A Phase II Study of Preoperative Single Fraction Stereotactic Body Radiotherapy to the Intact Breast in Early Stage Low Risk Breast Cancer: Analysis of Radiation Response
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

October 10, 2023 
Principal Investigator: Jean Wright M.D.  
IRB IRB00128074 
 
 
 
 
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PROTOCOL TITLE:   
 
A Phase II Study of Preoperative Single Fraction Stereotactic Body Radiotherapy to 
the Intact Breast in Early Stage Low Risk Breast Cancer: Analysis of Radiation 
Response 
 
 
 
Principal Investigator: 
 
 
 
Jean Wright 
  
 
Department of Radiation Oncology  
  
 
401 North Broadway 
Baltimore, MD 21287 
Phone: 202 537 4787 
Fax: 202 537 4964 
 
Co-Investigators: 
Fariba Asrari Radiation Oncology (East Baltimore) 
Torie Croog Radiation Oncology (Sibley) 
Andrea Richardson Pathology (overall) 
David Euhus Surgery (East Baltimore) 
Pouneh Razavi Radiology (Sibley) 
Chen Hu Radiation Oncology (statistician) 
 
NCT03043794 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

October 10, 2023 
Principal Investigator: Jean Wright M.D.  
IRB IRB00128074 
 
 
 
 
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TABLE OF CONTENTS 
 
1. Study Design/Summary 
1.1 SUMMARY 
1.2 SCHEMA 
 
2. OBJECTIVES 
2.1 PRIMARY OBJECTIVE 
2.2 SECONDARY OBJECTIVES 
 
3. BACKGROUND 
3.1 INVESTIGATIONAL AGENTS 
3.2 STUDY DISEASE 
3.3 RATIONALE 
 
4. PATIENT SELECTION 
4.1 INCLUSION CRITERIA 
4.2 EXCLUSION CRITERIA 
4.3 INCLUSION OF WOMEN AND MINORITIES 
 
5. REGISTRATION PROCEDURES 
5.1 RECRUITEMENT 
5.2 INFORMED CONSENT 
5.3 SCREENING/BASELINE ASSESSMENT AND PROCEDURES 
 
6. TREATMENT PLAN 
6.1 FIDUCIAL PLACEMENT 
6.2 SIMULATION 
6.3 MRI FUSION 
6.4 RADIATION TREATMENT PLANNIN 
6.5 SURGERY 
6.6 PATHOLOGIC ASSESSMENT 
6.7 ADJUVANT THERAPIES 
6.8 CRITERIA FOR DISCONTINUATION FROM PROTOCOL TREATMENT 
6.9 DURATION OF THERAPY 
6.10 DURATION OF FOLLOW-UP 
 
7. EXPECTED TOXICITIES 
7.1 POSSIBLE TOXICITIES FROM RADIATION 
 
8. STUDY CALENDAR 

October 10, 2023 
Principal Investigator: Jean Wright M.D.  
IRB IRB00128074 
 
 
 
 
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9. CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
9.1 PATHOLOGIC RESPONSE 
9.2 ACUTE TOXICITY 
9.3 COSMESIS 
 
10. ADVERSE EVENT REPORTING 
10.1 GENERAL 
10.2 DEFINITION OF ADVERSE EVENT 
10.3 EXPECTEDNESS 
10.4 ATTRIBUTION 
10.5 REPORTING PROCEDURES  
10.6 INSTITUTIONAL REVIEW BOARD 
 
11. DATA AND SAFETY MONITORING PLAN  
 
12. REGULATORY CONSIDERATIONS 
 
13. STATISTICAL CONSIDERATIONS 
    13.1 PRIMARY ANALYSIS, SAMPLE SIZE, ACCRUAL AND MONITORING 
    13.2 ANALYSIS OF SECONDARY OBJECTIVES 
    13.3 MONITORING 
 
14. REFERENCES 
 
15. APPENDICES 
15.1 BCTOS  
15.2 CTCAE V 4.0 
15.3 RTOG COSMESIS SCALES 
 
 
  
 
 
 
 
 
 
 

October 10, 2023 
Principal Investigator: Jean Wright M.D.  
IRB IRB00128074 
 
 
 
 
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1. 
STUDY DESIGN/SUMMARY  
 
1.1 
SUMMARY:  This is a single arm phase II study design, evaluating the pathologic 
response (primary endpoint) as well as toxicity, cosmetic outcome, quality of life, and 
oncologic outcomes (secondary endpoints) to pre-operative stereotactic body 
radiotherapy  (SBRT) to intact breast tumors in patients with hormone-receptor positive 
early stage breast cancer.  
 
1.2 
SCHEMA 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Localization: placement of radio-opaque clip  
-Biopsy clip may be used  
-Fiducial marker if no clip placed at biopsy 
Treatment Planning: 
-CT simulation 
-GTV contoured with MRI fusion 
-SBRT treatment planning 
Treatment Delivery 
-SBRT 21 Gy delivered with CBCT 
registration 
Breast Conserving Surgery 
-Within 7-14 days of SBRT 
-Pathologic response assessed using RCB scale 
 
Eligibility:  
-> 50 yo 
-Invasive ductal histology 
-Tumor ≤2 cm radiographically 
-cN0 
-ER+,  Her 2 neu- 
Favorable Pathologic Factors:  
No additional local treatment  
Unfavorable Features (node+, margin +):  
Adjvuant whole breast +/- nodal radiation at 
discretion of treating physician 

October 10, 2023 
Principal Investigator: Jean Wright M.D.  
IRB IRB00128074 
 
 
 
 
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2. 
OBJECTIVES  
 
2.1 PRIMARY OBJECTIVE: To determine the rate of Residual Cancer Burden (RCB) 
designation 0 (also known as pathologic complete response (pCR)) and RCB I designation 
(combined endpoint of either of those designations) 7-14 days after pre-operative SBRT to 
intact breast tumors.  
 
2.2 SECONDARY OBJECTIVES  
 
2.2.1 To determine the rate of severe acute toxicity, defined as any CTCAE v4 grade 3 or 
higher toxicity noted from RT delivery up to 90 days after completion of surgery. 
2.2.2  To determine the rate of poor cosmetic outcomes from both provider and patient 
perspectives up to 3 years after pre-operative SBRT to intact breast tumors using the 
RTOG (Radiation therapy oncology group) cosmesis scale and digital images.  
2.2.3 To measure local recurrence rate 
2.2.4 To assess patient reported satisfaction and quality of life with treatment using the 
Breast Cancer Treatment Outcomes Scale (BCTOS) 
 
3. 
BACKGROUND   
 
3.1 INVESTIGATIONAL AGENTS: none 
 
3.2 STUDY DISEASE: Early stage clinically node-negative hormone receptor positive breast 
cancer 
 
3.3 RATIONALE:    
 
Standard treatment for early stage breast cancers includes a 3-6.5 week course of whole 
breast radiation following breast conservative surgery.  Studies have demonstrated that 
the requirement for multiple consecutive weeks of adjuvant radiation treatment puts 
older women, those who live in low-income areas, and those who live far from radiation 
centers at a disadvantage, leading to omission of this key part of definitive therapy.1,2 At 
the same time, it has been observed that patients with certain low-risk features such as 
small (≤ 2cm) estrogen receptor (ER) positive tumors and negative lymph nodes have 
lower rates of local recurrence, and tend most commonly to recur in the lumpectomy bed 
as opposed to elsewhere in the breast.3 
 
These observations have led to the development of abbreviated radiation treatment 
regimens focused solely on the tumor bed, rather than the whole breast, an approach 
known as accelerated partial breast irradiation (APBI). This approach was developed in the 
1990’s and over time various techniques for the delivery of APBI have been developed, 
including interstitial catheter-based brachytherapy, balloon-based brachytherapy, and 

October 10, 2023 
Principal Investigator: Jean Wright M.D.  
IRB IRB00128074 
 
 
 
 
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APBI delivered using standard external beam radiotherapy with multiple non co-planar 
beam angles.  Despite variability in technique, all these approaches are most commonly 
delivered in 10 treatment sessions delivered twice daily over 5 days; each treatment 
session delivers a higher dose of radiation as compared to conventional techniques with 
the goal of achieving a biologically equivalent dose to the tumor bed in fewer sessions.  
 
Single-institution and registry data compiled since the inception of the APBI approach 
have demonstrated low rates of locoregional recurrence in appropriately selected 
patients and the early favorable experience with APBI led to a randomized trial, NSABP B-
39/RTOG 0413 , which compared outcomes with the various techniques for APBI with the 
standard approach of whole breast irradiation.4,5  This study accrued over 4000 patients, 
and closed in 2013.  Locoregional outcomes have not yet been published, and at this time 
there is no published phase III data demonstrating the equivalence of APBI and standard 
whole breast RT.  However, in light of the weight of evidence accumulated from decades 
of retrospective data on the approach of APBI, consensus guidelines for the appropriate 
use of APBI outside the setting of a clinical trial were developed in 2009, and the ASTRO 
update was recently published in late 2016.6  In summary of these guidelines, APBI has 
been found to be an acceptable technique for patients with early stage, node-negative 
breast cancer with low-risk features, and we await randomized data to determine if the 
approach can be expanded to patients with higher-risk features.  
 
Thus, at this time, there is considerable data to support the use of APBI in well-selected 
low risk patients, but the optimal technique for delivery of APBI has not been determined.  
The ideal technique would combine accessibility (delivered using widely available 
technology, with low expense, and using the lowest number of treatment fractions) with 
excellent cosmetic results (recalling that the movement for breast conservation emerged 
from the desire to provide equivalent oncologic outcomes compared to mastectomy with 
superior cosmetic results).   
 
The most accessible technique for APBI is external beam radiation, as this can be 
delivered via a standard linear accelerator and does not require extensive technical 
training.  On the NSABP B-39 study, which allowed any of the three common techniques 
for APBI, 75% of patients were treated with EBRT.  However, this technique has been 
associated with poorer cosmesis and higher rates of soft tissue fibrosis compared to 
whole breast radiation.7,8  We await formal publication of the cosmetic outcomes using 
EBRT from NSABP B-39, but at this time there is ongoing concern that this approach 
results in inferior cosmesis compared to whole breast RT due to asymmetric fibrosis of the 
breast in the treated area.  In addition, this approach still requires 10 treatment sessions 
delivered twice daily, 6 hours apart, a schedule that is cumbersome for many women.  
 
Single-fraction approaches offer a more convenient schedule, and have been explored 
most commonly in the setting of intra-operative treatment.  There are several techniques 

October 10, 2023 
Principal Investigator: Jean Wright M.D.  
IRB IRB00128074 
 
 
 
 
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for this approach.9,10  The most widely marketed IORT approach in the US has been the 
Targit technique, using a KV source to deliver radiation intra-operatively in a setting that 
does not require special shielding.  However, a phase III study comparing this approach to 
whole breast external beam radiation demonstrated higher local recurrence risk with the 
Targit technique compared to whole breast RT.9  This finding may relate to the very low 
radiation dose that reaches a depth of 1 cm deep to the surface of the tumor bed, a depth 
generally considered to be within the clinical target volume for breast cancer.  While 20 
Gy is prescribed to the cavity surface, a sub-therapeutic dose of 7 Gy penetrates to a 
depth of 1 cm, a minimum depth presumed to be at risk for microscopic disease.   Similar 
findings were reported using the ELIOT electron-based IORT technique, with a higher risk 
of local recurrence using IORT as compared to whole breast RT.10   In addition, the 
technology needed to deliver IORT using Targit and ELIOT techniques is costly and this not 
widely available in the US.  
 
Thus, none of the currently popular approaches to APBI is ideal, either due to inferior 
efficacy, poorer cosmesis, high cost/need for specialized equipment, and/or 
inconvenience. 
 
An alternative to the above strategies that mitigates many of these limitations is pre-
operative single fraction SBRT. There are several potential advantages to this approach 
over a post- or intraoperative approach. First, it can be delivered with standard radiation 
equipment using linear accelerator technology that is available in the majority of radiation 
oncology departments in the US.  Second, by treating an intact tumor and using MRI 
fusion for target delineation, the radiation target is well-defined compared to a 
postoperative bed that can be difficult to identify.  Third, because the tumor is intact, the 
treatment area is smaller than a typical postoperative bed, decreasing radiation exposure 
to normal tissue, and the majority of the targeted volume is subsequently resected. 
Fourth, by treating pre-operatively, we overcome the theoretical concern of 
postoperative hypoxia in the tumor bed. Finally, a preoperative approach allows for real-
time study of radiation response.   
 
Investigators at Duke University have piloted this approach with excellent results: in a 
cohort of 32 patients, a maximum tolerated dose of 21 Gy has been determined, no grade 
3 or 4 toxicities were seen, fibrosis at 18 months followup was minimal (58% grade 1, 10% 
grade 2, 3% grade 3) and cosmesis was rated as excellent or good in all patients.11  While 
these phase I results are promising, the study cohort is very small. These findings warrant 
replication in a Phase II study such as the one we propose here.  
 
Authors in the Netherlands recently published their preliminary results of preoperative 
accelerated partial breast irradiation using a hypofractionated approach of 40 Gy in 10 
fractions delivered once daily over 2 weeks.  Eligible patients include those aged > 60 
years, cT1-2, pN0 and invasive ductal histology. Median follow-up for 70 patients was 23 

October 10, 2023 
Principal Investigator: Jean Wright M.D.  
IRB IRB00128074 
 
 
 
 
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months, and two ipsilateral breast tumor recurrences were diagnosed. In terms of patient 
reported outcomes, at 3 years 79% of patients were satisfied to very satisfied with their 
cosmetic result.  After 36 months, only 11 (19%) patients were noted to have any fibrosis, 
and all cases were mild. In summary, the authors concluded that given the good to 
excellent cosmetic results and low complication and fibrosis rates, pre-operative APBI is a 
feasible technique for low-risk breast cancer patients.12   This approach to ABPI has the 
disadvantage of a longer course of therapy as compared to SBRT.  Pathologic response 
was not reported in this series. 
 
Pathologic response to chemotherapy has been shown to be prognostic for both 
locoregional and survival outcomes in breast cancer, and has become an increasingly 
utilized endpoint in preoperative chemotherapy studies.   Studies have demonstrated that 
lower-risk tumors such as those with ER positive/HER2 negative phenotype are less 
chemosensitive and thus less likely to show a pathologic complete response to 
chemotherapy.13  At the same time, response to chemotherapy is less prognostic in this 
setting.14  A more nuanced system of evaluating response in those tumors that do not 
show a pCR is the residual cancer burden (RCB) scoring system (REF), which evaluates 
tumor size, nodal involvement and cellularity has been demonstrated to be predictive of 
outcome and is used to define categories of less than complete response.15 
 
While response to pre-operative chemotherapy is less prognostic in ER-positive disease, 
the opposite may be true in terms of radiation response.  There is little data evaluating 
response to radiation to intact breast tumors, but data looking at the benefit of adjuvant 
radiation in breast cancer shows a greater impact of RT in reduction of locoregional 
recurrence, and a greater survival impact in ER positive tumors as compared to ER 
negative or triple negative.13,15 Thus, a better understanding of tumor response to 
radiation is critical.  Unlike chemotherapy response, response to radiation may in fact be 
prognostic based on adjuvant RT data, and can be used as a baseline for future study.    
 
Additionally, we also plan to study pathologic specimens for change in hormone receptor 
status, conversion of Ki 67, and presence of residual DCIS and evaluate the utility of these 
as biomarkers to predict response.  
 
4. 
PATIENT SELECTION  
 
4.1 INCLUSION CRITERIA 
 
4.1.1 Female sex 
4.1.2 Age > 50 
4.1.3 Invasive ductal carcinoma 
4.1.4 Clinically and radiographically T1 tumor 
4.1.5 Clinically node negative 

October 10, 2023 
Principal Investigator: Jean Wright M.D.  
IRB IRB00128074 
 
 
 
 
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4.1.6 Clearly demarcated tumor on magnetic resonance imaging (MRI), as determined by 
treating physician (MRI may be done after enrollment if not done prior) 
4.1.7 Planning breast conserving surgery  
4.1.8 ≥10% expression of ER and/or PR  
4.1.9 HER2- using the current College of American Pathologists guidelines 
4.1.10 Post-menopausal  
4.1.11 Willing and able to provide informed consent  
4.1.12 Patient’s case has been reviewed and approved for trial by medical oncologist 
 
4.2 EXCLUSION CRITERIA  
 
4.2.1 Medical conditions that may increase risk for poor cosmetic outcome (i.e.  Lupus, 
rheumatoid arthritis, scleroderma 
4.2.2 Pure DCIS without invasive cancer 
4.2.3 Patients who have received or will be receiving neoadjuvant systemic therapy, 
endocrine therapy, or targeted agents 
4.2.4 Breast implant in the involved breast unless the implant will be removed prior to 
initiation of study treatment 
4.2.5 Subjects without placement of a biopsy clip at the diagnostic procedure who are 
unwilling to undergo clip placement. 
4.2.6 Unable to meet dosimetric constraints due to tumor location and/or patient 
anatomy 
4.2.7 Planning mastectomy 
4.2.8 Unable to tolerate prone positioning 
 
4.3 INCLUSION OF WOMEN AND MINORITIES  
 
Individuals of all races and ethnic groups are eligible for this trial. This trial is open to the 
accrual of post-menopausal women only. 
 
5. 
REGISTRATION PROCEDURES  
 
5.1 RECRUITMENT  
 
Patients will be identified by screening in the surgical clinics. Patients will be referred to 
radiation oncology pre-operatively after screen identification. Once a subject has 
successfully completed all of the screening procedures and is considered eligible by the 
principal investigator, the subject can be enrolled in the study. 
 
5.2 INFORMED CONSENT  
 
All subjects considered for enrollment in the study must complete an IRB approved 

October 10, 2023 
Principal Investigator: Jean Wright M.D.  
IRB IRB00128074 
 
 
 
 
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informed consent prior to any study-specific procedures being performed. 
The investigator (or his/her designee) will explain to each subject the nature of the study, 
its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved and any discomfort it may entail. Each subject will be informed that 
participation in the study is voluntary, that she may withdraw from the study at any time, 
and that withdrawal of consent will not affect her subsequent medical treatment or 
relationship with the treating physician(s) or institution. The informed consent will be 
given by means of a standard written statement, written in non-technical language, which 
will be IRB approved.  The subject should read and consider the statement before signing 
and dating it, and will be given a copy of the document. No subject will enter the study or 
have study-specific procedures performed before her informed consent has been 
obtained. 
 
In accordance with the Health Information Portability and Accountability Act (HIPAA), 
the written informed consent document (or a separate document to be given in 
conjunction with the consent document) will include a subject authorization to release 
medical information to the study sponsor and supporting agencies and/or allow these 
bodies, a regulatory authority, or Institutional Review Board access to subjects’ medical 
information that includes all hospital records relevant to the study, including subjects’ 
medical history. 
 
5.3 SCREENING/BASELINE ASSESSMENT AND PROCEDURES  
 
Patients must undergo complete history and physical exam including complete clinical 
breast and regional nodal exam, weight, and Karnofsky performance status assessment 
within 30 days prior to enrollment. Patients must also have a biopsy confirmed invasive 
ductal breast cancer on which ER, PR, and Her2 receptor status must be assessed per CAP 
guidelines, as well as Ki67 documented.  If possible, percent tumor cellularity should be 
reported on the biopsy specimen. Bilateral mammograms must have been performed 
within 120 days of study entry for all patients with an intact contralateral breast. A 
medical oncologist will also review the case prior to enrollment and determine need for 
formal consultation pre-operatively, specifically to ensure that adequate information is 
available based on the available tissue to inform treatment decisions in the event of pCR.   
MRI is not required to be done before enrollment but if an MRI was already done, this can 
be used for study purposes.  The MRI must have been completed within 60 days of 
enrollment. 
 
6.       
TREATMENT PLAN  
 
6.1. FIDUCIAL PLACEMENT 
 

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Prior to treatment patients must have at least one radio-opaque fiducial marker placed in 
the tumor, which will be used for image guidance for precise radiation delivery. If a clip or 
clips have been placed at biopsy, they may serve as fiducial markers.  The markers must 
be located within the tumor on the treatment planning MRI.   
 
6.2 SIMULATION 
 
All patients will undergo standard CT simulation with 2 mm cuts in the prone position with 
arms overhead and treated breast pendant, per our institutional procedure for prone 
breast simulation; if the treating physician deems appropriate, supine positioning is 
allowed. If MRI simulation is available in the clinical location, MRI simulation may be 
performed. Any palpable tumor will be marked with a BB.  A Vac-fix bag will be required 
to standardize immobilization.  Verification of fiducial marker placement and visibility will 
be confirmed at the time of simulation.  
 
6.3 MRI FUSION 
 
All patients will undergo MRI for target delineation. If patients have had diagnostic MRI 
within 60 days of study enrollment, this will be fused in our planning system to the CT 
simulation scan. This diagnostic MRI must have been performed in a dedicated breast 
surface coil with arms overhead. If the patient has not had such an MRI prior to 
enrollment, they will undergo MRI simulation in a breast surface coil. The following 
sequences will be fused to the CT scan for gross tumor delineation: axial T1, axial T2 with 
fat saturation, diffusion weighted imaging, and any additional sequences on which the 
tumor is clearly delineated as determined by the physician contouring.   
 
6.4 RADIATION TREATMENT PLANNING 
 
6.4.1 Target Volumes:   The gross tumor volume (GTV) will be contoured using the fused 
MR images as well as the fiducial clip and any abnormality noted on CT. A uniform 1.5 cm 
expansion will be applied around the GTV to create the clinical target volume (CTV).  The 
first 5mm of tissue deep to the patient’s body surface and any chest wall (pectoralis 
muscle and deeper) if >1cm from the GTV will be excluded from this CTV volume. The 
exclusion of tissue under body surface relates to concerns for inaccurate dosimetry in the 
build-up region; this is standard in cooperative group breast protocols.  The exclusion of 
chest wall from the target volume relates to the anatomic boundary created by this 
structure. To account for set-up uncertainty at the machine, we will generate two 
planning target volumes for generation of beam apertures: a GTV_21_PTV which is a 0.5 
cm expansion of the GTV, and a CTV_15_PTV which is a 0.5 cm expansion of the CTV. 
Beam apertures may be smaller than 5 mm if dose constraints below can be met with 
smaller margins. 
 

October 10, 2023 
Principal Investigator: Jean Wright M.D.  
IRB IRB00128074 
 
 
 
 
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6.4.2 Organs at risk to be contoured will include: skin, each lung, each breast, spinal cord, 
heart, esophagus, thyroid and brachial plexus.  
 
6.4.3 Treatment planning will be completed by a dosimetrist and may utilize arc therapy, 
multiple conformal beams, or intensity-modulated therapy, or a combination of these 
techniques. Dose will be normalized to provide a desired coverage to the GTV and CTV, 
detailed below.  There is no restriction on photon energy, but electrons are prohibited.  
Patients will receive a single fraction of 21 Gy delivered to the GTV and 15 Gy to the CTV 
using a dose-painting method. 
 
6.4.4 Target Localization and Treatment Delivery: All institutional protocols for 
stereotactic body radiotherapy pre-treatment quality assurance will be followed. At the 
time of treatment, patients will be positioned and immobilized as they were at the time of 
CT simulation, per institutional procedures. After set-up, cone beam CT (CBCT) will be 
used for localization as described in the section on target localization, unless CBCT is not 
technically feasible in a given patient. In addition to CBCT, kilovoltage on-board imaging 
(OBI) may also be used at the treating physician’s discretion. Both biopsy clips and soft 
tissue will be used for registration. These images will be approved by the treating 
radiation oncologist before treatment proceeds.  
 
6.4.5 Dose Constraints:  Dose constraints are derived from the phase I experience with 
pre-operative SBRT at Duke University, establishing the safety of 21 Gy in a single fraction 
observing the following constraints: 
 
6.4.5.1 Target volumes.  All beam apertures will be demarcated by the PTVs to account 
for setup uncertainty.  Beam apertures may be smaller than 5 mm if dose constraints 
below can be met with smaller margins. The GTV and CTV will be utilized for target dose-
volume analysis. Subjects will receive a single fraction of 21Gy to the GTV, and 15 Gy to 
the CTV.   The prescribed doses will cover >95% of the GTV and CTV respectively without 
exceeding maximum dose of 110% of the maximum prescribed dose. 
 
6.4.5.2 Normal breast: <30% of the whole breast volume should receive 50% or more of 
the prescribed dose and <15% of the whole breast volume should receive the prescribed 
dose.  This constraint is in line with the majority of partial breast irradiation protocols and 
will select for a group of patients with larger breasts.  Irradiation to a larger relative 
volume of the breast may be associated with poorer cosmetic outcomes.  
 
6.4.5.3 Contralateral breast: the contralateral whole breast volume should receive <10% 
of the prescribed dose to any point 
 
6.4.5.4 Lungs:  
 1 Mean lung dose <3.6Gy  

October 10, 2023 
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IRB IRB00128074 
 
 
 
 
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 2 <37% of lung volume should receive 8Gy 
  3 <1500cc to 7Gy 
 4 <1000cc 7.6Gy 
 
6.4.5.5 Heart: 1) Mean should not exceed 1.5Gy; 2) Point dose <5Gy. 
 
6.4.5.6 Chest wall: D20cc <16.3Gy. 
 
6.4.5.7 Thyroid: maximum point dose <10% of the prescribed dose 
 
6.4.5.8 Brachial plexus: no point in the brachial plexus should receive more than 10% 
(2.1Gy maximum) of the maximum prescribed dose. The brachial plexus will be contoured 
as per RTOG consensus. 
 
6.4.5.9 Skin dose: 1) Maximum dose will not exceed prescription dose. 2) Dose to 1cc: 
<15Gy dose to 10cc <8Gy.  Of note the skin contour will consist of a 2 mm rind around the 
patient’s body surface. The skin contour should extend to a level at least 10 cm above and 
10 cm below the CTV-PTV structure. 
 
6.4.5.10 Cord: maximum dose to 1 cc should be 1 Gy. 
 
6.5 SURGERY   
  
Resection of the tumor will be completed 7-14 days after delivery of radiation.  Surgery 
will include sentinel node assessment per our institutional standards, but omission of 
sentinel biopsy is permitted in patients age 70 and over with no clinical evidence of nodal 
involvement.  Resection of the tumor must include a 2mm margin of normal tissue.  A re-
excision vs post-operative whole breast RT should be considered if the margin is less.  
Positive margins must be re-excised unless deemed technically not feasible by the 
surgeon (eg anterior margin dissected to skin).  
 
6.6 PATHOLOGIC ASSESSMENT:  
  Standard pathologic assessment per our institutional guidelines will be followed and 
additionally will include RCB analysis and repeat evaluation of Ki67 and receptor status 
(ER, PR and HER2) if there is any residual invasive cancer.  
 
6.7 ADJUVANT THERAPIES 
 
6.7.1 RADIATION: 
 
Following standard pathologic assessment, patients will be assessed for any adverse 
features that would warrant adjuvant whole breast radiation with or without regional 

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Principal Investigator: Jean Wright M.D.  
IRB IRB00128074 
 
 
 
 
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nodal radiation. This would include margins <2mm, positive lymph nodes, or as 
recommended by treating radiation oncologist due to any other adverse feature 
identified. Hypofractionated and conventionally fractionated regimens (40.50-50 Gy) can 
be considered by the treating radiation oncologist. In these patients requiring adjuvant 
radiation, a boost will not be delivered.  
 
6.7.2 ADJUVANT SYSTEMIC THERAPY 
 
Adjuvant systemic therapies including chemotherapy and endocrine therapy will be at the 
discretion of the medical oncologist.  If Oncotype DX or other genetic scoring is desired for 
evaluation, this will be sent on the pre-treatment biopsy specimen obtained before 
enrollment on study and which was used for initial diagnosis.   Medical oncology approval 
via case discussion or formal consultation is required prior to pre-operative SBRT to 
ensure the medical oncologist will be able to obtain all needed information to determine 
adjuvant systemic recommendations.  
  
6.8 CRITERIA FOR DISCONTINUATION FROM PROTOCOL TREATMENT.   
 
Because SBRT is delivered in one day, discontinuation is unlikely.  However if at any time 
the constraints of this protocol are detrimental to the patient’s health and/or the patient 
no longer wishes to continue on the study long-term, the patient shall be removed from 
the protocol follow-up. In this event the reason(s) for discontinuation of study 
participation will be noted by the PI in the Radiation Oncology record.  Subjects who 
prematurely withdraw will not be replaced unless radiation has not been initiated. 
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 
 
6.9 DURATION OF THERAPY: 
 
The duration of protocol-specified therapy will be approximately 2 months.  It is expected 
that treatment planning may take 2 weeks from simulation to treatment delivery, and 
that 4-6 weeks will elapse from treatment delivery to surgery. 
 
6.10 
DURATION OF FOLLOW-UP 
 

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Follow-up for this study includes physical exam by member of oncology team every 6 
months for the first 2 years, every 6-12 months through year 5, and annually through year 
10. Bilateral mammogram will be obtained annually. Other laboratory or radiographic 
studies will be obtained as directed by patient symptoms or physical exam.  Quality of life 
and cosmetic assessments by both physician and patient will be performed at 6 months, 1 
year, and then annually through 3 years of follow-up. Loco regional recurrence will be 
monitored on protocol at each follow-up visit. Please see study calendar, section 8.0, for 
detail. Standard follow-up should continue per NCCN guidelines, off protocol, after 3 
years.   
 
7. 
EXPECTED TOXICITIES 
 
7.1 
POSSIBLE TOXICITIES FROM RADIATION  
 
7.1.1 Potential Short Term Reactions  
  
Common:  
 Skin redness and irritation in area treated  
 Darkened skin and dryness in area treated 
 Fatigue 
 Temporary hair loss in the area treated 
 Occasional aches and pains in the breast 
 Temporary edema in treated breast  
 
Uncommon: 
 Post-operative bleeding at the time of surgery 
 Increased risk of post-operative wound infection 
 Seroma formation 
 Skin blistering or ulceration 
 
7.1.2 Potential Long Term Reactions  
 
Common: 
 Minor pigment change in the treated breast  
 Occasional discomfort and sensitivity in the treated area 
 Mild to moderate increased firmness of the treated breast 
 Mild swelling of the treated breast which can last a number of years 
 Minor shrinkage of the treated breast 
 
Uncommon:  
 Significant increase in firmness or fibrosis of the treated breast 

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Principal Investigator: Jean Wright M.D.  
IRB IRB00128074 
 
 
 
 
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 Significant shrinkage of the treated breast 
 Breast Pain 
 
Rare: 
 Lung inflammation and scarring 
 Rib fractures in the treated area 
 
Extremely Rare:  
 Damage to the heart causing heart failure or heart attack 
 Tumors caused by radiation 
 Damage to the nerves of the arm 
 
  
8.  
STUDY CALENDAR 
 
In order to minimize the need for research-only in-person visits, telemedicine visits may be 
substituted for in person clinical trial visits or portions of clinical trial visits where 
determined to be appropriate and where determined by the investigator not to increase the 
participants risks. Prior to initiating telemedicine for study visits the study team will 
explain to the participant, what a telemedicine visit entails and confirm that the study 
participant is in agreement and able to proceed with this method. Telemedicine 
acknowledgement will be obtained in accordance with the Guidance for Use of 
Telemedicine in Research. In the event telemedicine is not deemed feasible, the study visit 
will proceed as an in-person visit. Telemedicine visits will be conducted using HIPAA 
compliant method approved by the Health System and within licensing restrictions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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a. 
Physical exam by member of oncology team every 6 months for the first 3 years. 
Bilateral mammogram annually for the first 3 years.  Follow-up will continue per NCCN 
guidelines, off protocol, after 3 years.   
b. 
Verify placement of a biopsy clip at diagnostic procedure and availability of pre-
treatment tissue for correlative science. 
 
 
Pre-SBRT 
(baseline) 
SBRT 
Post-SBRT 
< 1 week 
prior to 
surgery 
Surgical Procedure 
4-6 
weeks  
Post-
Surgery 
From time of surgery.  All visits have a window of  +/-  1 
Month except where indicated 
Month 
6 
Month 
12 
Month 
18 
Month 
24 
Month 
30 
Month 
36 
History/Physical 
Xa 
 
X 
X 
X 
X 
X 
X 
X 
Vitals signs, 
height weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
Demographics  
X 
 
 
 
 
 
 
 
 
Breast imaging 
(mammogram 
minimum)  
Xa 
 
 
 
X 
(+/- 3 
months) 
 
X 
(+/- 3 
months) 
 
X 
(+/- 3 
months) 
Core 
Biopsy/fiducial 
markers 
Xb 
 
 
 
 
 
 
 
 
Medical Oncology 
Approval 
X 
 
 
 
 
 
 
 
 
Planning MRI 
X 
 
 
 
 
 
 
 
 
Patient 
Questionnaire 
(BCTOS) 
Xd 
 
X 
X 
X 
 
X 
 
X 
Patient Cosmesis 
evaluation (RTOG) 
Xe 
 
X 
X 
X 
 
X 
 
X 
Physician 
Cosmesis 
evaluation 
(RTOG) 
Xe 
 
X 
X 
X 
 
X 
 
X 
Digital image of 
breasts 
X 
 
 
 
X 
 
 
 
X 
Performance 
Status (KPS)  
X 
 
X 
X 
X 
X 
X 
X 
X 
Toxicity 
Assessment 
Xc 
Xc 
X 
X 
X 
X 
X 
X 
X 

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IRB IRB00128074 
 
 
 
 
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c. 
Post-SBRT toxicity evaluation in Radiation Oncology within 1 week prior to 
surgery and again 4-6 weeks after surgery. 
 
d. 
BCTOS to be completed by patient at baseline (prior to treatment), at first FU 4-6 
weeks after surgery, six months and one year after surgery, and then annually for 2 
additional years.   
 
e. 
RTOG cosmesis scoring to be completed by physician and patient at baseline 
(prior to treatment), at first FU 4-6 weeks after surgery, six months and one year after 
surgery and then annually for 2 additional years.   
 
 
9.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS  
 
9.1 PATHOLOGIC RESPONSE – Standard pathologic assessment per our institutional 
guidelines will be followed. Additionally, we will include calculation of percent cellularity 
on the biopsy specimen, residual cancer burden (RCB) analysis and repeat evaluation of 
Ki67 and receptor status (ER, PR and Her2) if there is any residual invasive cancer at 
surgery.  Residual cancer burden will be assessed by staff pathologists and is calculated 
using a published continuous index that combines pathologic measurements of the 
primary tumor (size and cellularity) and nodal metastases (number and size) (reference 
Symanns). This RCB index has been validated as a predictor of distant relapse.  
 
9.2 ACUTE TOXICITY- Acute toxicity will be graded with the Common Terminology Criteria 
for Adverse Events (CTCAE) version 4. Grade ≥3 acute toxicity will be considered severe 
(Appendix 15.2).  
 
9.3 COSMESIS- As noted in the introduction, early cosmetic results from other published 
pre-operative radiation series for early stage breast cancer have been favorable.11 We 
expect similar favorable outcomes, and for the pre-operative single fraction cosmetic 
results to be equivalent to that of partial breast radiation results. We expect cosmesis to 
stabilize at 3 years following treatment and thus our endpoint will be to measure results 
at this timepoint. We will also assess cosmesis at specified time points per the study 
calendar to quantify changes in breast cosmesis over time. 
 
Cosmetic results will be evaluated by both the patient and the physician. Patients will rate 
cosmesis using the Breast Cancer Treatment Outcome Scale (BCTOS), which will also be 
used to evaluate patient reported quality of life (Appendix 15.1). This self-report 
instrument has been used in a number of studies for this purpose and has both reliability 
and validity (reference Stanton AL, Krishnan L, Collins CA. Form or function? Part 1. 
Subjective cosmetic and functional correlates of quality of life in women treated with 
breast-conserving surgical procedures and radiotherapy. Cancer 91:2273-2281, 2001) 

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Patients will first complete this after informed consent, and then at multiple intervening 
assessment points up to 3-years of follow-up (see Study Calendar). At the same time 
points, patients will also score cosmesis using the RTOG 4-point scale. 
 
The cosmetic evaluation will also be completed by the radiation oncologist or surgeon 
after consent and prior to treatment. This will be done using the RTOG scale, using criteria 
established in previous RTOG trials (Appendix 15.3).  
 
Lastly, digital images of patients’ breasts will be taken after consent and prior to initiation 
of treatment, as well as at later time points (see Study Calendar). Two pictures will be 
taken at each time point, taking care to exclude the patient’s face. As done in NSABP B39, 
the first image will be of the breast to be treated and at a 45 degree oblique angle with 
arms elevated overhead. The second image should be at a straight angle and frontal view 
of both breasts taken in either a standing or seated position with the patient's hands on 
her hips, taking care to exclude her face. These pictures will be taken at baseline (prior to 
any treatment), at 1-year and 3-year assessment points.  
 
 
10.  
ADVERSE EVENT REPORTING  
 
10.1 GENERAL  
 
Adverse event collection and reporting is a routine part of every clinical trial. This study 
will use the descriptions and grading scales found in the NCI Common Terminology 
Criteria for Adverse Events version 4.0 (CTCAE v 4.0) that is available at 
http://ctep.cancer.gov/reporting//ctc.html.  
Information on all adverse events, whether reported by the participant, directly observed, 
or detected by physical examination, laboratory test or other means, will be collected, 
recorded, followed and reported as described in the following sections.  
Adverse events experienced by participants will be collected and recorded from initiation 
of study medication, throughout the study, and within 90 days of the definitive surgery. 
Participants who experience an ongoing adverse event related to a study procedure 
and/or study medication beyond 90 days post-op will continue to be contacted by a 
member of the study team until the event is resolved, stabilized, or determined to be 
irreversible by the participating investigator.  
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. The investigator should notify the IRB 
and any other applicable regulatory agency of any unanticipated death or adverse event 
occurring after a participant has discontinued 
 
10.2 DEFINITION OF ADVERSE EVENT (AE) Serious adverse event (SAE)  
 

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A serious adverse event is an undesirable sign, symptom, or medical condition which:  
• is fatal or life-threatening;  
• requires or prolongs inpatient hospitalization;  
• results in persistent or significant disability/incapacity;  
• constitutes a congenital anomaly or birth defect; or  
• jeopardizes the participant and requires medical or surgical intervention to prevent one 
of the outcomes listed above.  
 
Events not considered to be serious adverse events are hospitalizations for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures  
• elective or pre-planned treatment for a pre-existing condition that did not worsen  
• emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission  
• respite care  
 
10.3 Expectedness  
• Expected: Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, an adverse 
event is considered expected when it appears in the current adverse event list, the 
Investigator’s Brochure (8.0), the package insert or is included in the informed consent 
document as a potential risk.  
• Unexpected: An adverse event is considered unexpected when it varies in nature, 
intensity or frequency from information provided in the current adverse event list, the 
Investigator’s Brochure (8.0), the package insert or when it is not included in the informed 
consent document as a potential risk  
 
10.4 Attribution  
Attribution is the relationship between an adverse event or serious adverse event and the 
study treatment. Attribution will be assigned as follows:  
• Definite – The AE is clearly related to the study treatment.  
• Probable – The AE is likely related to the study treatment.  
• Possible – The AE may be related to the study treatment.  
• Unlikely - The AE is doubtfully related to the study treatment.  
• Unrelated - The AE is clearly NOT related to the study treatment.  
 
10.5 REPORTING PROCEDURES  
All adverse events will be captured on the appropriate study-specific case report forms 
(CRFs). 
 
10.6 INSTITUTIONAL REVIEW BOARD  
Institutional Review Board  

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IRB IRB00128074 
 
 
 
 
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All adverse events and serious adverse events will be reported to the IRB per current 
institutional standards. If an adverse event requires modification of the informed consent, 
these modifications will be provided to the IRB with the report of the adverse event. If an 
adverse event requires modification to the study protocol, these modifications will be 
provided to the IRB as soon as is possible  
 
11.  
DATA AND SAFETY MONITORING PLAN  
 
This is a DSMP Level I study under the SKCCC Monitoring Plan. A Level I study requires 
both internal and external data monitoring. The Principal Investigator is responsible for 
internal monitoring for both safety and data quality. External data monitoring will be 
performed by the SKCCC at Johns Hopkins Clinical Research Office Quality Assurance 
Program (CRO QA).  
 
Data and safety monitoring oversight will be conducted by the SKCCC at Johns Hopkins 
Safety Monitoring Committee. Per the SKCCC at Johns Hopkins Safety Monitoring plan, 
the CRO AQ will forward summaries of all monitoring reports to the Safety Monitoring 
Committee for review. All reportable anticipated and unanticipated protocol 
events/problems and amendments that are submitted to the IRB will also be reviewed by 
the Safety Monitoring Committee Chair (or designee) and QA manager. 
 
12.  
REGULATORY CONSIDERATIONS  
 
Information regarding study conduct and progress will be reported to the Institutional 
Review Board (IRB) per the current institutional standards.  
 
12.2 Informed Consent  
 
The investigator (or his/her designee) will explain to each subject the nature of the study, 
its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved and any discomfort it may entail. Each subject will be informed that 
participation in the study is voluntary, that she may withdraw from the study at any time, 
and that withdrawal of consent will not affect her subsequent medical treatment or 
relationship with the treating physician(s) or institution. The informed consent will be 
given by means of a standard written statement, written in non-technical language, which 
will be IRB approved. The subject should read and consider the statement before signing 
and dating it, and will be given a copy of the document. No subject will enter the study or 
have study-specific procedures done before his/her informed consent has been obtained.  
In accordance with the Health Information Portability and Accountability Act (HIPAA), the 
written informed consent document (or a separate document to be given in conjunction 
with the consent document) will include a subject authorization to release medical 
information to the study sponsor and supporting agencies and/or allow these bodies, a 

October 10, 2023 
Principal Investigator: Jean Wright M.D.  
IRB IRB00128074 
 
 
 
 
Page 22 of 30 
regulatory authority, or Institutional Review Board access to subjects’ medical information 
that includes all hospital records relevant to the study, including subjects’ medical history.  
 
 
12.3 Ethics and GCP  
This study will be carried out in compliance with the protocol and Good Clinical Practice, 
as described in:  
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996.  
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 
56 concerning informed consent and IRB regulations).  
3. Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, 
amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996).  
 
The investigator agrees to adhere to the instructions and procedures described in it and 
thereby to adhere to the principles of Good Clinical Practice that it conforms to. 
  
12.4 PROTOCOL REVIEW AND AMENDMENTS  
Any changes to the protocol will be made in the form of an amendment and must be 
approved by the IRB prior to implementation.  
 
13. 
 STATISTICAL CONSIDERATIONS  
 
This is a prospective, single-arm study to determine the pathologic outcomes, acute 
toxicities, cosmetic outcomes, and local recurrence rates of preoperative singe fraction 
partial breast radiation in early stage breast cancer. All analyses will be undertaken in the 
enrolled population who initiate treatment.  
 
13.1 Primary analysis, sample size, accrual and monitoring  
 
The pCR and RCB status as assessed at surgery (defined in Section 2) will be tabulated, and 
the number and percentage of patients who achieve RCB 0/pCR or RCB 1 will be reported 
with two-sided 90% CIs. The primary endpoint will be rate of RCB 0 or 1.  
 
Simon's two-stage design (Simon, 1989) will be used. The null hypothesis that the true 
response rate is 0.1 will be tested against a one-sided alternative. In the first stage, 16 
patients will be accrued. If there are 1 or fewer responses in these 16 patients, a study 
team will be convened to determine if the study should proceed. Otherwise, 24 additional 
patients will be accrued for a total of 40. The null hypothesis will be rejected if 7 or more 
responses are observed in 40 patients. This design yields a type I error rate of 0.089 and 
power of 86.9% when the true response rate is 0.25. 
 

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Principal Investigator: Jean Wright M.D.  
IRB IRB00128074 
 
 
 
 
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13.2 Analysis of secondary objectives 
 
Acute toxicities (up to 90 days after completion of surgery) will be collected using CTCAE 
v4.0 and will be tabulated by body system, type and grade. The number and percentage of 
patients who experience at least one grade 3 or higher AE will also be reported. The 
presence or absence of all CTCAE toxicities included in Appendix 15.2 will be assessed in 
addition to those listed here: breast pain, dermatitis, atrophy, fatigue, fibrosis, 
lymphedema, pruritis, seroma, surgical would dehiscence, fat necrosis, surgical site 
infection, hyperpigmentation, skin ulceration. We will use continuous toxicity monitoring 
throughout the trail as described below.   Stopping rules are described below in 13.3. 
  
Local recurrence rates will be calculated using cumulative incidence function, where death 
without local recurrence is considered as competing event.  The associated 95% 
confidence intervals at landmark timepoints including 6 months, 1 year, 2 years and 3 
years will also be provided. 
 
Physician assessment of cosmesis (see Section 9.3) will occur at baseline, 4-6 weeks after 
surgery, 6 months, 1, 2 and 3 years. The secondary endpoint of poor cosmetic outcome is 
a physician-assessment of unacceptable (fair or poor) cosmesis at any time point through 
3 years and/or occurrence of grade 3 or higher toxicity through 3 years. The number and 
percentage of patients, with 2-sided x% CIs, will be reported. The timepoint of 
unacceptable cosmesis assessment and of the grade 3 or higher AEs will be summarized 
descriptively. Additionally, when all enrolled subjects have had 1 year of follow-up, a 
working group of investigators will be assembled to evaluate cosmesis on all patients.  
 
Patient-reported satisfaction with cosmetic outcome will be assessed at baseline, 6 
months, 1, 2 and 3 years. Satisfaction over time will be summarized descriptively and 
graphically.  
 
13.3 Monitoring  
 
To minimize the risks of preoperative SBRT, safety will be monitored by A Bayesian 
stopping rule for the rate of acute toxicity grade > 3 convincingly greater than 
10%.  Specifically, the Bayesian toxicity monitoring rule that suspends the accrual any time 
if the posterior probability of acute toxicity grade > 3 risk being larger than 10% is 75% or 
higher.  We assume a priori that this experimental regimen has an average risk around 5% 
and there is about 10% chance that the risk will be 10% or higher.  This corresponds to a 
Beta (1,20) prior distribution.  The following table gives the corresponding stopping rule 
for the 40 patients. For example, if 3 patients out of the first 5 treated patients experience 
acute toxicity grade > 3, we will suspend accrual temporarily and the principle 
investigators and study team will review the toxicity data and recommend either 
modification or termination of the trial. 

October 10, 2023 
Principal Investigator: Jean Wright M.D.  
IRB IRB00128074 
 
 
 
 
Page 24 of 30 
 
 
# patients with toxicity 
3 
4 
5 
6 
7 
Out of total # patients treated 
5 
6-14 
15-22 
23-31 
32-40 
 
 
 
 
14.  REFERENCE 
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. 2001;19(8):2254-2262. 
 
2. Nattinger AB, Kneusel RT, Hoffmann RG, Gilligan MA. Relationship of distance from a 
radiotherapy facility and initial breast cancer treatment. J Natl Cancer Inst. 
2001;93(17):1344-1346. 
 
3. Smith BD, Arthur DW, Buchholz TA, et al. Accelerated partial breast irradiation 
consensus statement from the american society for radiation oncology (ASTRO). Int J 
Radiat Oncol Biol Phys. 2009;74(4):987-1001. 
 
4. Baglan KL, Sharpe MB, Jaffray D, et al. Accelerated partial breast irradiation using 3D 
conformal radiation therapy (3D-CRT). Int J Radiat Oncol Biol Phys. 2003;55(2):302-311. 
 
5. Keisch M, Vicini F, Kuske RR, et al. Initial clinical experience with the MammoSite 
breast brachytherapy applicator in women with early-stage breast cancer treated with 
breast-conserving therapy. Int J Radiat Oncol Biol Phys. 2003;55(2):289-293. 
 
6. Correa C, Harris EE, Leonardi MC, et al. Accelerated partial breast irradiation: Executive 
summary for the update of an ASTRO evidence-based consensus statement. Pract Radiat 
Oncol. 2016. 
 
7. Jagsi R, Ben-David MA, Moran JM, et al. Unacceptable cosmesis in a protocol 
investigating intensity-modulated radiotherapy with active breathing control for 
accelerated partial-breast irradiation. Int J Radiat Oncol Biol Phys. 2010;76(1):71-78. 
 
8. Hepel JT, Tokita M, MacAusland SG, et al. Toxicity of three-dimensional conformal 
radiotherapy for accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys. 
2009;75(5):1290-1296. 
 
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. 2014;383(9917):603-613. 

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Page 25 of 30 
 
10. Veronesi U, Orecchia R, Maisonneuve P, et al. Intraoperative radiotherapy versus 
external radiotherapy for early breast cancer (ELIOT): A randomised controlled 
equivalence trial. Lancet Oncol. 2013;14(13):1269-1277. 
 
11. Horton JK, Blitzblau RC, Yoo S, et al. Preoperative single-fraction partial breast 
radiation therapy: A novel phase 1, dose-escalation protocol with radiation response 
biomarkers. Int J Radiat Oncol Biol Phys. 2015;92(4):846-855. 
 
12. van der Leij F, Bosma SC, van de Vijver MJ, et al. First results of the preoperative 
accelerated partial breast irradiation (PAPBI) trial. Radiother Oncol. 2015;114(3):322-327. 
13. von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic 
complete response on prognosis after neoadjuvant chemotherapy in various intrinsic 
breast cancer subtypes. J Clin Oncol. 2012;30(15):1796-1804. 
 
14. Kyndi M, Overgaard M, Nielsen HM, Sorensen FB, Knudsen H, Overgaard J. High local 
recurrence risk is not associated with large survival reduction after postmastectomy  
radiotherapy in high-risk breast cancer: A subgroup analysis of DBCG 82 b&c. Radiother 
Oncol. 2009;90(1):74-79. 
 
15. Symmans WF, Peintinger F, Hatzis C, et al. Measurement of residual breast cancer 
burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol. 
2007;25(28):4414-4422. 
 
16. Stroun M, Maurice P, Vasioukhin V, et al. The origin and mechanism of circulating 
DNA. Ann N Y Acad Sci. 2000;906:161-168. 
 
17. Diehl F, Li M, Dressman D, et al. Detection and quantification of mutations in the 
plasma of patients with colorectal tumors. Proc Natl Acad Sci U S A. 2005;102(45):16368-
16373. 
 
18. Beaver JA, Jelovac D, Balukrishna S, et al. Detection of cancer DNA in plasma of 
patients with early-stage breast cancer. Clin Cancer Res. 2014;20(10):2643-2650. 
  
 
 
 
 
 
 
 
 

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15. APPENDICES:   
15.1 BCTOS 
15.2 CTCAE V 4.0 
15.3 RTOG COSMESIS SCALES 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 15.1 BCTOS 
 
 
 
 
 
 
 
 
 

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Appendix 15.2 CTCAE v. 4 
 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 
 
 
 

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Appendix 15.3.1  RTOG cosmesis scale- PHYSICIAN FORM 
 
 
 
(Circle the number next to the word that best describes the cosmetic results.) 
 
 
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 
Breast shrinkage 
0 
1 
2 
Other significant tx effects 
Specify: _______________ 
0 
1 
2 
 
 
 

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IRB IRB00128074 
 
 
 
 
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Appendix 15.3.2 RTOG cosmesis scale- PATIENT FORM 
 
 
1.  How satisfied with your treatment are you? 
 
Extremely satisfied 
Very satisfied Satisfied 
Unsatisfied 
 
2. Would you choose this treatment again? 
 
 
Yes 
No 
 
3. Please circle the number that correlates with your assessment of the cosmetic result of 
your treatment: