treatment 
Surgery Form 
Following surgery 
HG-PBI Form 
Following RT 
Follow-Up Form 
EORTC-QLQ30 
EORTC-BR23 
Patient Cosmetic Evaluation Form 
Physician Cosmetic Evaluation Form 
Pain Assessment Form 
 
Baseline (all but follow-up form) 
2 weeks 
8 weeks 
6 months 
12 months 
18 months 
24 months 
36 months 
4 years 
5 years 
Mammography Form 
Baseline 
6 months 
18 months 
36 months 
4 years 
5 years 
Acute Toxicity Form 
8 weeks 
Late Toxicity Form 
6 months 
12 months 
18 months 
24 months 
36 months 
4 years 
5 years 
  
 
9.0 
REGULATORY AND REPORTING REQUIREMENTS 
The entities providing oversight of safety and compliance with the protocol require reporting as outline 
below. 
 
The Washington University Human Research Protection Office (HRPO) requires that all events meeting 
the definition of unanticipated problem or serious noncompliance be reported as outlined in Section 9.2. 
 
9.1 
Definitions 
 
9.1.1 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
 

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Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all 
toxicity reporting.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP 
website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human 
Services’ Office for Human Research Protections (OHRP).  A copy of this guidance can 
be found on OHRP’s website: 
 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
9.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse experience occurring at any dose that results in any of the 
following outcomes: 
• 
Death 
• 
A life-threatening adverse drug experience 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant disability/incapacity (i.e., a substantial disruption of a 
person’s ability to conduct normal life functions) 
• 
A congenital anomaly/birth defect 
• 
Any other experience which, based upon appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above 
 
9.1.3 Unexpected Adverse Experience 
 
Definition: any adverse experience, the specificity or severity of which is not consistent 
with the current investigator brochure (or risk information, if an IB is not required or 
available). 
 
9.1.4 Life-Threatening Adverse Experience  
 
Definition: any adverse experience that places the subject (in the view of the investigator) 
at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction 
that, had it occurred in a more severe form, might have caused death. 
 
 
 
9.1.5 Unanticipated Problems 
 
Definition: 
 
• 
unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the characteristics 
of the subject population being studied; 
• 
related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 

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• 
suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
 
9.1.6 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that govern 
human 
subjects 
research 
or 
failure 
to 
follow 
the 
determinations 
of 
the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate choice to 
ignore regulations, institutional policies, or determinations of the IRB. 
 
9.1.7 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in substantial harm 
to subjects or others, or that materially compromises the rights or welfare of participants. 
 
9.1.8 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the research 
team’s control. Exceptions apply only to a single participant or a singular situation. 
 
Pre-approval of all protocol exceptions must be obtained prior to the event. 
 
9.2 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 
• 
Any unanticipated problems involving risks to participants or others which occur at WU, 
any BJH or SLCH institution, or that impacts participants or the conduct of the study. 
• 
Noncompliance with federal regulations or the requirements or determinations of the IRB. 
• 
Receipt of new information that may impact the willingness of participants to participate 
or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of the event 
or notification to the PI of the event.  The death of a research participant that qualifies as a 
reportable event should be reported within 1 working day of the occurrence of the event or 
notification to the PI of the event. 
 
9.3 
Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU or any 
BJH or SLCH institution that has been reported to and acknowledged by HRPO as reportable.  
(Unanticipated problems reported to HRPO and withdrawn during the review process need not be 
reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to a 
QASMC auditor. 
 

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9.4 
Timeframe for Reporting Required Events  
 
Reportable adverse events will be tracked for 30 days following the last day of study treatment.  
For the purposes of this protocol, grade 4 myelosuppression or aplasia are not considered 
reportable. All events of interest should be captured on the adverse event data form.  
 
10.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the Principal 
Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington University Quality 
Assurance and Safety Monitoring Committee (QASMC) semi-annually beginning six months after accrual 
has opened (if at least five patients have been enrolled) or one year after accrual has opened (if fewer than 
five patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least every six months, and provide a semi-annual 
report to the QASMC. This report will include: 
• 
HRPO protocol number, protocol title, Principal Investigator name, data coordinator name, 
regulatory coordinator name, and statistician 
• 
Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date of 
HRPO expiration, date of most recent QA audit, study status, and phase of study 
• 
History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, error, 
or breach of confidentiality including start/stop dates and reason 
• 
Study-wide target accrual and study-wide actual accrual 
• 
Protocol activation date 
• 
Average rate of accrual observed in year 1, year 2, and subsequent years 
• 
Expected accrual end date 
• 
Objectives of protocol with supporting data and list the number of participants who have met 
each objective 
• 
Measures of efficacy  
• 
Early stopping rules with supporting data and list the number of participants who have met the 
early stopping rules 
• 
Summary of toxicities 
• 
Abstract submissions/publications 
• 
Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious toxicities on an 
ongoing basis. Once the principal investigator or Research Patient Coordinator becomes aware of an 
adverse event, the AE will be reported to the HRPO and QASMC according to institutional guidelines. 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Specific Aims 
 
11.1.1 Specific Aim 1 
 
We will quantify the tolerance of HG-PBI by estimating the rate of acute and late treatment-
related grade 3 or higher toxicity (per CTCAE, v.4.0) or any other grade 4 or 5 toxicity 
attributed to the therapy.  Toxicities of concern include breast pain, delayed wound healing, 
persistent seroma fluid accumulation, breast fibrosis and fat necrosis in the treated breast.  

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Rare toxicities include radiation pneumonitis and pericarditis.  Hypothesis: Morbidity 
occurs in approximately 5-8% of patients with a maximum allowable proportion with grade 
3-5 toxicities of 12%.  A sequential probability ratio stopping rule will be used to monitor 
the toxicity rate during the trial. 
 
11.1.2 Specific Aim 2 
 
We will estimate the ipsilateral breast tumor recurrence rate at 5 years after HG-PBI as the 
sole radiation therapy technique following partial mastectomy.   Hypothesis: The IBTR 
will be less than 15.9% with 95% confidence resulting in a treatment strategy worthy of 
further investigation in a larger clinical trial. 
 
11.1.3 Specific Aim 3 
 
We will estimate the change in breast cosmesis over time using the validated, quantitative 
parameter pBRA.  Hypothesis: The pBRA will not significantly change over time.  We 
have previously demonstrated this in the setting of multicatheter APBI.[20] 
 
11.2 
Study Endpoints 
 
The principal endpoints are the proportion of patients who are free of serious treatment related 
toxicity as discussed below and the proportion of patients who are free of breast cancer in the treated 
breast (IBTR).  Secondary endpoints are the proportion of patients who are free of breast cancer in 
the regional lymph nodes (ipsilateral axilla, infraclavicular, supraclavicular, and internal mammary 
groups), free from distant disease, and proportion surviving.  Additional secondary endpoints are 
quality of life as measured by the EORTC QLQ-C3 and QLQ-BR23, cosmesis as measured 
quantitatively by the BRA and pBRA, cosmesis as measured qualitatively by the Aronson modified 
Harris scale, the presence or absence of complications, the occurrence of mastectomy after 
completion of initial breast-conserving treatment and the frequency of any CTCAE v4.0 grade 3-4 
toxicities. 
 
11.3 
Study Design and Analysis Plan 
 
This is a single arm, non-randomized phase I/II study of 50 patients with stage 0 (tumor size ≤ 2cm) 
or I breast cancer.  The primary study goal is to quantify the tolerance of HG-PBI by estimating the 
rate of acute and late treatment-related grade 3 or higher toxicity (per CTCAE, v.4.0) or any other 
grade 4 or 5 toxicity attributed to the therapy.  Toxicities of concern include breast pain, delayed 
wound healing, persistent seroma fluid accumulation, breast fibrosis and fat necrosis in the treated 
breast.  Rare toxicities include radiation pneumonitis and pericarditis.  These are expected to occur 
in approximately 5-8% of patients with a maximum allowable proportion with grade 3-5 toxicities 
of 12%.  A sequential probability ratio stopping rule will be used to monitor the toxicity rate during 
the trial. For example, the study will be suspended for review of toxicity if 4 cases of grade 3-5 
toxicity are seen among the first 14 patients, or 5 among the first 26 patients.  The full criteria for 
monitoring are given in the table below.  All toxicities and other serious adverse events will be 
reported to the Clinical Trials Office and to QASM as described. 
 
 
 
The study will be suspended for review  if: 
 
this number of patients are 
before this number of patients 

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observed with grade 3-
5 toxicity: 
have completed the 
trial: 
4 
14 
5 
26 
6 
38 
7 
50 
 
Patients will be followed for 5 years.  The primary goals of the study involve tolerance to treatment; 
the proportion of patients who are breast cancer free 5 years after treatment will be calculated with 
a 95% confidence interval.  Cosmetic outcome will be assessed qualitatively by patients and 
physicians over the years after treatment.  The two sets of scores will be plotted using histograms 
showing the proportion rating the outcome excellent, good, fair and poor.  Kappa statistics with 
95% confidence intervals will be calculated to assess the agreement between patient and physician 
scores before treatment, at 4-6 months at 1 year, and at subsequent visits.  The pBRA will be used 
to assess cosmesis quantitatively.  This instrument includes a formula expressing the extent of 
displacement of the treated breast relative to the contralateral breast and other anatomical features.  
pBRA scores will be plotted at the assessment points and presented graphically.  Quality of life 
will be assessed using the 30 items of the EORTC QLQ-C30 and 23 items of the QLQ-B23 and the 
Visual Analog Scale for Pain.  The QLQ-C30 includes 6 general questions and 24 questions in 9 
subscales measuring physical, role, emotional, cognitive and social function, as well as global 
health status, nausea/ vomiting, pain and fatigue.  The QLQ-B23 provides 23 questions in 8 breast 
cancer specific subscales, 4 measuring symptoms and 4 measuring function.  Each of the subscales 
will be tabulated and presented graphically over the assessment times.  Mixed repeated measures 
models will be generated to describe the nature of change in quality of life over time.  
Complications will be tabulated and frequencies presented graphically.  The rate of mastectomy 
within five years of treatment will be calculated with a 95% confidence interval. 
11.4 
Sample Size and Study Power 
 
Although the primary goals of this study include tolerance to treatment, the sample size for this 
study is based on the proportion of patients who remain free from an ipsilateral breast cancer 
recurrence (IBTR) 5 years after treatment which will be compared with the current expected value 
in the medical literature.  Fyles reported that the five-year IBTR in a large population of women ≥ 
50 yr with pT1N0 estrogen receptor positive breast cancers treated with partial mastectomy and 
tamoxifen but no radiation therapy was 5.9%[39].  HG-PBI will be considered worthy of further 
investigation if 1) the treatment-related toxicity rate as described above is less than 12%  and 2) the 
five-year IBTR is not significantly greater than 10% higher than that observed in the Fyles study.  
Binomial proportion power analysis, assuming an alpha-level of 0.05, determined that we will 
obtain approximately 70% power to detect a proportion significantly larger than 15.9% given the 
true five-year IBTR is the same as that observed in the Fyles study.  If 50 patients complete the 
trial and more than 3 recurrences are observed in the first five years, then the observed rate will be 
significantly larger than the acceptable proportion.  Consequently, if 3 or fewer recurrences are 
observed among 50 patients and the tolerance parameters are met, the study will conclude that there 
is preliminary evidence that HG-PBI as performed in this trial is worthy of further study.  
 
 
 
11.5 
Treatment Failure 
 
It should be noted that ipsilateral breast tumor recurrences (IBTR) do not cause a diminished overall 
survival.  Nonetheless, they do represent a failure of breast conservation.  We will assess the 

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possibility of an unexpected rise in IBTR by comparing the observed IBTR rate to that expected 
from an exponential distribution with an event rate of 5% over 5 years.  The assessment is repeated 
every 6 months during the patient accrual phase of the study and once a year thereafter to the end 
of the five-year follow-up period.  A Hochberg stepdown procedure, implemented by SAS proc 
multtest, will be used to adjust the p-values for multiple looks. 
 
11.6 
Accrual 
 
It is estimated that less than 10% of the patients treated in this study will be lost to follow up.  
Therefore, because the accrual goal is 50 evaluable patients (at 5 years post-treatment), target 
accrual is 55 patients to account for the 10% anticipated drop-out.  It is estimated that patient accrual 
will take two to three years. 
 
The investigators are well aware that several prior clinical trials that involved breast cancer at the 
Washington University Medical Center and the Siteman Cancer Center suffered from poor accrual.  
We believe that this trial will have excellent patient accrual.  The primary source of patients who 
may be eligible for this study is via the breast surgeons of the Section of Endocrine and Oncologic 
Surgery here at Washington University.  The chief breast surgeon is a collaborator in this study and 
is very supportive.  The fact that a large fraction of patients with a common cancer disease are 
eligible for this study should lend further reassurance that this study ought to enjoy excellent patient 
accrual.  The following series of conservative estimates provide an approximation of patient 
accrual: in 2012 more than four hundred patients with breast cancer were seen by physicians in the 
Department of Radiation Oncology.  A conservative estimate is that 20% of these patients had an 
early stage breast cancer that would be eligible for this study.  A further conservative estimate is 
that a third of these patients will consent to participate in this study.  This yields an estimated 
accrual of just over 25 patients per year. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12.0 
REFERENCES 
 
 
1. 
Fisher, B., et al., Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, 
total mastectomy, and total mastectomy followed by irradiation. The New England journal of 

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medicine, 2002. 347(8): p. 567-575. 
2. 
Veronesi, U., et al., Twenty-year follow-up of a randomized study comparing breast-conserving 
surgery with radical mastectomy for early breast cancer. The New England journal of medicine, 
2002. 347(16): p. 1227-1232. 
3. 
Fisher, B., 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, 2002. 347(16): p. 1233-41. 
4. 
Pandey, M., et al., Early effect of surgery on quality of life in women with operable breast cancer. 
Japanese journal of clinical oncology, 2006. 36(7): p. 468-72. 
5. 
Fisher, B., et al., Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: 
findings from National Surgical Adjuvant Breast and Bowel Project B-17. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology, 1998. 16(2): p. 441-52. 
6. 
Julien, J.P., et al., Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first 
results of the EORTC randomised phase III trial 10853. EORTC Breast Cancer Cooperative Group 
and EORTC Radiotherapy Group. Lancet, 2000. 355(9203): p. 528-533. 
7. 
Holmberg, L., et al., Absolute risk reductions for local recurrence after postoperative radiotherapy 
after sector resection for ductal carcinoma in situ of the breast. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology, 2008. 26(8): p. 1247-1252. 
8. 
Smith, G.L., et al., Breast-conserving surgery in older patients with invasive breast cancer: current 
patterns of treatment across the United States. Journal of the American College of Surgeons, 2009. 
209(4): p. 425-433 e2. 
9. 
Jackson, L.C., et al., Patterns of care analysis among women with ductal carcinoma in situ in North 
Carolina. American journal of surgery, 2008. 195(2): p. 164-9. 
10. 
Nattinger, A.B., et al., Geographic variation in the use of breast-conserving treatment for breast 
cancer. The New England journal of medicine, 1992. 326(17): p. 1102-7. 
11. 
Imamura, H., et al., Relationship between the morphological and biological characteristics of 
intraductal components accompanying invasive ductal breast carcinoma and patient age. Breast 
Cancer Res Treat, 2000. 62(3): p. 177-84. 
12. 
Veronesi, U., et al., Radiotherapy after breast-conserving surgery in small breast carcinoma: long-
term results of a randomized trial. Ann Oncol, 2001. 12(7): p. 997-1003. 
13. 
King, T.A., et al., Long-term results of wide-field brachytherapy as the sole method of radiation 
therapy after segmental mastectomy for T(is,1,2) breast cancer. Am J Surg, 2000. 180(4): p. 299-
304. 
14. 
Vicini, F.A., et al., Accelerated treatment of breast cancer. J Clin Oncol, 2001. 19(7): p. 1993-
2001. 
15. 
Kuske, R.R., et al., Phase II trial of brachytherapy alone after lumpectomy for select breast cancer: 
toxicity analysis of RTOG 95-17. Radiation Oncology Biology, 2006. 65(1): p. 45-51. 
16. 
Beitsch, P.D., et al., Tumor bed control with balloon-based accelerated partial breast irradiation: 
incidence of true recurrences versus elsewhere failures in the American Society of Breast Surgery 
MammoSite((R)) Registry Trial. Annals of Surgical Oncology, 2012. 19(10): p. 3165-70. 
17. 
Vicini, F., et al., Initial efficacy results of RTOG 0319: three-dimensional conformal radiation 
therapy (3D-CRT) confined to the region of the lumpectomy cavity for stage I/ II breast carcinoma. 
Int J Radiat Oncol Biol Phys, 2010. 77(4): p. 1120-7. 
18. 
Shah, C., et al., Five-Year Outcomes and Toxicities Using 3-Dimensional Conformal External 
Beam Radiation Therapy to Deliver Accelerated Partial Breast Irradiation. Clin Breast Cancer, 
2012. 
19. 
Ferraro, D.J., et al., Comparison of accelerated partial breast irradiation via multicatheter 
interstitial brachytherapy versus whole breast radiation. Radiat Oncol, 2012. 7(1): p. 53. 
20. 
Garsa, A.A., et al., Cosmetic Analysis Following Breast-Conserving Surgery and Adjuvant High-
Dose-Rate Interstitial Brachytherapy for Early-Stage Breast Cancer: A Prospective Clinical Study. 
Int J Radiat Oncol Biol Phys, 2012. 

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21. 
Garsa, A.A., et al., Analysis of fat necrosis after adjuvant high-dose-rate interstitial brachytherapy 
for early stage breast cancer. Brachytherapy, 2012. 
22. 
Smith, B.D., et al., Accelerated partial breast irradiation consensus statement from the American 
Society for Radiation Oncology (ASTRO). in International Journal of Radiation Oncology Biology 
Physics2009. p. 987-1001. 
23. 
Vaidya, J.S., et al., Targeted intra-operative radiotherapy (Targit): an innovative method of 
treatment for early breast cancer. Ann Oncol, 2001. 12(8): p. 1075-80. 
24. 
Vaidya, J.S., et al., Targeted intraoperative radiotherapy (TARGIT) yields very low recurrence 
rates when given as a boost. Int J Radiat Oncol Biol Phys, 2006. 66(5): p. 1335-8. 
25. 
Vaidya, J.S., et al., Targeted intraoperative radiotherapy versus whole breast radiotherapy for 
breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 
3 trial. Lancet, 2010. 376(9735): p. 91-102. 
26. 
Bradley, J., So far, so good for lung cancer SBRT. J Thorac Oncol, 2009. 4(7): p. 781-2. 
27. 
Harris, J.R., et al., Analysis of cosmetic results following primary radiation therapy for stages I and 
II carcinoma of the breast. Int J Radiat Oncol Biol Phys, 1979. 5(2): p. 257-61. 
28. 
Pezner, R.D., et al., Limited usefulness of observer-based cosmesis scales employed to evaluate 
patients treated conservatively for breast cancer. Int J Radiat Oncol Biol Phys, 1985. 11(6): p. 
1117-9. 
29. 
Aaronson, N.K., et al., Evaluation of breast conserving therapy: clinical, methodological and 
psychosocial perspectives. Eur J Surg Oncol, 1988. 14(2): p. 133-40. 
30. 
Whelan, T., et al., Randomized trial of breast irradiation schedules after lumpectomy for women 
with lymph node-negative breast cancer. J Natl Cancer Inst, 2002. 94(15): p. 1143-50. 
31. 
Pezner, R.D., et al., Breast retraction assessment: an objective evaluation of cosmetic results of 
patients treated conservatively for breast cancer. Int J Radiat Oncol Biol Phys, 1985. 11(3): p. 575-
8. 
32. 
Vrieling, C., et al., Validation of the methods of cosmetic assessment after breast-conserving 
therapy in the EORTC "boost versus no boost" trial. EORTC Radiotherapy and Breast Cancer 
Cooperative Groups. European Organization for Research and Treatment of Cancer. Int J Radiat 
Oncol Biol Phys, 1999. 45(3): p. 667-76. 
33. 
Vrieling, C., et al., The influence of the boost in breast-conserving therapy on cosmetic outcome in 
the EORTC "boost versus no boost" trial. EORTC Radiotherapy and Breast Cancer Cooperative 
Groups. European Organization for Research and Treatment of Cancer. Int J Radiat Oncol Biol 
Phys, 1999. 45(3): p. 677-85. 
34. 
Aaronson, N.K., et al., The European Organization for Research and Treatment of Cancer QLQ-
C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer 
Inst, 1993. 85(5): p. 365-76. 
35. 
Fayers P, A.N., Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of the EORTC Quality 
of Life Study Group., The EORTC QLQ-C30 Scoring Manual (3rd Edition)2001, Brussels: 
European Organization for Research and Treatment of Cancer. 
36. 
Groenvold, M., et al., Validation of the EORTC QLQ-C30 quality of life questionnaire through 
combined qualitative and quantitative assessment of patient-observer agreement. J Clin Epidemiol, 
1997. 50(4): p. 441-50. 
37. 
McLachlan, S.A., G.M. Devins, and P.J. Goodwin, Validation of the European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) as a measure of 
psychosocial function in breast cancer patients. Eur J Cancer, 1998. 34(4): p. 510-7. 
38. 
Sprangers, M.A., et al., The European Organization for Research and Treatment of Cancer breast 
cancer-specific quality-of-life questionnaire module: first results from a three-country field study. 
J Clin Oncol, 1996. 14(10): p. 2756-68. 
39. 
Fyles, A.W., et al., Tamoxifen with or without breast irradiation in women 50 years of age or older 
with early breast cancer. N Engl J Med, 2004. 351(10): p. 963-70. 
40. 
Jemal, A., E. Ward, and M.J. Thun, Recent trends in breast cancer incidence rates by age and 

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tumor characteristics among U.S. women. Breast Cancer Res, 2007. 9(3): p. R28. 
41. 
Fisher, B. and S. Anderson, Conservative surgery for the management of invasive and noninvasive 
carcinoma of the breast: NSABP trials. National Surgical Adjuvant Breast and Bowel Project. 
World J Surg, 1994. 18(1): p. 63-9. 
 
 
 

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APPENDIX I: Patient Evaluation of the Treated Breast 
 
You have been treated with breast-conserving therapy for breast cancer. As you know, a reason for choosing 
this treatment is the potential for keeping a breast that looks and feels as close to normal as possible. Your 
opinion concerning the appearance of your breast is valuable to us. 
  
I. Please circle the word below which best describes your judgment of the cosmetic results of therapy at 
this time:  
EXCELLENT 
when compared to the untreated 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 mild thickening or scar tissue within the breast 
or skin, but not enough to change the appearance.  
GOOD  
there is mild asymmetry between the breasts, which means that there is a slight 
difference in the size or shape of the treated breast as compared to the opposite 
breast. There may be some mild reddening or darkening of the breast. The 
thickening or scar tissue within the breast causes only a mild change in the shape. 
FAIR  
moderate deformity of the breast, with an obvious difference in the size and shape 
of the treated breast. This change involves 1/4 or less of the breast. There is 
moderate thickening or scar tissue of the skin and the breast, and obvious color 
changes.  
POOR 
marked change in the appearance of the treated breast involving more than 1/4 of 
the breast tissue. The skin changes are very obvious. There is severe scarring and 
thickening of the breast.  
 
II. In summary, regarding your breast conservation therapy, your overall feeling is: 
A) completely satisfied with the treatment and results.  
B) not totally satisfied, but would choose breast conservation therapy again. 
C) dissatisfied with breast conservation therapy.  
 
III. If you had it all over to do again, would you prefer to have your breast cancer treated:  
A) just the way you were treated. 
B) with a mastectomy, not requiring radiation therapy. 
 
IV. It is sometimes very difficult to tell if the changes in your treated breast are due to the surgery, the 
radiation therapy, or both. Try to remember what the breast looked like after the surgery, but before the 
radiation treatments began. Now compare that memory to the appearance of the breast now. The changes 
within your breast at this time are in your opinion: 
A) caused mostly by the radiation. 
B) caused by both the radiation and surgery, but mostly by the radiation. 
C) caused by both the radiation and surgery, but mostly by the surgery.  
D) caused mostly by the surgery.  
E) can't judge which treatment caused the change. 
F) there are no changes. 
 
PLEASE PRINT YOUR NAME:                                                     DATE: _________________________ 

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APPENDIX II: Physician Evaluation of the Treated Breast 
 
The physician should never share his evaluation with the patient, as it may influence subsequent patient 
evaluations. Also, do not glance at previous evaluations...it is the evolution of cosmetic changes we are 
studying. 
 
PATIENT'S NAME:_____________________________ DATE: ____________ 
EVALUATOR: __________________ 
 
I. Please assess the cosmetic results of breast conservation therapy at this time (Circle one): 
EXCELLENT 
when compared to the untreated 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 mild thickening or scar tissue within the breast 
or skin, but not enough to change the appearance. 
GOOD 
there is mild asymmetry between the breasts, which means that there is a slight 
difference in the size or shape of the treated breast as compared to the opposite 
breast. There may be some mild reddening or darkening of the breast. The 
thickening or scar tissue within the breast causes only a mild change in the shape. 
FAIR 
moderate deformity of the breast, with an obvious difference in the size and shape 
of the treated breast. This change involves 1/4 or less of the breast. There is 
moderate thickening or scar tissue of the skin and the breast, and obvious color 
changes. 
POOR 
marked change in the appearance of the treated breast involving more than 1/4 of 
the breast tissue. The skin changes are very obvious. There is severe scarring and 
thickening of the breast. In retrospect, the breast may have been better treated by 
a mastectomy. 
 
II. In the physician's opinion, the changes within the treated breast are: 
A) caused mostly by the radiation. 
B) caused by both the radiation and surgery, but mostly by the radiation. 
C) caused by both the radiation and surgery, but mostly by the surgery. 
D) caused mostly by surgery. 
E) can't judge which treatment caused the change. 
F) there are no changes. 
 
III. Instructions: For each of the breast characteristics presented above, please rate the treated breast as 
compared to the untreated breast.  Place a check mark in the appropriate cell for each characteristic. 
 
 
No 
Difference 
A Small 
Difference 
A Moderate 
Difference 
A Large 
Difference 
Not 
Evaluable 
 
0 
1 
2 
3 
4 
Breast Size 
 
 
 
 
 
Breast Shape 
 
 
 
 
 
Skin Color 
 
 
 
 
 
Location of the areola 
and nipple 
 
 
 
 
 
Shape of the areola 
and nipple 
 
 
 
 
 
 
 
 

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IV.  How would you rate the appearance of the surgical scars?  Please circle your assessment. 
 
0 = Very unobstrusive 
 
1 = Visible but not affecting cosmetic results 
 
2 = Visible and detracting somewhat from cosmetic results 
 
3 = Visible and detracting a great deal from cosmetic results 
 
4 = Not evaluable 
 
V.  Measure and record the Breast Retraction Assessment parameters (see Appendix III): 
 
a1 = __________ 
 
 
b1 = __________ 
 
 
a2 = __________ 
 
 
b2 = __________ 

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APPENDIX III: Quantitative Cosmetic Analysis 
 
 
 
Determining the Breast Retraction Assessment (BRA) and percent BRA (pBRA).  From [32] 
 
 

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APPENDIX IV: EORTC QLQ-C30 and BR23 
 

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APPENDIX V: Brief Pain Assessment 
INSTRUCTIONS: 
 
Make a mark on the line below 
showing how severe your breast pain 
is at this moment.  
No Pain 
 
 
 
 
           The Worst Imaginable Pain