A Single Center Phase II Prospective Clinical Trial to Assess the Feasibility of Preoperative Radiation Boost in Breast Cancer Patients
Phase: NA
Conditions: Anatomic Stage 0 Breast Cancer AJCC v8, Anatomic Stage I Breast Cancer AJCC v8, Anatomic Stage IA Breast Cancer AJCC v8, Anatomic Stage IB Breast Cancer AJCC v8, Anatomic Stage II Breast Cancer AJCC v8, Anatomic Stage IIA Breast Cancer AJCC v8, Anatomic Stage IIB Breast Cancer AJCC v8, Invasive Breast Carcinoma, Non-Metastatic Breast Carcinoma, Prognostic Stage 0 Breast Cancer AJCC v8, Prognostic Stage I Breast Cancer AJCC v8, Prognostic Stage IA Breast Cancer AJCC v8, Prognostic Stage IB Breast Cancer AJCC v8, Prognostic Stage II Breast Cancer AJCC v8, Prognostic Stage IIA Breast Cancer AJCC v8, Prognostic Stage IIB Breast Cancer AJCC v8, Prognostic Stage III Breast Cancer AJCC v8, Prognostic Stage IIIA Breast Cancer AJCC v8, Prognostic Stage IIIB Breast Cancer AJCC v8, Prognostic Stage IIIC Breast Cancer AJCC v8
Sponsor: Rutgers, The State University of New Jersey

 
 
Official Title: 
A Phase II Prospective Clinical Trial to Assess the Feasibility of 
Preoperative Radiation Boost in Breast Cancer Patients 
NCT number: 
04871516 
Document Type:  
 Protocol and SAP 
Date of the 
Document: 
01/03/2023 
 
 

Protocol Title: Preoperative Radiation Boost in Breast Cancer Patients 
Protocol Version and Date: 16.0: 03JAN2023  
PI: Dr. Bruce Haffty 
Page 1 of 38 
INTERVENTIONAL 
RESEARCH PROTOCOL TEMPLATE 
(HRP-503a) 
STUDY INFORMATION 

Title of Project: A PHASE II PROSPECTIVE CLINICAL TRIAL TO ASSESS THE
FEASIBILITY OF PREOPERATIVE RADIATION BOOST IN BREAST CANCER
PATIENTS

Principal Investigator Name
Bruce G. Haffty, MD

Principal Investigator Div. & Dept. Department of Radiation Oncology
CINJ, RWJMS, NJMS

Principal Investigator Contact Info:
hafftybg@cinj.rutgers.edu, 732-235-5203
Rm 2012 CINJ
195 Little Albany St.
New Brunswick, NJ 08901
Protocol Version and Date:
16.0: 03JAN2023 
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Protocol Title: Preoperative Radiation Boost in Breast Cancer Patients 
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PI: Dr. Bruce Haffty 
 
 
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Table of Contents 
Skip To Section: Hold CTRL + Click (Below) To Follow Link in Blue 
1.0 
Research Design 
1.1 
Purpose/Specific Aims 
1.2 
Research Significance 
1.3 
Research Design and Methods 
1.4 
Preliminary Data 
1.5 
Sample Size Justification 
1.6 
Study Variables 
1.7 
Drugs/Devices/Biologics 
1.8 
Specimen Collection 
1.9 
Data Collection 
1.10 Timetable/Schedule of Events 
2.0 
Project Management 
2.1 
Research Staff and Qualifications 
2.2 
Research Staff Training 
2.3 
Resources Available 
2.4 
Research Sites 
3.0 
Multi-Center Research 
4.0 
Subject Considerations 
4.1 
Subject Selection and Enrollment Considerations 
4.2 
Secondary Subjects 
4.3 
Number of Subjects 
4.4 
Consent Procedures 
4.5 
Special Consent Populations 
4.6 
Economic Burden and/or Compensation For Subjects 
4.7 
Risks of Harm/Potential for Benefits to Subjects to Subjects 
5.0 
Special Considerations 
5.1 
Health Insurance Portability and Accountability Act (HIPAA) 
5.2 
Family Educational Rights and Privacy Act (FERPA) 
5.3 
Code of Federal Regulations Title 45 Part 46 (Vulnerable Populations) 
5.4 
General Data Protection Regulation (GDPR) 
5.5 
NJ Access to Medical Research Act (Surrogate Consent)  
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6.0 
Data Management Plan 
6.1 
Data Analysis 
6.2 
Data Security 
6.3 
Data Safety And Monitoring 
6.4 
Reporting Results 
 
6.5 
Secondary Use of the Data 
7.0 
Research Repositories – Specimens and/or Data 
8.0 
Approvals/Authorizations 
9.0 
Bibliography 
 
 
 
1.0 Research Design 
1.1 Purpose/Specific Aims 
 The purpose of our study is to assess feasibility of preoperative radiation boost in breast cancer 
patients. Primary outcome is acute wound complication rate. We also aim to evaluate cosmetic 
outcome and loco-regional control as secondary outcomes. Another goal is to look into the 
histopathology of tumors before and after radiation to assess response and other immunologic 
changes to the tumor and the tumor environment elicited by the radiation treatment. We hope that 
this will guide future trials that could change practice in certain patient subgroups 
- 
A.  Objectives Our primary Objective is to demonstrate that the incidence of grade 3 or 
more wound complications in patients with non-metastatic node negative breast cancer or 
DCIS who are eligible for BCS and treated with pre-operative radiation boost at 1 month 
after end of whole breast radiation is no worse than the rates in the current standard of 
care (6-20%). Our secondary objective is to demonstrate that the physician reported 
cosmetic outcome at 1 and 3 years after the end of treatment is better than what has been 
reported for the current standard of practice for patients undergoing BCS and 
hypofractionated WBI (around 35% reported poor/fair cosmesis at 3 years, Shaitelman et 
al.). Tertiary objectives are to measure the acute and late radiation related toxicities such 
as radiation dermatitis, telangiectasia and fibrosis in this cohort of patients.  
- 
To measure the pre-operative boost CTV and compare to the post-op CTV volume that 
would have been contoured as CTV if the boost was to be delivered post-operatively.  
- 
To measure the incidence of fair/poor patient reported cosmetic outcome using the 
BCTOS cosmetic scale  
- 
To study the cancer biology before and after radiation treatment. 
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B.  Hypotheses / Research Question(s) 
Pre-operative radiation treatment approach allows for more accurate targeting of the tumor and 
thus of the high-risk areas of subclinical disease. It is possible that the treatment volumes would 
be smaller compared to when treating post-operative seroma for boost.  This could result in a better 
cosmetic outcome and decreased toxicity.  Our study aims to assess the feasibility of this approach 
and to assess the cosmetic and loco-regional outcomes with this novel approach.  
1.2 Research Significance 
The current standard of care for patients with invasive non-metastatic breast cancer or DCIS who 
are candidates for Breast Conserving Surgery (BCS) is adjuvant whole breast radiation followed 
by an additional boost to the tumor bed. The benefit of tumor bed boost in reducing the local 
recurrence rates is established from historic clinical trials. However, the sequential delivery of the 
boost after surgery and radiation is done out of convention rather than any particular scientific 
rationale. Delivering the boost in the pre-operative setting provides the benefit of accurately 
directing the high radiation dose at the tumor and thus sparing normal breast tissue. It also takes 
advantage of a non-hypoxic microenvironment leading to an increase in the therapeutic ratio and 
superior outcome. We hypothesize that delivering the radiation boost pre-operatively will not result 
in a significantly higher risk of surgical wound complications. We also think that this approach 
will result in better cosmesis and less radiation toxicity to normal tissue.  
The picture below is an example to illustrate the difference between the pre-operative and 
postoperative targets for radiation boost. The pre-operative boost target would be the actual tumor; 
the post-operative tumor bed that we traditionally boost is usually defined by surgical clips; 
presence of seroma and other variables that are surrogates for where the tumor used to be. This 
volume delineation can vary between different radiation oncologists and is not as accurate as when 
we are treating the visualized tumor.  
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1.3 Research Design and Methods 
This study is a Phase II prospective, non-randomized, single arm clinical trial evaluating the 
feasibility of delivering the radiation boost pre-operatively in non-metastatic, node negative 
breast cancer patients who are eligible for breast conserving surgery.  
Schema:  
Post‐operative boost  
target 
Pre‐operative boost target 
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A. Research Procedures 
Patients will be recruited from the Cancer Institute of New Jersey Comprehensive Breast Care  
Center, or the Radiation Oncology Facility. Patients will be enrolled via the Rutgers Cancer 
Institute of New Jersey’s Office of Human Research Services (OHRS).  A unique study number 
will be issued for each patient after enrollment. We will be evaluating the feasibility of 
preoperative radiation boost in these patients. Eligible patients will be consented to enroll on the 
trial when seen by the surgical oncology team for a consult. Consents will be done by the PI, 
resident or other study personnel. Patients who consent to be enrolled will undergo a baseline 
breast MRI. They will then undergo pre-operative radiation boost which is the main clinical 
intervention in this trial. After the pre-operative boost, patients will go on for their scheduled 
surgery. Surgery will not be different from what the patient would have been assigned for if not 
on trial. After surgery, patients will proceed with the rest of radiation treatment. If the patients is 
a candidate for adjuvant chemotherapy, they will proceed with chemotherapy after completion of 
the radiation course. 
Modification (03JAN2023): 
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In collaboration with Ankit Saxena, PhD, Managing Director of the Immune Monitoring Flow 
Cytometry shared resource (IMFC-SR), we propose to assess the frequencies, and co-inhibitory 
molecule expression of immune cell populations in tumor, before and after radiation therapy. We 
will measure the following immunologic parameters that may be indicative of responsiveness to 
treatment using advanced multi-parameter flow cytometry. The frequencies of T, B, NK, 
myeloid, Myeloid derived suppressor cells (MDSC’s) subsets will be analyzed by flow 
cytometry using antibodies for CD45, CD3, CD4, CD8, CD11b, CD11c, CD14, CD15, CD66, 
CD19, NKG2D, HLA-DR, CD206, CD80, PD-1, TIM3, LAG-3, FOX-P3, Ki-67. Special 
attention will be paid to CD8 T cell: CD4 Treg and NK: CD4 Treg cell ratios as well as 
MDSC’s. We hypothesize that increased effector (CD8 and NK cell subsets versus Treg subsets 
and MDSC’s) following radiation therapy will be a biomarker positively associated with 
responsiveness to treatment and other major prognostic indicators for survival.  
 
B. Data Points 
Demographic data, known breast cancer risk factors, family history, age and stage at diagnosis, 
tumor characteristics, previous and current treatments and medication history will be collected at 
first visit. After surgery, and in the consecutive follow up visit after completion of RT, acute 
toxicities, cosmesis and disease outcomes and relapse will be collected.  We will then collect 
toxicities and clinical outcomes every three months for at least 3 years. Patient and physician 
reported cosmetic outcomes will be collected at 1 month follow up, 6 months follow up, 1 year, 2 
years, and 3 years after completion of RT.  
Study Duration 
We expect to complete enrollment within 3 years of study opening date. We will follow the 
patients up for at least 3 years after completion of radiation.  
C. Endpoints 
Primary endpoint: Grade 3 wound complication after breast conserving surgery as defined by the 
CTCAE V5.0 to require operative intervention. The incidence of wound complications after 
breast surgery have been variably reported to be between 6% and 30% [13, 14, and 15]. In soft-
tissue extremity sarcoma and rectal cancer, we know that pre-operative radiation results in higher 
acute wound complications after surgery. 
Historic data from clinical trials using pre-operative radiation to the breast have reported higher 
wound complication rates and surgical delays with radiation [16]. However, these trials utilized 
old radiation techniques, irradiated the whole breast, the majority of them utilized neoadjuvant 
chemotherapy combination. There is a small risk with this trial that the wound complication rate 
would be higher than the baseline expected wound complicated rate after breast conserving 
surgery; hence, this is a phase I trial to assess safety of this approach.  
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Secondary endpoint: Physician reported cosmetic assessment at 1 month, 6 months,1 year, 2 
years, and 3 years after WBI using the Harvard Cosmesis assessment Scale for Breast Cancer 
Patients which is a 4point scale describing the breast cosmetic outcome (excellent, good, fair or 
poor). 
Modification (04OCT2022):  
In this modification, we are proposing an expansion cohort so we are able to demonstrate that the 
good-excellent cosmetic outcome exceeds 90%. Our preliminary data indicate good-excellent 
cosmesis in a majority of patients, exceeding 90%.  The original trial, which was powered to 
evaluate Grade 3 surgical complications, is not powered for cosmetic outcome. In this 
modification, we propose to expand the cohort to definitively demonstrate a cosmetic outcome of 
good-excellent exceeding 90%, as compared to historical control rate of 80% in hypofractionated 
whole breast radiation including a boost. The specific rationale for the expansion cohort given in 
the statistical section.  
Breast Conserving Surgery (BCS) was primarily developed to reduce the morbidity and improve 
the cosmetic outcome in comparison to mastectomy; these factors are crucial to patients’ quality 
of life.  The RAPID trial which is a phase III non-inferiority trial comparing APBI to whole 
breast; 88% of the patients who had whole breast irradiation and had excellent or good cosmesis 
at baseline, maintained excellent or good cosmesis after 3 years of RT [17].  
 
Shaitelman et. Al, reported a rate of poor or fair physician reported cosmetic outcome after 
hypofractionated WBI with boost to be 35.4% at 3 years after completion of radiation [18]. Table 
1.0 shows the Harvard scale. Administering the radiation boost pre-operatively, we expect better 
targeting of the tumor bed because the tumor can be visualized and targeted and smaller treated 
volume which hypothetically associated with a better cosmetic outcome.  
 
Tertiary endpoints:  
1. Overall end point of acute and late radiation toxicity which includes:  
 Rate of fibrosis (different grades per the CTCAE V 5.0)  
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 Rate of telangiectasia formation (different grades per the CTCAE V 
5.0)  
 Rate of radiation dermatitis (different grades per the CTCAE V 5.0) 
 Changes in pathology between the biopsy and the surgical specimen 
1. Patient reported cosmetic outcomes at 1 month, 6 months, 1 year, 2 years, and 3 years 
after WBI using the Breast Cancer Treatment Outcomes Scale (BCTOS). The BCTOS 
cosmetic scale describes patient-reported changes in the treated breast and surrounding 
area relative to the contralateral breast, which serves as an internal control. Items were 
scored on a 1 to 4 scale, with 1 indicating no difference between the treated breast and 
untreated contralateral breast, 2 indicating a slight difference, 3 indicating a modest 
difference, and 4 indicating a large difference. The BCTOS patient reported cosmetic 
outcome score is the arithmetic mean of the nine items that assess the cosmetic outcome 
[19].  
2. The difference between the pre-operative boost CTV volume and the post-op CTV 
volume that would have been contoured as CTV if the boost was to be delivered post-
operatively.  
1.4 Preliminary Data 
Breast cancer is the most commonly diagnosed cancer among women worldwide [1]. In the 
United States, the estimated number of new cases and deaths from breast cancer in 2019 is 
approximately 295,290 and 65,540 respectively [2]. Due to the effectiveness of screening tests, 
for most patients in the developed world, <10% of patients are first diagnosed with advanced 
stages [3]. Locoregional therapies for breast cancer patients consist of either mastectomy or 
lumpectomy followed by whole breast radiation therapy (WBRT). Both have been shown to be 
equivalent to mastectomy in terms of local control and overall survival [4].  
 
A radiation boost targeted at the tumor bed is routinely administered to breast cancer patients as 
part of breast-conserving therapy. The rationale for a boost is based on the patterns of recurrence 
data that has demonstrated that the vicinity of the original index tumor is the most common site 
of local recurrence and therefore requires a higher tumoricidal dose from RT compared to the 
rest of the breast [5]. Several randomized controlled trials have shown that the addition of a boost 
to standardly fractionated whole breast RT (WBRT) in women with localized breast cancer led to 
an improvement in local control [5, 6]. The largest of these trials, the EORTC 22881, included 
5318 patients with stage I-II breast cancer who underwent lumpectomy + axillary lymph node 
dissection [6]. Following WBRT (50 Gy/25 fractions), patients were randomized to +/- 16 Gy 
boost. With a median of 17.2 years of follow-up, the cumulative incidence of local failure was 
13% in boosted patients compared with 9% in the non-boost group HR 0.65 (99% CI 0.52-0.81, 
p<0.0001). The benefit of a boost was observed in all age groups. 
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Today, oncoplastic surgery and rearrangement of breast tissue has been increasingly used in 
order to optimize the cosmetic outcome. While the rearrangement of the tumor bed may optimize 
long-term cosmetic results, is also has the unintended consequence of relocating the tumor bed 
tissue thought to be at highest risk of local recurrence, the area to which a radiation tumor bed 
boost is typically delivered. As a result, it is sometimes not feasible to localize the tumor bed and 
a tumor bed boost is either omitted or a much larger volume of the breast is irradiated in order to 
target what is believed to be at risk tissue. This is concerning particularly because those patients 
undergoing oncoplasty appear to relatively younger in age, for whom a tumor bed boost has been 
shown to have the greatest benefit [7, 8]. Delivering the boost pre-operatively would enable a 
more accurate delineation of the tumor and high-risk vicinity.  
In breast cancer, the data on pre-operative radiation treatment delivery is limited. Retrospective 
breast cancer series from France have looked at patients treated definitively with pre-operative 
radiation therapy between the 1970s and 1980s.  Pathologic CR rate was achieved in 10% of all 
patients and in 26% in patients with TNBC; the post-operative complication rate (grade>2) was 
19% with 4.3% of localized skin necrosis [9].   
Another study from Russia compared neoadjuvant chemoRT to RT alone prior to mastectomy in 
patients with Stage II and III breast cancer and reported pCR in 19.4% of patients undergoing 
pre-operative RT alone and 29.1% in patients who had pre-operative chemoRT; statistical 
significance was not assessed for pCR. Among the post-surgical complications was a high 
incidence of prolonged (3-4 weeks) lymphorrhea, observed in 18.2% of patients receiving 
neoadjuvant chemotherapy, and in 16.4% of those treated with preoperative radiotherapy alone. 
Suppuration of the postoperative wound occurred in 4.3% of patients treated with neoadjuvant 
chemotherapy, and in 6.7% of those treated with preoperative radiotherapy alone [10].  
The current standard of care in breast cancer treatment is adjuvant radiation after completion of 
surgery and chemotherapy (when needed). 
Few more recent trials were conducted assessing pre-operative radiation in the breast; these trials 
used different dose fractionation than the standard adjuvant RT fractionation. In a phase I dose 
escalation trial of single-dose preoperative partial breast irradiation in early stage breast cancer 
patients, 32 patients were enrolled and no acute dose-limiting grade 3 or 4 radiation related 
toxicities were reported. They did not see wound dehiscence in any of the patients. Patients who 
only received the pre-operative partial breast treatment all had good or excellent cosmesis as 
rated by the physicians.  They reported 3 patients who received post-operative external beam 
radiotherapy because of upgrade of pathology at the time of surgery. Among these three, two 
grade 3 chronic toxicities were seen in a patient from this group who was diagnosed post 
treatment with a connective tissue disorder. Another patient with diabetes developed a 
postoperative wound infection and all three had fair/poor cosmetic outcomes [11].  
Another dose escalation study of stereotactic body radiation therapy (SBRT) combined with 
neoadjuvant chemotherapy in breast cancer patients was published from France in 2013. Five 
dose levels of SBRT were tested concomitantly with neoadjuvant chemotherapy. Of the 25 
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women that were treated, Maximum tolerable dose was not reached. Only 1 case of dose-limiting 
toxicity was reported (grade 3 dermatologic toxicity), and SBRT was overall well tolerated. The 
pCR rate was 36%, with none being observed at the first 2 dose levels, and the highest rate being 
obtained at dose level 3 (25.5 Gy delivered in 3 fractions)  [12]. 
In this study, we aim to deliver the radiation boost portion pre-operatively using the same dose 
fractionation as we would in the post-operative setting. We will benefit from the more accurate 
targeting of the high radiation dose at the tumor and we anticipate sparing more normal breast 
tissue. As mentioned above, this approach will also take advantage of a non-hypoxic 
microenvironment leading to an increase in the therapeutic ratio. These factors combined may 
lead to a superior outcome.  
1.5 Sample Size Justification:  
Our sample size calculation is based on data reporting incidence of wound complications after 
breast surgery to be between 6% and 30% [13, 14, and 15]. Data from soft-tissue extremity 
sarcoma and rectal cancer, as well as historic data on breast pre-operative RT, describes higher 
acute wound complications rates after surgery in the pre-operative RT settings [16]. 
In this study; we aim to deliver the boost dose in the pre-operative setting.  Because of the boost 
low dose and because this irradiated tissue will be resected; we expect the wound complication 
rate to be comparable to the standard treatment.  
We have calculated a sample size of 50 subjects to provide 80% power using a two-sided exact 
test for binomial proportion to conclude that the combined Grade 3 or greater wound 
complication rate is less than 20%, assuming an expected rate of Grade 3 wound complications 
in our cohort of 6% or less as detailed below. We will account for a 10% loss to follow up rate; 
so, we will aim for a sample of 55 subjects.  
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Figure 1. The estimated statistical power of the two-sided 0.05 level exact binomial test for 
testing the null hypothesis that grade 3 wound complication rate is less than 20%. 
A key concern is to ensure that that rate is no higher than 20%. Thus, we plan to stop the trial if, at 
any point, we are 80% sure that that rate is higher than 20%, using a Bayesian calculation of the 
posterior probability using a non-informative prior. The stopping rules are outlined in the following 
table: 
Number of patients enrolled  
Allowed complications 
10  
2 
14  
3 
19  
4 
24 
5 
29 
6 
34 
7 
39 
8 
44 
9 
For example, if there were 3 complications among the first 14 patients, the trial would be allowed 
to continue. But if there were 4 complications among these 14 patients, the trial would stop for 
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an excessive rate of wound healing complications. Grade 3 and above wound complications will 
be reported as Events of special interest. 
1.6 Study Variables 
A. Independent Variables, Interventions, or Predictor Variables  
All patients enrolled on this trial will receive a pre-operative radiation boost the breast 
cancer tumor which is the study intervention. The standard of care would be 
postoperative radiation followed by boost; but this is a single arm trial and patients will 
not be randomized. 
B. Dependent Variables or Outcome Measures  
Wound complications post operatively will be measured. Cosmesis and locoregional 
control will be assessed every 3- 6 months interval for at least 3 years after completion of 
radiation treatment.  
1.7 Drugs/Devices/Biologics  
Pre-operative radiation boost will be delivered the same way as we would for post-operative 
radiation boost which is standard of care. External beam radiation using photon or electron plans 
will be utilized. CTV will be contoured based on baseline MRI to help delineate the tumor. The 
boost dose fractionation will be 333 cGy x 4 fractions. The boost is delivered in one fraction per 
day for four consecutive days, not including weekends or holidays. If the boost were to start on a 
Wednesday for example, the last fraction will be on the Monday after.  
 
Specifics of Radiation Treatment:  
 
Dose Prescription:  
- 
Dose to the PTV_ Boost: 333 cGy x 4 fractions to a total of 1332 cGy using EBRT. 
- 
WBRT dose Post-lumpectomy: 333 cGy x11 fractions to a total of 3663 cGy.  
- 
RLN dose (if at surgery it was determined there is need to treat regional LN): 333 cGy x 11 
fractions to a total of 3663 cGy.  
 
Patient simulation: A CT simulation is required for the boost treatment. The patient will need 
another CT simulation for WBRT after surgery. Diagnostic MRI will be used to assist delineate 
the Boost volume. Patient positioning will be performed based on the discretion of the treating 
radiation oncologist, who will determine this based on the patient’s unique anatomy and the 
ability to delineate the tumor volume on CT (boost CT sim may be done prone to facilitate 
fusion with the MRI if needed). Four surface BB’s will be placed on the breast at the time of 
simulation to assist with alignment for treatment delivery; this can vary per the attending 
discretion.  
 
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Treatment Planning:  
- 
Gross tumor volume (GTV) is contoured on the CT sim using the CT image as well as the 
MRI images. If fusion cannot be obtained accurately, the physician can use the MRI to 
localize the tumor on CT; this should be done per the attending discretion.   
- 
Clinical target volume (CTV) will be delineated with a uniform expansion of 0.5 cm 
subtracted off the chest wall musculature and within the first 0.5cm of the external skin 
surface. 
- 
Planning Treatment Volume (PTV) an additional uniform margin of 0.5 cm from the CTV. 
For the purposes of dosimetric coverage evaluation, an evaluative PTV (PTV_Eval) will be 
created, which is the PTV subtracted 5mm from the skin surface and from the chest wall 
musculature. 
- 
Treatment planning with electrons/ photons (6, 10 or 15 MV) will depend on the patient 
anatomy and the depth of the tumor.  
- 
95 % of the PTV_EVAL is to be covered by >= 90% of the prescribed dose and 100% of the 
GTV to be covered by 100% of the prescription dose. (Minor deviation if < 95% of 
PTV_eval covered by >=90% of prescribed dose; unacceptable if less than 88% of the 
PTV_eval is covered by prescribed dose).     
- 
Max dose % preferred < 110% but acceptable if <115%; consider using wedges or field in 
field to decrease hotspots  
 
WBRT post-op 
- 
Whole breast to be covered by >= 95% of the prescribed dose (unacceptable if =< 88%).  
Acceptable constraints:  
- 
Max dose < 110%  
- 
V105% =< 200 cc; minor deviation if < 400 cc  
- 
V107% =< 2cc; minor deviation if < 30 cc  
- 
 Mean heart dose =< 2 Gy  
- 
Heart V5 < 40% (less than 50% for L sided breast) 
- 
Total Lung V20 < 15%  
 
If Node positive at surgery:  
- 
Whole breast to be covered by >= 95% of the prescribed dose  
- 
Nodal CTV covered by > 90% of prescribed dose; IMN coverage is at the discretion of the 
treating physician.  
Acceptable constraints:  
- 
Max dose < 115%  
- 
V105% =< 200 cc; minor deviation if < 400 cc  
- 
V107% =< 2cc; minor deviation if < 30 cc  
- 
Mean heart dose =< 5 Gy  
- 
Heart V5 < 40% (less than 50% for L sided breast) 
- 
Total Lung V20 < 35%  
- 
Total lung V40 < 20%  
A. Drug/Device Accountability and Storage Methods NA  
1.8 Specimen Collection 
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A. Primary Specimen Collection 
 Types of Specimens: The patients will be given the option to provide blood & tissue 
samples that will could be used in the future. The patient can still participate in the 
study if they refuse to provide samples. If the patient consents for blood and tissue 
collection, a frozen section tumor samples from the lumpectomy specimens will be 
sent to CINJ tissue repository.  A peripheral whole blood sample will be collected 
from every patient. This can be done at any point during the study. Blood collection 
will be done at the office by the nurse using venipuncture. The samples will be places 
in cryovials and will be labeled with the patient’s assigned study number. These will 
be transported from the clinic to the biospecimen repository services (BRS) at the 
Rutgers Cancer institute of New Jersey on the day that it is obtained. Transport will 
be the responsibility of the study personnel. Whole blood samples will be collected 
using a peripheral venous line into 1 EDTA (purple top) tube (10 ml), a maximum of 
30 ml can be drawn for the purpose of the study (total of 3 tubes). Each site will use 
their own tubes. Once collected in EDTA tube, they will be gently inverted 5-10 
times to mix. Specimens will be maintained at ambient temperature (room 
temperature) during collection and transport.  
 Annotation: Bloods samples are to be labeled with: 
- 
A generated specimen ID (which includes the treatment protocol number and 
the study Patient ID) 
- 
Specimen type (blood) 
- 
Collection period (specifying “Simulation” versus Surgery”). 
- 
Collection date. 
 Transport: BRS will collect and transport the tubes to CINJ biorepository from all 
the sites (shipping address: CINJ biorepository, 195 little Albany St. New Brunswick, 
NJ 08901). Specimen can be shipped the day of collection or the day after collection.  
 Processing: This is to be determined.  
 Storage: The tubes will be stored in a -80◦c freezer in CINJ biorepository. 
 Disposition: The specimen will be kept indefinitely.  
 
B. Secondary Specimen Collection-Frozen section tumor samples from the lumpectomy 
specimens will be sent to CINJ tissue repository for potential immunologic markers 
(Only CINJ subjects that consent to tissue collection).  
 Types of Specimens: Tissue samples from lumpectomy.  
 Annotation:  
- 
A generated specimen ID (which includes the treatment protocol number and 
the study Patient ID) 
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- 
Specimen type (breast tumor) 
- 
Collection period (specifying “Simulation” versus Surgery”). 
- 
Collection date 
 Transport: BRS will collect and transport tissue sample to immunology core 
 Storage: Per immunology core 
 Disposition: Kept indefinitely 
 
1.9 Data Collection 
A. Primary Data Collection 
 Location: Patients will be seen for follow up per protocol in a similar schedule to 
what would be the case if they were not on trial. The collected data will be similar to 
what we would collect on a patient if not on trial.  
 Process of Data Collection: Data will be collected by the resident, APN or attending 
physician who is taking care of the patient. 
Timing and Frequency: Patients will be seen at 1 month follow up after completion 
of RT and then every 3 months for 1 year; then every 6 months for 2 additional years. 
Data on clinical outcome, side effects and cosmesis will be collected at each follow 
up.  
 Procedures for Audio/Visual Recording: NA 
Study Instruments: We will use the BCTOS and Harvard scale to assess cosmesis at 
1 month, 6 months after RT and at 1, 2, and 3 years.  BCTOS is a self-report 
instrument that has high reliability and validity. The Harvard Cosmesis scale is a 
physician rated form that will be used by the physician to assess cosmesis at each time 
point as above (see appendix).  
 
 Ethnographic Studies, Interviews, Or Observation: NA  
 Subject Identifiers: Each patient will be assigned a study ID which will be linked to 
the patient MRN. The link will be available on Oncore and access will be limited to PI 
and study personnel. The link will be available indefinitely. 
B. Secondary Data Collection NA 
 Type of Records: NA 
 Location: NA 
 Inclusion/Exclusion: NA 
 Data Abstraction Form(s): NA  
 
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1.10 Timetable/Schedule of Events 
Procedures  
First Visit (Pre-Boost) 
Boost-RT  
(any day of Boost)  
Post-Operative Visit 
 (WBI simulation) 
Last day WBRT 
 (EOT summary)  
FU 1 month (+/- 2 weeks)  
FU 3 months (+/-6 weeks) # 
FU 6 months (+/-6 weeks) 
FU 9 months (+/-6 weeks) # 
FU 12 months (+/-6 weeks) 
FU 18 months (+/-6 weeks) 
FU 24 months (+/-6 weeks) 
FU 30 months (+/-6 weeks) 
FU 36 months (+/-6 weeks) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Performance Status 
(ECOG)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Mammogram  
X 
 
 
 
 
 
 
 
 
 
 
 
 
MRI  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sample* 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Tissue Sample^ 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease status 
Evaluation 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BCTOS  
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Photographs* 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Harvard Cosmesis  
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Wound Evaluation† 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Radiation Toxicity 
Evaluation†  
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
# Optional visits 
^ Optional (CINJ Subjects) 
* Optional and can be obtained at any time point  
† per CTCAE V5.0 criteria  
 
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2.0 Project Management 
2.1 Research Staff and Qualifications: All Co-investigators are CITI trained Rutgers faculty or 
staff.  
2.2 Research Staff Training: All Co-investigators are CITI trained Rutgers faculty or staff.  
2.3 Resources Available: Research intervention will be done within RWJ radiation oncology 
department which is staffed with the capabilities of performing the pre-operative boost and the 
rest of the study parameters.   
2.4 Research Sites: Robert Wood Johnson University Hospital – Hamilton, Robert Wood 
Johnson University Hospital-Somerset, Rutgers Cancer Institute of New Jersey at University 
Hospital, Cooperman Barnabas Medical Center, Community Medical Center, Monmouth 
Medical Center, Monmouth Medical Center Vantage Point Infusion Center, Trinitas Regional 
Medical Center, Jersey City Medical Center, Newark Beth Israel Medical Center, and Clara 
Maass Medical Center. 
3.0 Multi-Center Research 
NA  
4.0 Subject Considerations 
4.1 Subject Selection and Enrollment Considerations  
A. Method to Identify Potential Subjects 
Patients will be primarily recruited from the Cancer Institute of New Jersey Comprehensive 
Breast Cancer Center, or the Radiation Oncology Facility.  
B. Recruitment Details 
We normally see around 8-15 clinically, node negative breast cancer patients per month with 
biopsies revealing invasive disease. Considering patients with multi-centric disease, those who 
cannot undergo a pre-operative MRI, and/or will not want to be on trial, we expect to enroll 
around 3-5 patients a month. The recruitment will happen at CINJ or at RWJ hospital in the 
Rad Onc department.  
 
 
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Subject Screening 
The treating physician – surgeon, medical oncologist or radiation oncologist will determine if 
the subject maybe eligible to the study. If so, a research nurse will meet with the patient to go 
over eligibility criteria.  
 Inclusion Criteria 
 Breast cancer patients with biopsy proven invasive cancer or DCIS  
 Clinically and radiographically node negative disease 
 No indication of metastatic disease  
 Age >= 18  
 Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. 
 Synchronous bilateral invasive cancer allowed  
 Negative serum pregnancy test 
 Willingness to participate in the clinical trial and adhere to the study protocol  
 Individuals of all races, genders and ethnic groups are eligible for this trial. 
 Ability to understand and consent to the study  
 Exclusion Criteria 
 Need for Neoadjuvant Chemotherapy  
 Inflammatory Breast Cancer (cT4) 
 Multicentric tumor  
 Prior ipsilateral breast or thoracic RT  
 Contraindication for baseline MRI  
 Contraindication for surgery  
 Distant metastatic disease  
 Other synchronous cancer (besides bilateral breast) 
 Contraindication to Radiation therapy (presence of scleroderma or other collagen 
vascular disease)  
 Any serious or uncontrolled medical disorder that, in the opinion of the investigator, 
may increase the risk associated with study participation or study drug administration, 
impair the ability of the subject to receive protocol therapy, or interfere with the 
interpretation of study results.  
 
 
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4.2 Secondary Subjects NA  
Registration/Enrollment 
Patients with breast cancer or DCIS who are eligible for the study will be enrolled in the clinical 
trial after they provide informed consent for study participation. A copy of the institution’s IRB 
approved informed consent document and written justification for any changes made to the 
informed consent for this protocol will be on file at Rutgers Cancer Institute of New Jersey’s 
Office of Human Research Services (OHRS) before any participating institutions may enter 
patients.  
All patients will be registered and enrolled through OnCore®, the Clinical Trials Management 
System for this study.   
• 
Registration:  The date the patient signs consent form and is registered in OnCore®. 
Signed consent form must be uploaded into OnCore®.  Screening should be completed 
within 28 days prior to enrollment. 
• 
Enrollment:  Once eligibility has been confirmed the patient will be enrolled (indicated 
as “On Study”) through OnCore®. The completed, signed and dated eligibility checklist 
must be uploaded into OnCore®. 
Patients will not start protocol treatment prior to enrollment. Trial treatment 
should begin within 30 days of enrollment.  
• 
On-Treatment date: The date the patient starts pre-operative boost. 
• 
Off-Treatment date: The last day of adjuvant radiation treatment after surgery will be 
listed as the off-treatment date. 
• 
Off-Study: Patient will be considered off-study if the patient does not complete the pre-
operative boost treatment or if discontinued by the PI, or the patient dies. Patients are 
considered to be lost to follow up if they do not show up for follow up after finishing the 
course of treatment for 3 appointments and with no response to phone calls. Those 
patients can be included until the last day they are seen on study. 
4.3 Number of Subjects 
A. Total Number of Subjects 
We have calculated a sample size of 50 subjects to provide 80% power using a two-sided 
exact test for binomial proportion to conclude that the combined Grade 3 or greater wound 
complication rate is less than 20%, assuming an expected rate of Grade 3 wound 
complications in our cohort of 6% or less as detailed below. We will account for a 10% loss 
to follow up rate; so, we will aim for a sample of 55 subjects.  
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A1. Modification: In order to demonstrate good to excellent cosmesis in over 90% of patients 
we will conduct an expansion protocol. Historically with hypofractionated whole breast 
radiation and a boost the good-excellent cosmesis outcome is 80%. With our smaller boost 
volume pre-operatively, we hypothesize that our good-excellent cosmesis is greater than 90%. 
In order to demonstrate this the following analysis indicates we would need a sample size of 
98 which would give us a 90% power to demonstrate an increase in good-excellent cosmesis 
in over 90% of patients with a 5% two-sided test of proportions.  
We therefore would like to proceed with an expansion cohort to bring the total sample size to 
98 from the current sample size of 55 in order to demonstrate good-excellent cosmesis in over 
90% of patients. To account for a 10% loss follow-up we propose a total sample size of 108 
patients. This includes the original 55 patients resulting in an expansion cohort of 53 patients. 
B. Total Number of Subjects If Multicenter Study: NA  
C. Feasibility: Since we see at least around 5-10 eligible subjects per month, we should be 
able to accrue the requested number within 3 years from initiation of trial. 
 
4.4 Consent Procedures 
A. Consent Process 
 Location of Consent Process 
Written informed consent will be obtained from all potential study participants in the 
clinic. The study will be explained to the prospective patient by the principal 
investigator or his designee. The timeline, potential risks and benefits will be 
explained in detail. The patient and the investigator will both sign and date the 
consent form. One copy will be provided to the patient and the other copy will be 
retained in the medical records and on OnCore®.  
 Ongoing Consent 
Patients will continue to be seen for follow up throughout the study duration (3 years) 
and they will be reminded at the time of follow up that they have the right to be taken 
off the study anytime they want to.  
 Individual Roles for Researchers Involved in Consent 
The PI, and other certified study personnel (residents, co-investigators that are listed 
on the IRB protocol) will be authorized to consent patients. They will be in charge of 
explaining to the patients in detail, the purpose of the study as well as outlining the 
possible side effects or benefits associated with the study.  
  
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 Consent Discussion Duration: The consent process will usually take 30 minutes to 
an hour. The patient will be able to ask more follow up questions on subsequent visits 
and to withdraw from the study at any time.  
 
 Coercion or Undue Influence 
The PI will ensure that all necessary steps are taken to minimize the possibility of any 
chance of coercion or undue influence. The PI will make sure that consent will be 
seek only under circumstances where the patient will have sufficient opportunity and 
understanding of whether to be on the study or not. The patients will be informed that 
whether they decide to enroll or not, it will not affect their care in any way (except for 
the change in treatment that is endorsed by the trial if they decide to be on it).  
 
 Subject Understanding 
The consent form will include the details of the study. A detailed description of 
potential risks and benefits will be included. The study personnel will go over all 
these will the patient and ensure understanding. The patients will be made aware that 
they can withdraw consent at any time and that this will not affect their care in any 
way.  
B. Waiver or Alteration of Consent Process  NA  
 Waiver or Alteration Details 
NA 
 Destruction of Identifiers 
NA 
 Use of Deception/Concealment 
NA 
a. Minimal Risk Justification 
NA 
b. Alternatives 
NA 
c. Subject Debriefing 
NA 
 
C. Documentation of Consent 
Documenting Consent 
We will make sure that the patient understands the consent form language and all the 
details listed on the consent form. The patient (or a patient representative) will print 
their name, date the consent and sign. The same steps will also be taken by the PI or 
other authorized personnel obtaining the consent. The patient will be provided a copy 
of the signed consent form and another copy will be retained in the patient chart and 
on OnCore®. 
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Waiver of Documentation Of Consent (i.e., will not obtain subject’s signature) 
NA  
4.5 Special Consent/Populations: NA  
A. Minors-Subjects Who Are Not Yet Adults  
 Parental Permission 
NA 
 Non-Parental Permission  
NA 
 Assent Process 
NA 
 Documentation of Assent 
NA 
 Reaching Age of Majority During Study 
NA 
B. Wards of the State 
NA 
Research Outside of NJ Involving Minors 
NA 
C. Non-English-Speaking Subjects 
 Process for Non-English-Speaking Subjects 
If subjects who do not speak English will be enrolled, a certified translation service 
will be used to facilitate the consent discussion. An IRB-approved short form in the 
subject’s native language will be obtained. The translator’s ID number will be 
documented on the consent form.  
 Short Form Consent for Non-English Speakers An IRB-approved short form 
consent will be obtained for any non-English speaking subjects. A short form consent 
will be used to consent no more than five subjects before a fully translated consent 
form in the given language is obtained.   
D. Adults Unable to Consent / Decisionally Impaired Adults; NA  
- 
NJ Law-Assessment of Regaining the Capacity to Consent NA  
- 
Capacity to Consent NA 
- 
NJ Law-Selecting A Witness  NA 
- 
Removing a Subject 
 
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Participants may withdraw voluntarily from the study at any time. The PI may discontinue a 
participant from the study. Based on patient follow up data from similar phase II trials that were 
carried out at our institution, we anticipate a drop-out rate of less than 10% [21, 22].  
If a subject enrolls on the study and then discontinue for any reason prior to the delivery of the 
pre-operative boost; she will be taken off the study and will not contribute to the study endpoint 
analysis. Subjects who have received the pre-operative boost will all contribute to the study end 
point analysis (could be censored if lost to follow up at some point). The calculated sample size 
is for patients who received the pre-operative boost.  
4.6 Economic Burden and/or Compensation for Subjects 
A. Expenses  
There should be no additional expenses incurred on the subjects by taking part in this study.  
B. Compensation/Incentives 
There will be no compensation provided to enrolled subjects  
 
C. Compensation Documentation NA  
 
4.7 Risks of Harm/Potential for Benefits to Subjects 
A. Description of Risks of Harm to Subjects 
 
 
Reasonably Foreseeable Risks of Harm 
Patients participating in this trial could be at a higher risk of wound complications after 
surgery. This risk is estimated to be lower than 10% and will be explained to the patients 
in detail. The rest of the study parameters should incur minimal risks on the subjects.  
Data from other cancer sites such as extremity soft-tissue sarcoma and rectal as well as 
the limited historic reports of pre-operative radiation in Breast [9, 10, 11, 12] suggest that 
the use of pre-operative radiation in breast cancer patients can be administered safely. 
Our suggested dose is lower than the doses used in sarcoma or other pre-operative RT 
regimen which would incur a very low risk on the patients.  
Administering the radiation boost pre-operatively theoretically will have several 
advantages including better targeting of the tumor bed because the tumor can be 
visualized and targeted, resulting in a smaller treated volume and a smaller volume of 
irradiated normal tissue. This study aims to assess the feasibility of administering pore-
operative boost in breast cancer patients.  
 
 
Risk of Harm from an Intervention on a Subject with an Existing Condition 
Subjects with any serious or uncontrolled medical disorder that, in the opinion of the 
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investigator, may increase the risk associated with study participation or study drug 
administration, impair the ability of the subject to receive protocol therapy, or interfere 
with the interpretation of study results will be excluded from the study.  
 
Other Foreseeable Risks of Harm 
Participant confidentiality and privacy is strictly held in trust by the participating 
investigators and their staff. This confidentiality is extended to cover testing of biological 
samples in addition to the clinical information relating to participants. Therefore, the 
study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor.   
All research activities will be conducted in as private a setting as possible.  
 
Observation and Sensitive Information NA 
 
B. Procedures which Risk Harm to Embryo, Fetus, and/or Pregnant Subjects NA 
C. Risks of Harm to Non-Subjects NA  
D. Assessment of Social Behavior Considerations NA  
E. Minimizing Risks of Harm 
 
The study participant’s contact information will be securely stored at the radiation oncology 
department for internal use during the study. At the end of the study, all records will continue to 
be kept in a secure location for as long a period as dictated by the reviewing IRB, Institutional 
policies, or sponsor requirements.  
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be also stored at the Radiation Oncology Department. The data will be 
deidentified; it will not include the participant’s contact or identifying information. Rather, 
individual participants and their research data will be identified by a unique study identification 
number. There will be a link to the patient’s MRN on Oncore which only the PI will have access 
to.  
 
Certificate of Confidentiality NA 
 
 
Provisions to Protect the Privacy Interests of Subjects 
Patients will be mainly interacting with the physician, APN or resident who are the 
same personnel that they would interact with have they not elected to be on the study.  
F. Potential Benefits to Subjects 
Administering the radiation boost pre-operatively theoretically will have several advantages 
including better targeting of the tumor bed because the tumor can be visualized and targeted, 
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resulting in a smaller treated volume and a smaller volume of irradiated normal tissue. By 
participating in this study, the patients may have better outcomes, with the understanding that 
this is investigational and could also not result in better outcomes.  
5.0 Special Considerations 
5.1 Health Insurance Portability and Accountability Act (HIPAA) NA 
 
5.2 Family Educational Rights and Privacy Act (FERPA) NA 
5.3 Code of Federal Regulations Title 45 Part 46 (Vulnerable Populations) NA 
A. Special Populations 
NA 
5.4 General Data Protection Regulation (GDPR) NA  
5.5 NJ Access to Medical Research Act (Surrogate Consent) NA  
6.0 Data Management Plan 
6.1 Data Analysis 
Sample size calculation was explained above. The outcome data analysis will be mainly 
descriptive data looking at the percentage of wound complications and the percentage of 
fair/poor cosmetic outcome using this new protocol. Descriptive analysis will be performed at 
baseline and will be presented as percentages, mean and standard deviation, median and range, 
depending on the respective variables.  
6.2 Data Security 
All participating staff are trained to protect data safety and security and are CITI certified. The 
study participant’s contact information will be securely stored at the radiation oncology 
department for internal use during the study. At the end of the study, all records will continue to 
be kept in a secure location for as long a period as dictated by the reviewing IRB, Institutional 
policies, or sponsor requirements.  
 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be also stored at the Radiation Oncology Department. The data will be 
deidentified; it will not include the participant’s contact or identifying information. Rather, 
individual participants and their research data will be identified by a unique study identification 
number. There will be a link to the patient’s MRN on Oncore which only the PI will have access 
to. 
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6.3 Data and Safety Monitoring 
A. Data/Safety Monitoring Plan 
Baseline assessment:  
At first consult (or at the time of consent): Each potential subject will undergo multi-disciplinary 
evaluation and will be evaluated by the treating physician in Radiation Oncology, in coordination 
with the clinical research team, to determine eligibility for participating in the clinical trial. The 
written informed consent will be signed before starting any protocol-related procedures or 
interventions. All patients will be informed during the Screening period that all available 
radiographic and laboratory values obtained during the Screening, Treatment, and Follow-up 
periods may be provided to the patient at the patient’s request. 
 
History and Physical examination: 
• 
History including histologically-confirmed primary cancer diagnosis and prior cancer 
treatment and significant prior and concurrent illness 
• 
Baseline existing signs and symptoms evaluation graded according to NCI-CTCAE version  
5.0.  
• 
Prior and concomitant medications  
• 
Physical examination: including weight, height, Breast exam, ECOG, and vital signs (heart 
rate/blood pressure/temperature/oxygen saturation/respiratory rate).  
Radiographic or lab assessments: 
• 
Mammogram to determine if multicentric disease in which case patient would not be eligible.  
• 
Breast MRI if available and if not this will be requested.  
• 
Blood sample collection if patient consents (optional). 
• 
Pregnancy test (serum or urine)  
 
Treatment Period Assessment:  
The following assessments and interventions will be performed on the specified days during the 
Treatment Period as described below. Adverse event data will be collected by the radiation 
oncologist or surgeon and provided to the institutional Data Safety and Monitoring Board 
(DSMB) for independent review and validation of adverse events and other relevant clinical 
outcomes. 
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First Visit (Pre-operative Radiation Treatment):  
History and Physical examination: 
• 
Any side effect of radiation including fatigue, radiation dermatitis, pain or other (signs and 
symptoms evaluation graded according to NCI-CTCAE version 5.0). 
• 
Any new medications  
• 
Physical examination: including weight, height, Breast exam, ECOG, and vital signs (heart 
rate/blood pressure/temperature/oxygen saturation/respiratory rate).  
 
Post-operative visit:  
 
History and Physical examination: 
• 
Any wound complications including dehiscence, infection, pain or other (signs and 
symptoms evaluation graded according to NCI-CTCAE version 5.0). 
• 
Any new medications  
• 
Physical examination: including weight, height, Breast exam, ECOG, and vital signs (heart 
rate/blood pressure/temperature/oxygen saturation/respiratory rate).  
 
END of Adjuvant Radiation:  
History and Physical examination: 
• 
Any side effect of radiation including fatigue, radiation dermatitis, pain or other (signs and 
symptoms evaluation graded according to NCI-CTCAE version 5.0). 
• 
Any new medications  
 
• 
Physical examination: including weight, height, Breast exam, ECOG, and vital signs (heart 
rate/blood pressure/temperature/oxygen saturation/respiratory rate).  
 
Follow-up Period Assessment:  
During the Follow-up Period, assessments will be collected as detailed below. After completing 
the adjuvant phase of the radiation, subjects will be seen on the last day of treatment, one month 
after treatment then every 3 months until 1 year, and then approximately every 6 months until 3 
years. The visits maybe alternating between the radiation oncologist and the surgeon.  All 
assessments below will be conducted at each Follow-up visit and as otherwise clinically 
indicated: 
 
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History and Physical examination: 
• 
Any adverse events of radiation/surgery including wound complications, fatigue, radiation 
dermatitis, pain or other (signs and symptoms evaluation graded according to NCI-CTCAE 
version 5.0). 
• 
Any new medications  
• 
Physical examination: including weight, height, Breast exam, ECOG, and vital signs (heart 
rate/blood pressure/temperature/oxygen saturation/respiratory rate).  
• 
Physician cosmesis assessment of breast  
 
Administration of questionnaires or other instruments: 
• 
Breast Cancer Treatment Outcomes Scale (BCTOS). The BCTOS cosmetic scale describes 
patient-reported changes in the treated breast and surrounding area relative to the 
contralateral breast which serves as an internal control. Patients will be trained to fill this 
scale (See appendix).  
Radiographic assessment of disease:  
• 
Breast mammogram or other imaging will be done per the NCCN guidelines [23].  
 
B. Data/Safety Monitoring Board Details 
The following assessments and interventions will be performed on the specified days during 
the Treatment Period as described below. Adverse event data will be collected by the 
radiation oncologist or surgeon and provided to the institutional Data Safety and Monitoring 
Board (DSMB) for independent review and validation of adverse events and other relevant 
clinical outcomes. 
 
Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence or experience in a patient 
or clinical investigation subject which occurs following the administration of the trial medication 
regardless of the dose or causal relationship. We are not delivering any medication in our study; 
an adverse event will be any medical occurrence in a patient subject during or after receiving the 
pre-operative breast boost. 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE 
(e.g., surgical insertion of central line) should not be recorded as an AE. Disease progression 
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should not be recorded as an AE, unless it is attributable to the study regimen by the site 
investigator. 
 
Adverse events related to treatment experienced by participants will be collected from initiation 
of study, throughout the study, and within 30 days of the last dose of adjuvant radiation 
treatment. Participants who experience an ongoing adverse events related to a study procedure 
and/or study medication beyond 30 days 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.  
Adverse events related to Radiation Treatment include (see appendix): 
1. Fatigue  
2. Dermatitis in the radiation field 
3. Pain in the radiation field 
4. Fat necrosis in the radiation field 
5. Fibrosis in the radiation field 
6. Breast or ipsilateral arm Lymphedema  
7. Breast scar wound healing  
8. Breast hyperpigmentation  
9. Radiation pneumonitis  
Adverse events related to surgery include: 
1. Wound dehiscence  
2. Infection  
3. Bleeding  
4. Hematoma/seroma formation  
5. Lymphedema  
 
All adverse events, whether observed by the physician or reported by the patient, occurring 
during the active portion of therapy, through 30 days after the last day of radiation of treatment 
will be graded by a numerical score according to the NCI’s Common Terminology Criteria for 
Adverse Events (CTCAE), Version 5.0 (http://ctep.cancer.gov/reporting/ctc.html) and recorded 
in the patient’s medical record.  Grade 2 and above adverse events related to treatment and all 
wound complication grades will be recorded on the adverse event CRF pages.  Information 
entered on the adverse event CRF pages will include:  
 
Specific type and duration of reaction (i.e., start and stop dates, resolution). 
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 
Severity/grade.  
 
Relationship to study drug (causality, attribution). 
 
Management of the event, if treated with medication and other actions taken to 
alleviate the clinical event. 
 
Whether or not it was considered a SAE.  
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
will be recorded as an adverse event if the frequency, intensity, or the character of the condition 
worsens during the study period. 
Serious Adverse Events (SAE)  
Adverse events and adverse drug reactions which are considered as serious are those which result 
in: 
• 
Death 
• 
A life-threatening event (i.e. the patient was at immediate risk of death at the time the 
reaction was observed) 
• 
Hospitalization or prolongation of hospitalization 
• 
Persistent or significant disability/incapacity 
• 
A congenital anomaly/birth defect 
• 
Any other medically important condition (i.e. important adverse reactions that are not 
immediately life threatening or do not result in death or hospitalization but may 
jeopardize the patient or may require intervention to prevent one of the other outcomes 
listed above)  
Unexpected adverse events are any adverse experience and/or specificity that is not listed in. 
the radiation side effect list.  
All “unexpected” (defined above), Events of Special Interest (section 1.5), and/or “serious” 
(defined above) adverse events occurring during the active portion of therapy, through 30 days 
after the last dose of treatment, will be reported to the Office of Human Research Services via 
OnCore within 24 hours of site notification. The completed SAE report (signed by the 
Investigator) must be sent to the Rutgers CINJ OHRS QA department. 
 
Events will be promptly reported, in writing, in accordance with the local and Rutgers Health 
IRB policy. If a death occurs the IRB will be notified within 24-hours of initial receipt of 
information.  All other SAEs must be reported to the IRB within 3 to 10 days of initial receipt of 
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information. Written follow-up reports are required when additional information is needed to 
fully characterize the event. Copies of each report sent to the IRB will be kept in the study 
regulatory file. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting 
documentation of the event may be requested by the study sponsor and should be provided as 
soon as possible. 
 
Relationship to Study Intervention: For each AE or SAE the investigator will determine whether 
there is a reasonable possibility demonstrated by evidence that suggests a causal relationship 
between radiation treatment and the AE 
 
Action Taken:  
In response to an AE, the investigator will take the appropriate actions regarding the study 
intervention. If the patient encounters a SAE during the pre-operative radiation period and before 
completion of the pre-operative radiation; the radiation oncologist may decide to stop treatment 
and take the patient off trial. The event will still be reported and counted in the outcome 
assessment (with an explanation of relation to study intervention).  
 
If a SAE or a grade 3 and above Event of clinical interest happens after surgery, such as wound 
infection or dehiscence requiring hospitalizations, the patients will receive the appropriate care 
and the adjuvant RT will be delayed until complete healing of the wound. Participants who 
experience an ongoing adverse event related to a study procedure and/or study medication 
beyond 30 days 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.   
6.4 Reporting Results 
A. 
Individual Subjects’ Results Not applicable  
B. 
Aggregate Result Not applicable  
 
C. 
Professional Reporting 
Any significant results will be published in medical literature and/or at national meetings.   
D. 
Clinical Trials Registration, Results Reporting and Consent Posting 
This research qualifies as a clinical trial that must comply with the federal requirement for public 
registration, results reporting and consent posting at its conclusion.  
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6.5 Secondary Use of the Data    
There is no plan to share data or specimens with other researchers. 
7.0 Research Repositories – Specimens and/or Data 
Research specimens will be stored in CINJ Biorepository and may be used in future research for 
subjects who have provided consent. 
 
8.0 Approvals/Authorizations 
SRB approval was already obtained.  
  
9.0 Bibliography 
1. Torre, L.A., et al., Global Cancer in Women: Burden and Trends. Cancer Epidemiol 
Biomarkers Prev, 2017. 26(4): p. 444-457. 
2. Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2019. CA Cancer J Clin, 2019. 
69(1): p. 7-34. 
3. Society, A.C. Breast Cancer Facts & Figures 2017-2018. 2017. 
4. Holland, R., et al., Histologic multifocality of Tis, T1-2 breast carcinomas. Implications 
for clinical trials of breast-conserving surgery. Cancer, 1985. 56(5): p. 979-90. 
5. Bartelink, H., et al., Whole-breast irradiation with or without a boost for patients treated 
with breast-conserving surgery for early breast cancer: 20-year follow-up of a 
randomised phase 3 trial. Lancet Oncol, 2015. 16(1): p. 47-56. 
6. Polgar, C., et al., Electron and high-dose-rate brachytherapy boost in the conservative 
treatment of stage I-II breast cancer first results of the randomized Budapest boost trial. 
Strahlenther Onkol, 2002. 178(11): p. 615-23. 
7. Vrieling, C., et al., Prognostic Factors For Local Control in Breast Cancer After 
Longterm Follow-up in the EORTC Boost vs No Boost Trial: A Randomized Clinical 
Trial. JAMA Oncol, 2016. 
8. Carter, S.A., et al., Operative and Oncologic Outcomes in 9861 Patients with Operable 
Breast Cancer: Single-Institution Analysis of Breast Conservation with Oncoplastic 
Reconstruction. Ann Surg Oncol, 2016. 23(10): p. 3190-8. 
9. Riet, F.G., et al., Preoperative radiotherapy in breast cancer patients: 32 years of 
followup. Eur J Cancer, 2017. 76: p. 45-51. 
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10. Semiglazov, V.F., et al., Primary (neoadjuvant) chemotherapy and radiotherapy 
compared with primary radiotherapy alone in stage IIb-IIIa breast cancer. Ann Oncol, 
1994. 5(7): p. 591-5. 
11. Horton, J.K., 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): p. 846-55. 
12. Bondiau, P.Y., et al., Phase 1 clinical trial of stereotactic body radiation therapy 
concomitant with neoadjuvant chemotherapy for breast cancer. Int J Radiat Oncol Biol 
Phys, 2013. 85(5): p. 1193-9. 
13. Sorenson LT et al.  Smoking as a risk factor for wound healing and infection in breast 
cancer surgery. Eur J Surg Oncol. 2002; 28:815–820.  
14. Tran CL et al. Does reoperation predispose to postoperative wound infection in women 
undergoing operation for breast cancer. Am J Surg. 2003; 69:852–856. 
15. Hall JC et al. The measurement of wound infection after breast surgery. Breast J. 2004; 
10:412–415. 
16. S.V. Lightowlers et al. Preoperative breast radiation therapy: indications and 
perspectives. European Journal of Cancer 2017; 82: 184-192 
17. T Whelan et al. External beam accelerated partial breast irradiation versus whole breast 
irradiation after breast conserving surgery in women with ductal carcinoma in situ and 
node-negative breast cancer (RAPID): a randomised controlled trial. Lancet 2019. 2019 
Dec 14; 394(10215):2165-2172. 
18. Shaitelman et al. Three-Year Outcomes with Hypofractionated versus Conventionally 
Fractionated Whole-Breast Irradiation: Results of a Randomized, Noninferiority Clinical 
Trial. J Clin Oncol. 2018 Oct 31:JCO1800317 
19. 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 
20. Gupta et al. 5-Year Results of a Prospective Phase 2 Trial Evaluating 3-Week  
Hypofractionated Whole Breast Radiation Therapy Inclusive of a Sequential Boost. Int J 
Radiat Oncol Biol Phys. 2019 Oct 1:105(2):267-274 
21. Fowler JF. The linear-quadratic formula and progress in fractionated radiotherapy. Br J 
Radiol 1989; 62:679-694. 
22. White J, T.A., Douglas A, Buchholtz T, MacDonald S, Marks L, Pierce L, Recht A, 
Rabinovitch R, Taghian A, Vicini F, Woodward W, Li X.A. Breast Cancer Contouring 
Atlas. 2019 [cited 2019; Available from:  
https://www.rtog.org/CoreLab/ContouringAtlases/BreastCancerAtlas.aspx. 
23. Network, N.C.C. NCCN Guidelines for Patients: Invasive Breast Cancer 2018; Available 
from: https://www.nccn.org/patients/guidelines/breast-invasive/44/index.html. 
 
 
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APPENDIX 
 
 
 
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HARVARD COSMESIS SCALE 
 
 
 
 
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CTCAE VERSION 5.0 FOR RELATED TOXICITIES  
CTCAE term  
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Wound 
complication  
Observation 
only  
Topical 
Intervention 
indicated  
Bedside local 
care indicated  
Operative 
intervention 
indicated  
Life-
threatening 
consequences 
Death  
Fibrosis  
Mild 
induration 
(able to move 
skin parallel to 
plan and 
perpendicular 
to plane)  
Moderate 
induration 
(able to slide 
skin, unable 
to pinch 
skin)- limiting 
instrumental 
ADLs  
Severe 
Induration; 
unable to 
slide or pinch 
skin, limiting 
self-care 
ADL  
Generalized 
associated 
with signs or 
symptoms or 
impaired 
breathing or 
feeding  
Death  
Telangiectasia  
Covering < 
10% of surface 
area  
Covering 
>10% of 
surface area 
- 
- 
- 
Fatigue  
Relieved by 
rest  
Not relieved 
by rest, 
limiting 
instrumental 
ADLs  
Not relieved 
by rest; 
limiting self-
care ADLs  
- 
- 
Dermatitis 
radiation 
Faint erythema 
or dry 
desquamation 
 
Moderate to 
brisk 
erythema; 
patchy moist 
desquamation, 
mostly 
confined to 
skin folds and 
creases; 
moderate 
edema 
 
Moist 
desquamation 
in areas other 
than skin 
folds and 
creases; 
bleeding 
induced by 
minor trauma 
or abrasion 
 
Life-
threatening 
consequences; 
skin necrosis 
or ulceration 
of full 
thickness 
dermis; 
spontaneous 
bleeding from 
involved site; 
skin graft 
indicated 
 
Death 
Breast Pain  
Mild pain 
Moderate pain 
limiting 
instrumental 
ADLs 
Severe pain 
limiting self-
care ADLs 
 
 
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Lymphedema  
Trace 
thickening or 
faint 
discoloration 
Marked 
discoloration; 
leathery skin 
texture; 
papillary 
formation; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self -
care ADL 
 
 
Radiation 
Pneumonitis  
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
intervention 
not indicated 
Symptomatic; 
medical 
intervention 
indicated; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self-
care ADL; 
oxygen 
indicated 
Life-
threatening 
respiratory 
compromise; 
urgent 
intervention 
indicated 
(e.g., 
tracheotomy 
or intubation) 
Death 
Wound Infection  
Localized, 
local 
intervention 
indicated 
Oral 
intervention 
indicated 
(e.g., 
antibiotic, 
antifungal, or 
antiviral) 
IV antibiotic, 
antifungal, or 
antiviral 
intervention 
indicated; 
invasive 
intervention 
indicated 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death  
Hematoma/seroma  Mild 
symptoms; 
intervention 
not indicated 
Minimally 
invasive 
evacuation or 
aspiration 
indicated 
Transfusion; 
invasive 
intervention 
indicated 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
 
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