Prone Partial Breast Irradiation (PBI): A Prospective Randomized Trial Comparing Five Versus Three Fractions
Phase: NA
Conditions: Breast Cancer
Sponsor: NYU Langone Health

Official Title: 
Prone partial breast irradiation (PBI): prospective randomized controlled 
non-inferiority trial to compare radiation fibrosis with five versus three 
fractions 
NCT Number: 
NCT02276885 
Study Number: 
 s14-01306 
Document Type: 
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
•
October 12, 2018

Protocol Version 3.3 dated 10/12/2018
Clinical Research Protocol 
NYU S14-01306
Prone partial breast irradiation (PBI): prospective randomized controlled non-inferiority trial to 
compare radiation fibrosis with five versus three fractions
Principal Investigator: 
Carmen A. Perez, M.D., Ph.D (radiation oncology)
Co-investigators: 
Naamit Gerber, M.D. (radiation oncology)
Nelly Huppert, M.D. (radiation oncology)
Richard Shapiro, M.D. (surgical oncology)  
Deborah Axelrod M.D (surgical oncology)
Amber Guth M.D. (surgical oncology)
Freya Schnabel, M.D. (surgical oncology)
Olivier Maisonet, N.P. (radiation oncology)
Biostatistician
Judith Goldberg, Sc.D. (biostatistics) 
Funding Support
NYU Langone Medical Center-Radiation Oncology

Protocol Version 3.3 dated 10/12/2018
Clinical Research Protocol 
Summary of changes :
Protocal version 3.3 dated 10/12/2018

Extending follow-up window frame from 60 to 90 days

Adddition to Sectio 13: All analyses may be stratified by whether a patient started 
treatment within 60 days from surgery or within 90 days from surgery.
Protocol version 3.2 dated 2/1/2018
Protocol version 3.1 dated 2/7/2017

Revisions to Study Summary and sections 5.1, to change inclusion criteria to include patients at 
least 50 years of age and older, previously stated patients older than 50; new language offers 
clarity to desired subject population’s age.

Revisions to sections 6.8 Follow up, 8.5 Rationale for Study Design and 11.0 Study Calendar to 
eliminate the 60 day follow up time point.  It is clinically not necessary to have such intense 
monitoring in the acute period, adds to burden imposed on the patient, and has demonstrated 
poor compliance.  The acute side effects will still be captured in the 30d ( + 2 week) visit, which 
is standard of care for radiotherapy treatments.
All subjects will be followed for 30 days (+ 2 weeks), at  90 days and 6 months ( + 6 weeks) , 
then yearly for 5 years ( +8 weeks)

Amendment to include in the main inclusion criteria patients with low-risk stage 0 disease that 
fit the criteria defined in the updated ASTRO evidence-based consensus statement for APBI.  
The recently updated consensus statement now includes low-risk pure DCIS as part of the 
“suitable” category for APBI outside of  a clinical trial.
Protocol version 3.0 dated 9/14/2016

Revisions to sections 6.8 Follow up, 8.5 Rationale for Study Design and 11.0 Study Calendar to 
change the duration of follow up from 10 years to 5 years (after the first year post-treatment).  
The follow up frequency remains unchanged, with language clarified to reflect 3 monthly visits 
during the first 90 days post-treatment, 3 months afterwards, and then yearly visits for the 
duration of follow up.
After the end of radiation treatment, each subject will be followed monthly (+/- 2 weeks) for the 
first 90 days for serious adverse event reporting.   Assessments will continue q6 for the first year, followed 
by yearly visits for the remaining 5 years.

Deletion of sections describing the collection of blood samples from patients, as the exploratory 
endpoint of identifying germline polymorphisms in radiation-relevant pathways was described 
in older versions of this protocol but was ultimately not pursued and removed from the most 
current versions of the protocol.  
From section 2.7:  We will prospectively collect blood samples before and after treatment on 
these patients to determine whether we can identify germline polymorphisms in radiation-relevant 
pathways which may be able to predict which patients may be at risk for developing late radiation 
fibrosis.  Since retraction/atrophy often reflect the extent of original surgery we will focus on measuring 
breast fibrosis to define the phenotype of late effects of radiation to the breast.
From section 6.0:  Research samples will be processed over at Dr. Robert Schneider's lab 
at NYU Alexandria Labs.

Protocol Version 3.3 dated 10/12/2018
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
Revision of language in section 2 Background and Hypotheses to address typographical errors 
(removed reference to Fig. 1C, as no such figure exists, repeated word “protocol”, and error in 
referenced appendix numbers).  Additional revision of language in Table 5 Study Schema to 
address typographical error regarding number of eligible subjects (changed to 284 from 200).

Removed Ms. Chandrashekhar and Dr. Yeh from protocol since they are no longer working with 
NYU.
Protocol version 2.2 dated 10/14/2015:
Changing the cover page to add Dr. Naamit Gerber as Co-Investigator.  Removing the following 
personnel who are no longer at NYU: Maria Fenton-Kerimian, NP, Keith DeWyngaert Ph.D., Ravindran 
Kathirithamby- Research Director and Sharanya Chandrasekhar- Research Coordinator
Protocol version 2.1dated 04/10/2015:
Changing Principal Investigator to Dr. Carmen Perez.
Adding Dr. Silvia Formenti as Co-Investigator
Removing Research Blood component from the protocol and consent.
Informed Consent dated 03/25/2015:
Changing the Principal investigator in the informed consent to Dr. Carmen Perez.
Summary of changes : Amendment version 1.1 dated 10/14/2014.
Section 8.0 : Radiation Therapy 
Revising the language in sections 8.3, 8.5, and 8.6.
8.3 Imaging: A treatment planning CT of the breast will be acquired with the patient in the treatment 
position (prone), utilizing the same immobilization devices as will be used for treatment. CT scan thickness 
should be < 0.375  < 0.375 cm through the tumor bed region. These images will be used in 3D treatment 
planning of the breast in accordance with the dose specification constraints. 
8.5 Immobilization Techniques: Patients will be set-up for treatment and CT scanning utilizing the NYU 
prone mattress a dedicated table designed to accommodate prone positioning for breast treatment [15]. 

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8.6 Target Positioning Verification: Digitally acquired radiographic images, acquired prior to each 
fraction, will be used to verify the position of the target with respect to the treatment machine’s isocenter 
using digitally reconstructed radiographs (DRRs) as a reference image set. Both kV and MV images may 
be used to verify setup.
 

Protocol Version 3.3 dated 10/12/2018
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Amendment for NYU S14-01306:  Prone partial breast irradiation (PBI):  prospective randomized 
controlled non-inferiority trial to compare radiation fibrosis with five versus three fractions
We propose an amendment to study NYU S14-01306 to include in the subject eligibility 
criteria patients with pure DCIS (i.e., stage 0 breast cancer) that is classified as low risk as per 
RTOG 9804 criteria (1):  screen-detected, low to intermediate nuclear grade, < 2.5cm in size, 
resected with negative margins at >3mm).  These patients would be included in the target accrual of 
284 subjects. This proposed change is in response to the recently published update (i.e, September 
2016) of an ASTRO evidence-based consensus statement regarding the use of accelerated partial 
breast irradiation (APBI) outside of a clinical trial (2).  The new recommendations categorize the 
aforementioned low risk pure DCIS patients in the “suitable” group (Table 1 below).    These clinical 
guidelines represent an executive summary in Radiation Oncology to guide the use of APBI, and as 
the low risk pure DCIS patients are now considered suitable candidates for this adjuvant breast 
radiotherapy strategy, it seems reasonable and safe to include this group in the study population of this 
clinical trial.  
The recommendation to classify the low risk pure DCIS as “suitable” was done with 100% 
agreement of the panel members. Based on results from the randomized clinical trial RTOG 9804, 
with a median follow up of 7.2 years, the risk of ipsilateral breast tumor recurrence in this population 
was low at 6.7% in the observation arm compared to 0.9% in the whole breast adjuvant irradiation arm 
(1).  Accordingly, patients in the ECOG 5194 prospective study meeting similar criteria to the patients 
in RTOG 9804 also experienced low rates of ipsilateral breast tumor recurrence (14.4%  at a median 
follow up of 12 years), and these patients were observed but not treated with adjuvant breast 
radiotherapy (3).   Therefore, observation is deemed to confer a low absolute risk of ipsilateral breast 
tumor recurrence in the subset of patients with low risk DCIS, for whom the addition of whole breast 
radiation confers a measurable but small absolute benefit in preventing a recurrence.  The therapeutic 
index of adjuvant breast radiation in this low risk population may be improved with APBI, given the 
convenience and smaller volume of irradiated tissue using this strategy.  Retrospective series support 
the efficacy of APBI in this setting, with 5 year risk estimates of ipsilateral breast tumor recurrence of 
0% (4), 1.4% (5),  and 2.6% (6).
The benefits of the proposed amendment include improved accrual rate based on a broader 
eligibility criteria, as well as representation of a group of breast cancer patients (i.e.,  low risk pure 
DCIS /stage 0 breast cancer) in which the use of APBI is projected to increase in practice based on the 
updated ASTRO evidence-based consensus statement.  If this group of patients is included in the trial, 
then the results from this study would be applicable to a broader representation of patients routinely 
treated with APBI.  This amendment has been discussed with members of the Breast DMG, who are in 
agreement. 
Table 1, from reference2:

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References for this amendment:
1.
McCormick B, Winter K, Hudis C, et al: RTOG 9804: a prospective randomized trial for good-risk ductal 
carcinoma in situ comparing radiotherapy with observation. J Clin Oncol 33:709-15, 2015
2.
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
3.
Solin LJ, Gray R, Hughes LL, et al: Surgical Excision Without Radiation for Ductal Carcinoma in Situ of 
the Breast: 12-Year Results From the ECOG-ACRIN E5194 Study. J Clin Oncol 33:3938-44, 2015
4.
Goyal S, Vicini F, Beitsch PD, et al: Ductal carcinoma in situ treated with breast-conserving surgery and 
accelerated partial breast irradiation: comparison of the Mammosite registry trial with intergroup study E5194. Cancer 
117:1149-55, 2011
5.
Jeruss JS, Kuerer HM, Beitsch PD, et al: Update on DCIS outcomes from the American Society of Breast 
Surgeons accelerated partial breast irradiation registry trial. Ann Surg Oncol 18:65-71, 2011
6.
Vicini F, Shah C, Ben Wilkinson J, et al: Should ductal carcinoma-in-situ (DCIS) be removed from the 
ASTRO consensus panel cautionary group for off-protocol use of accelerated partial breast irradiation (APBI)? A pooled 
analysis of outcomes for 300 patients with DCIS treated with APBI. Ann Surg Oncol 20:1275-81, 2013

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Study Summary
TABLE OF CONTENTS 
Title
Prone partial breast irradiation (PBI):  prospective randomized controlled non-
inferiority trial to compare radiation fibrosis with five versus three fractions
Protocol Number
S14-01306
Study Duration
5 years
Study Center (s)
Perlmutter Cancer Center
Study Hypothesis
A regimen of 8 Gy X 3 over 5 days (every other day) is as safe (well tolerated) and 
effective as 6 Gy X 5 over five consecutive days.
Objectives
1.
To prospectively randomize patients to one of two fractionation regimens of 
image –guided prone breast radiotherapy (PBI) as part of breast preservation in 
post-menopausal women with low risk-Tis or T1 breast cancers:  600cGy X 5 
over five consecutive days (arm 1) versus 8 GyX3 given every other day (arm 
2).
2.
To test the hypothesis that rate of post-treatment radiation fibrosis (grades 2+3) 
on the 8 Gy x3 arm is not more than 10% worse than the rate on 6 Gy x5.
3.
To estimate local control and evaluate cosmetic outcomes on the two arms.
Number of 
Subjects
Maximum number of patients to be enrolled 284.
Main Inclusion 
Criteria

Post-menopausal women (50-90 years old) defined as either 
     1) at least 2 years without menstrual period or 
     2)  patients at least 50 years or older  with serological evidence of post-  
          menopausal status or 
     3) hysterectomized patients of any age with FSH confirmation of 
                        post-menopausal status. 

pT1 or low risk-pTis breast cancer, excised with negative margins. 
Criteria for low risk-pTis:
-
Screen-detected
-
Low to intermediate nuclear grade
-
< 2.5cm in size
-
Resected with negative margins at >3mm)

Clinically N0 or pN0 including sentinel node negative 
Study Product, 
Dose Route, 
Regimen
Prone partial breast irradiation (PBI)
Statistical 
Methodology
Approximately 1 out of 10 patients experience grade 2-3 fibrosis after lumpectomy and 
partial breast radiation. 
Based on our prior experience, we observed a 10% rate of grade 2-3 fibrosis in these 
patients. With 142 patients randomized to each of the two treatment arms,  we can test 
the hypothesis that the rate of fibrosis with 8Gy x3 is not more than 10% worse than 
the expected rate on the 6 Gy x 5 arm with one sided alpha =0.025 and power =80%.

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SCHEMA 
1.0
OBJECTIVES ...................................................................................................................11
2.0
BACKGROUND AND HYPOTHESES .........................................................................11
3.0
RESEARCH RISKS & BENEFITS ................................................................................14
4.0
STAGING CRITERIA.....................................................................................................18
5.0
RESEARCH POPULATION...........................................................................................18
6.0
REGISTRATION GUIDELINES ...................................................................................20
7.0       METHODS & PROCEDURES .......................................................................................22
8.0
RATIONALE FOR STUDY DESIGN............................................................................24
9.0
RADIATION THERAPY/TREATMENT PLAN .........................................................25
10.0
TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS...............26
11.0
STUDY CALENDAR…………………………………………………………………   26
12.0
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS........................30
13.0
STATISTICAL AND DATA MANAGEMENT CONSIDERATIONS.......................30
14.0     ADVERSE EVENT REPORTING  AND DSMC..........................................................32
15.0
STUDY FINANCES .........................................................................................................36
16.0
REFERENCES..................................................................................................................37
APPENDIX 1................................................................................................................................39

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation                          Explanation
...................
cGy
                            Centigray
CTV
Clinical target volume
CBCT
Cone-beam CT
CBF
Contralateral breast failure
CSS
Cancer-specific survival
DCIS                                  Ductal carcinoma in situ
DF
Distant failure
DFS
Disease-free survival
DVH
Dose-Volume Histogram
EB
External beam technique
FSH
Follicle stimulating hormone
Gy
Gray unit
IBF
Ipsilateral breast failure
IGRT
Image guided Radiotherapy
IMRT
Intensity Modulated Radiation Therapy
INF
Ipsilateral nodal failure
kV
Kilovoltage
MV
Megavoltage
OS
Overall survival
PBI
Partial breast irradiation
PBR
Prone breast radiotherapy
APBI
Accelerated partial breast irradiation
PTV
Planning target volume
s/p
status pos

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1.0
Objectives
1.1 To prospectively randomize patients to one of two fractionation regimens of image –guided 
prone breast radiotherapy (PBI) as part of breast preservation in post-menopausal women 
with T1 or low risk-Tis breast cancers:  600cGy X 5 over five consecutive days (arm 1) 
versus 8 GyX3 given every other day (arm 2).
1.2  To test the hypothesis that rate of post-treatment radiation fibrosis (grades 2+3) on the 8 Gy 
x3 arm is not more than 10% worse than the rate on 6 Gy x5.
1.3 To estimate local control and evaluate cosmetic outcomes on the two arms.
2.0
Background and Hypotheses
Partial breast irradiation (PBI) is becoming a new paradigm for breast cancer radiation [1]  No type 
I or II evidence is currently available to demonstrate equivalence to standard whole breast 
radiotherapy, and a prospective randomized trial jointly sponsored by NSABP and RTOG (NSABP 
B-39 and RTOG 0413) has completed accruing patients, comparing whole breast radiotherapy to 
PBI, either by brachytherapy or external beam techniques (EB):  results of this trial are pending. 
Until results of this or similar trials are available, PBI remains a research domain, and it should be 
offered to patients only in the context of a clinical experimental protocol. 
2.1
Advantages of PBI through external beam radiotherapy
Despite the fact that less extensive experience than that of brachytherapy is available, PBI delivery 
through an external-beam has many advantages. First of all, it is likely to be more acceptable to the 
patient since it is non-invasive and it does not require a surgical procedure or anesthesia. Moreover, 
since it is delivered after surgery, the pathological analysis of the segmental mastectomy specimen 
is available to inform the selection of the best candidates. In addition, EB-PBI is likely to become 
more widely reproducible, since it does not rely on the experience and skills of the radiation 
oncologist performing the brachytherapy implant. Besides, once the technique is established, it can 
be widely applied at any facility provided with a linear accelerator, without the risk presented by 
some brachytherapy approaches that cannot be completed because of the unfavorable interplay of 
patient’s anatomy with the technical limitations of the applicator [2]. Finally, in terms of health 
care economics, an external beam approach spares the costs of an extra surgical procedure and 
several days as inpatient (in the case of LDR brachytherapy) [3].
EB-PBI was originally tested in a prospective randomized trial that compared it to whole breast 
and nodal radiation, at Christie Hospital, in Manchester, UK [4]. At a follow up of 65 months, while 
survival in the two arms was comparable, the PBI arm had twice the local recurrence rate than the 
whole breast arm (20 versus 11%). Noticeably, eligibility to the trial included tumors as large as 4 
cm in diameter and EB-PBI was delivered by 8 or 14 MeV electrons, through a generally small 
field, without the imaging support available nowadays to target the tumor bed. Certain histological 
characteristic of the primary tumor, lobular type and/or presence of DCIS in the specimen, were 
more likely to be associated with recurrence. Conversely, in carriers of infiltrating ductal 
carcinomas treated by PBI, the failure rate outside the original quadrant was only 5.5 %. 
This experience informed the more careful patient selection of the contemporary EB-PBI clinical 
trials, that limit eligibility to patients with smaller tumors with negative margins of resection and 

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without an extensive intraductal component.[5-8] The clinical target volume (CTV) usually 
consists of the tumor cavity visualized at CT planning, plus 1-1.5 cm of margin. An extra 1-2 cm 
is added to the CTV to create the planning target volume (PTV), taking into account some 
variability in the daily positioning. 
2.2 
The NYU experience of prone PBI 
A prone approach for partial breast radiation has been tested at NYU in a clinical trial sponsored 
by an IDEA grant of the Department of Defense (NYU 00-23). Results of the first 47 patient 
accrued originally demonstrated feasibility [7]. Eligibility to this study was limited to post-
menopausal women with non-palpable, mammographically detected tumors. In addition, the 
protocol required patients to have first refused to undergo standard six-week radiotherapy. Five 
fractions of 6 Gy were delivered to the PTV over ten days . The dose and fractionation was based 
on radiobiological modeling, aimed at determining a dose to deliver in five fractions that would 
achieve equivalence to the tumor control estimates of 50 Gy in 25 fractions, while maintaining a 
risk of fibrosis at the tumor bed comparable to that of a standard regimen of 60 Gy in 30 fractions 
[7] [9]. An α/β = 4 for tumor control was used, and its validity has been recently confirmed by the 
results of a prospective randomized trial comparing accelerated to standard whole breast 
radiotherapy [10]. We recently reported the 5y results of this trial (see below, 2.3)
RTOG tested conformal EB-PBI in the supine position in a Phase I-II trial (RTOG 0319) which 
rapidly accrued its target population of 58 patients [8]. This important trial confirmed the feasibility 
of EB-PBI in a supine position, through multi-institutional accrual. Ten fractions of either 3.4 Gy 
or 3.85 Gy were delivered twice a day, separated by an interval of 6 hours, to a total dose of 34 Gy 
or 38.5 Gy. The dose/fractionations were chosen to mimic the extensive experience acquired by 
PBI through brachytherapy, based on the original assumption of α/β=10 for tumor control. 
At the early follow-up point of 2-3 years, it is encouraging to notice that either technique achieves 
excellent local control and cosmetic results. However, the results of prone EB-PBI are slightly 
superior in terms of normal tissue sparing, due to the fact that when prone, the treating beam can 
be directed to avoid exiting through the rest of the body [11]. 

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Table 1. Series of Partial Breast Radiation Therapy 
Table 1. reproduced from Taghian AG et al, IJROBP: 64(4):1092-99, 2006 [12]. The table depicts 
the similarities between the three published series of accelerated partial breast irradiation. The 
prone technique achieves better normal tissue sparing. 
2.3 
Results of NYU 00-23: five year local control
The 5-year results of the initial clinical trial of prone PBI mentioned in 2.2 were recently reported 
(Formenti et al. Int J Radiat Oncol Biol Phys. 2012 November 1; 84(3): 606-611. 
doi:10.1016/j.ijrobp.2012.01.039). Post-menopausal patients with Stage I breast cancer with non 
palpable <2 cm tumors, negative margins, and negative nodes, positive hormonal receptors, and no 
extensive intraductal component (EIC) were eligible to NU 00-23. The trial was offered only once 
eligible patients had refused to undergo standard whole-breast radiotherapy. Patients were 
simulated and treated on a dedicated table for prone set-up. Radiation was delivered conformally, 
and was 30 Gy in five 6 Gy/daily fractions over 10 days with port film verification at each 
treatment. Recurrence in the ipsilateral breast, ipsilateral nodal, contralateral breast, and distant 
failure (IBF, INF, CBF, DF) were estimated using the cumulative incidence method. Disease-free, 
overall, and cancer-specific survival (DFS, OS, CSS) were recorded.
One hundred patients accrued to this IRB-approved prospective trial, one with bilateral breast 
cancer. One patient withdrew consent after simulation and another elected to interrupt radiotherapy 
after receiving two treatments. Ninety-eight patients are evaluable for toxicity and, in one case, 
both breasts were treated with PBI. Median patient age was 68 years (range 53-88 years); in 55% 
the tumor size was <1 cm. All patients had hormonal receptor positive cancers: 87% underwent 
adjuvant anti-hormonal therapy.
At a median follow-up of 64 months (range, 2-125 months), there was one local recurrence (1% in 
breast failure,  IBF) and one contralateral breast cancer (1%  contralateral breast failure,CBF). 
There were no deaths due to breast cancer by 5 year. Grade 3 late toxicities occurred in 2 patients 
(1 breast edema, 1 transient breast pain). Cosmesis was rated good/excellent in 89% of patients 

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Figure 1A and B. Changes of the seroma over time, 2 
and 6 weeks after surgery, respectively.
with at least 36 months follow-up. The encouraging results of this trial have generated interest to 
further reduce the number of radiotherapy sessions for partial breast radiation, and compare five to 
three fractions, the purpose of this protocol.
2.4 
Inter-fraction reproducibility: the role of IGRT 
A recognized challenge of partial breast irradiation 
is the daily identification of the correct target. 
Kader et al [13] have studied the evolution of the 
seroma with time (Fig 1A and 1B). When patients 
are treated in the supine position: both the volume 
of the cavity and the profile of the breast change 
over time (Fig 1A and 1B),  a similar course is 
likely to occur during prone treatment. Clearly, an 
accelerated course, to complete within one week, 
has the advantage of treating a more stable volume. 
Ideally, daily target verification could both confirm 
the planning volume and enable correction of inter-
fraction, setup-derived, changes of the target. 
Published evidence suggests that image guided 
radiotherapy, IGRT can be utilized to reduce setup 
errors in partial breast radiation therapy delivery. 
The Princess Margaret Hospital reported on cone-
beam CT (CBCT) guidance for setup error 
reduction 
and 
soft 
tissue 
visualization 
in 
accelerated partial breast irradiation (APBI)[14]. A 
total of 315 CBCT data sets revealed that 
systematic errors for the skin-mark setup were 
reduced from 2.7, 1.7, and 2.4 mm to 0.8, 0.7, and 
0.8 mm in the right–left, anterior–posterior, and 
superior–inferior directions, respectively with 
CBCT guidance. The random errors were reduced 
from 2.4, 2.2, and 2.9 mm for skin-marks to 1.5, 1.5, and 1.6 mm for CBCT guidance in the right–
left, anterior–posterior, and superior–inferior directions, respectively. Implementing CBCT 
guidance for APBI was shown to reduce the random and systematic setup error by almost half when 
compared with a skin-mark setup. 
In our previous protocol of PBI, cone-beam CT (CBCT) was for the first and for the last radiation 
fraction in order (1) determine the errors for a conventional skin-mark setup, (2) measure the 
accuracy of a CBCT-guided setup and to compare with megavoltage portal images, and (3) 
determine the visibility of the post-lumpectomy seroma on the CBCT images. Results from this 
experience suggest high reliability of the prone setup, permitting to only obtain a CBCT, at 
baseline, before treatment starts.
2.5 
Optimal accelerated fractionated regimen over a five days interval of time. 
The optimal accelerated dose fraction for external beam partial breast irradiation remains to be 
established. One of the main objectives of this study will be to determine the acute effects using a 
regimen of 6 Gy x 5 daily fractions over five consecutive days. Our prior protocol evaluated the 

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feasibility of 6 Gy x 5 fractions over 10 days. In our preliminary experience there have been very 
minimal acute effects with this regimen. 
The biologically equivalent doses of different fractionation schedules are the total doses for which 
the probabilities of a certain outcome/complication are the same. Certainly, they can be different 
for specific outcomes/complications. 
The biologically equivalent doses in regard of several outcomes/complication to a treatment 
delivered in the standard 2 Gy fractions five times a week was estimated by the widely used 
formula[16, 17]: 
Dnew=Dref* (α / β+ dref) / (α / β+ dnew) 
or - in this case - using 5 fractions of dref dose: 
Dnew=5*dref* (α / β+ dref) / (α / β+ 2) 
where α / β is a tissue dependent parameter, arising from the radiobiological linear - quadratic cell 
survival model. The resulting equivalent total doses are shown in Table 2. 
TABLE 2. Equivalent total doses based on α / β Biologically Effective Doses (BED) 
Dosexfractions
α / β
(Gy) 
BED 
Standard 
2 Gy x 30 fx 
BED 
Standard 
2 Gy x 
25fx 
BED 
RTOG/NSABP 
3.85 Gy x 10fx 
BED  
NYU 
6 Gy x 5fx 
BED
NYU
8 Gy x 3fx
Erythema 
8 
75 Gy8 
63 Gy8
57 Gy8
53 Gy8
48 Gy8
Desquamation 
11 
71 Gy11
59 Gy11
52 Gy11
46 Gy11
41 Gy11
Telangiectasia 
4 
90 Gy4
75 Gy4
76 Gy4
75 Gy4
72 Gy4
Fibrosis 
2 
120 Gy2
100 Gy2
113 Gy2
120 Gy2
120 Gy2
Tumor 
4 
90 Gy4
75 Gy4
76 Gy4
75 Gy4
72 Gy4

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As shown in Table 2, the proposed hypo-fractionated schedule of 8Gy X 3 results in equivalent 
tumor control when compared with the standard regimen of six weeks of daily radiotherapy. In 
addition, as compared with the on-going NSABP trial (NSABP B-39 and RTOG 0413) and the 
NYU 6 Gy x 5 schedule, the proposed experimental schedule of 8 Gy x 3 fraction results in a lower 
calculated probability of acute effects and erythema, a similar probability for developing late 
radiation fibrosis as the NYU 6 Gy x 5 schedule and a slightly higher probability for developing 
late radiation fibrosis as compared to NSABP B-39/RTOG 0413. Specifically, we predict that the 
new 8 Gy X 3 schedule will result in comparable local control and toxicity of the previously tested 
6GyX5 one, where the incidence of radiation fibrosis among 292 patients accrued ranged between 
20-30%.
2.7 
Risk of developing post-radiotherapy fibrosis: correlating a phenotype to a genotype 
– Genomic Analysis in order to determine genetic markers.
Exceeding a total dose of 60 Gy has shown to be associated with increased risk of fibrosis at the 
treated site. Even when the total dose is reduced, like in this trial (30 or 24Gy, respectively for arm 
1 and 2), the use of fraction sizes in excess of the standard dose of 2 Gy may reflect in increased 
risk of fibrosis. This complication however occurs only in a minority of irradiated patients that 
currently cannot be identified in advance.  While some induration at the original site is expected 
and it reflects the result of lumpectomy healing and seroma organization, fibrosis and retraction 
exceeding grade 1 (grade 2,3), is likely to represent a late effect of radiation. 
Table 3 LENT SOMA DEFINITION OF FIBROSIS AND RETRACTION (appendix 2)
Not only does fibrosis compromise the cosmetic result but it also impairs the clinical exam of the 
breast. Post-radiation therapy fibrosis is characterized by mesenchymal cells replacing the normal 
tissue and overproducing extracellular matrix and it is clinically measured following the 
LENT/SOMA classification (Table 3 and appendix 2).
Table 4 summarizes the incidence of fibrosis and retraction (grade 1-3) among 276 patients treated 
in our current protocol of Image guided Radiotherapy for PBI, using five consecutive fractions of 
6Gy. While the degree of this complication also reflects the different surgical techniques of 
segmental mastectomy, it appears that approximately 1/3 patients suffer some degree of breast 
distortion/fibrosis with the current hypo-fractionated regimen of 6GyX5. The current trial is 
designed as a non-inferiority study, powered to enable the detection of 10% or more difference in 
the incidence of fibrosis.

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Recently, Quarmby et al. reported on TGFbeta1 gene polymorphisms on DNA obtained from 103 
breast cancer patients who received radiotherapy. Patients who are carriers of specific 
polymorphisms of TGF-beta -509TT or +869CC alleles were between 7 and 15 times more likely 
to develop severe fibrosis. [18]    
.
2.8 
Study Hypotheses 
A regimen of 8 Gy X 3 over 5 days (every other day) is as safe (well tolerated) and effective as 6 
Gy X 5 over five consecutive days.
3.0
RESEARCH RISK & BENEFITS
3.1  
Risk of Study treatment
The risks involved in using the treatment machine or the CT scanning are described as possible 
fatigue, skin damage, swelling, muscle tightness, and position-induced muscle aches (back and 
shoulder).  
3.2  
Other Risks of Study Participation
Additional risks to study participation include breach of confidentiality.  Privacy protection 
procedures are in place and good clinical practice guidelines are followed throughout the study to 
minimize the risks associated with breach of confidentiality.
3.3  
Potential Benefits
The potential benefits to subjects with study participation are improved overall survival.  The 
information obtained from this research may help others with this disease in the future.
Table 4 INCIDENCE OF FIBROSIS AND RETRACTION
 (276 women treated with prone partial breast radiotherapy 6 Gy x 5)
Fibrosis
Retraction/
Atrophy
Grade
Number of 
patients
Percent
Number of 
patients
Percent
1
68
24.64
63
22.83
2
18
6.52
21
7.61
3
3
1.09
4
1.45
 
 
 
 
 
Total Patients 
with Grades 1-3
89
32.25
88
31.89
 
 
 
 
 
Total Number of 
Patients in Study
276
 
276
 

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3.4
Drug Information
NA 
4.0
Staging Criteria
TNM Stage I, T1 N0 M0 breast cancer patients. 
TNM Stage 0, TisNxM0 breast cancer patients.
5.0
RESEARCH POPULATION
Patient Eligibility
284 study subjects at least over the age of 50-90 female are to be entered into this study across all 
NYU School of Medicine and Bellevue Hospital (satellite campus). This study will be an out-
patient study.  We do not plan to enroll vulnerable population and there are no restrictions on 
race/ethnicity.
 
Inclusion criteria: 
5.1 
Post-menopausal women defined as either 
1) at least 2 years without menstrual period or 
2) patients at least 50 years or older  with serological evidence of post-menopausal 
status or 
3) hysterectomized patients of any age with FSH confirmation of post-menopausal 
status. 
5.2 
pT1 breast cancer, excised with negative margins. 
Low risk-pTis breast cancer, excised with negative margins. 
Criteria for low risk-pTis:
-
Screen-detected
-
Low to intermediate nuclear grade
-
< 2.5cm in size
-
Resected with negative margins at >3mm)
5.3 
clinically N0 or pN0 including sentinel node negative 
Exclusion criteria: 
5.4 
Previous radiation therapy to the ipsilateral breast. 
5.5 
Presence of a proportion of DCIS in the core biopsy specimen which is compatible 
with extensive intraductal component (EIC). 
5.6
Subject Recruitment, Registration and Screening
All efforts will be made to actively recruit and retain members of minority groups in this study.  
The inclusion and exclusion criteria in this study should not have a negative effect on the 
enrollment of these populations.  

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Target enrollment for this study is 284 patients.  Each cohort will consist of 142 patients.  Patients 
will be recruited from physicians at the NYU Perlmutter Cancer Center and Bellevue Hospital.  
Consenting, screening, and treatment takes place at the NYU PCC under the supervision of the 
Principal Investigator.  Prospective subjects receive detailed information about this study its 
investigational nature, required study procedures, alternative treatments, risks and potential 
benefits of the study.  They also receive the informed consent document to read.  All questions 
are answered by the PI and qualified research personnel.  
The Principal Investigator will:
1.
Obtain signed and dated informed consent from the potential patient before ant study 
specific procedures are performed.
2.
Determine patient eligibility See Sections 5.1 through 5.5.
3.
Submit registration to NYU Perlmutter Cancer Center CTO
4.
Receive registration confirmation from the Research Coordinator at NYU Perlmutter 
Cancer Center CTO, including a unique study identification number assigned to the 
patient by the research coordinator, which will be distributed to the study team upon 
registration.
Recruitment and consenting will take place in a private area such as an exam room to protect the 
patient’s privacy.  The informed consent process and documentation follows the established 
procedures of the NYU PCC CTO.
5.7
Informed Consent
Consent will be obtained only by a participating investigator who has completed requisite training 
for human subject research and has been instructed by the Principal Investigator about the 
patients and address any questions or concerns prior to obtaining written informed consent for 
participation and HIPAA authorization.
Patients will be given adequate time to read the consent form.  They will be given time to ask 
questions about the study in private exam rooms.  Questions will be answered by a participating 
physician, or qualified research study team member all of whom have completed requisite 
training for human subject research.  Investigators will review the informed consent form with 
patients and address any questions or concerns prior to obtaining written informed consent for 
participation.  Investigators will stress that participation in the study is completely voluntary and 
will not affect the care patients receive or result in any loss of benefits to which patients are 
otherwise entitled.
For non-English speaking patients, institutional translation services will be utilized. For these 
patients the consent letter and all other information will be administered orally and a witness, not 
related to the research project, will be present while the oral presentation is given. A short form 
will be utilized for the subject to sign in his/her name and the translator and/or witness must sign 
the short form. The translator will also sign the main consent form.
For patients who cannot read. A witness, not related to the research study will be present. The 
consent will be read to the patient. The patient will also be allowed to ask any questions s/he may 
have. The investigator will ask the patient questions to ensure s/he understands the study. If the 

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investigator determines the subject understands the study, the patient will mark an X where 
his/her name would go and the witness will sign the consent form.
5.8
Documentation of Consent
The Principal Investigator or IRB approved sub-investigator will be responsible for 
documentation in the medical record that consent has been obtained from all participants. A 
signed copy of the consent form will be given to each participant. Original consent forms will be 
stored in the subject’s medical chart.
6.0
REGISTRATION GUIDELINES
Patients will be registered with the Clinical Investigations Support Office of the department of 
Radiation Oncology and with the Clinical Research Office of the Cancer Center. 
6.1
At the time of registration, one signed and dated informed consent will be obtained, 
along with three copies for patient, medical record, Clinical Investigations Support 
Office of the department of Radiation Oncology and with the Clinical Research 
Office of the Cancer Center. 
6.2
At the time of registration, the eligibility registration worksheet will be completed. 
6.3
A flow sheet to record baseline characteristics including demographic and disease 
characteristics will be used to collect data as well as detailing clinical parameters and 
toxicity. The flow sheets will be maintained during therapy and the entire duration 
of the study (5 years).
6.4
Confidentiality 
All data and medical information obtained once a patient has decided to participate 
in this research, will be kept confidential to the extent permitted by law and will not 
be released without the patient’s written permission except as described in this 
paragraph. The study information will be recorded on study report forms . In all study 
forms, patients will be identified only by their initials and patient number. Patient 
names will not be reported in any publication; only the data obtained as a result of 
their participation in this study will be made public. 
All patients will be required to sign a written informed consent prior to being registered on this 
study.  Every effort will be made to answer questions raised by patients and their families or 
advocates regarding the protocol and alternative therapies prior to asking a patient to sign the 
consent form.  
Once eligibility is verified, a unique patient study number will be issued within 24 hours of 
receiving all required registration material.  The patient will not be identified by name.  This is 
the point, at which, the patient is considered on study.  Subjects must not start any protocol 
procedures prior to registration.

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6.5
Screening Process
During the screening visit, the following will happen:
1.
The study doctor will ask the subject questions about their medical history, including 
information about other medical problems.
2.
You will be asked what prescription medications, over-the-counter (OTC) 
supplements, herbal products, vitamins, and any other OTC products you are taking.
3.
The study doctor will perform a physical examination and collect your vital signs (heart 
rate, breathing rate, blood pressure and temperature).
6.6
Selection Process
If subject is eligible to participate in this study, the subject is randomly assigned to one of two 
radiation treatment groups:
Group 1 (Arm 1):  will receive a radiation dose of 6Gy each day for 5 
consecutive days.
Group 2 (Arm 2):  will receive a radiation dose of 8Gy every other day 
over a period of 5 days.
Before starting radiotherapy, you will be required to undergo a radiation therapy planning 
session/simulation session to enable your radiation doctor to carefully design the radiation 
treatment so that only the area that is affected by tumor is radiated while trying to avoid 
surrounding normal tissue.  A simulation session is required to obtain images of your chest to 
tailor the radiation treatment to your body shape. During this simulation session, you will lie 
prone (on your belly) so that we can best cover the radiation target region (the tumor bed) while 
avoiding heart and lung tissue as much as possible.  The tumor bed is where your tumor was 
before you had it surgically removed.
6.7
Early Withdrawal of Subjects
A subject has the right to voluntarily discontinue treatment or withdraw from the study at any 
time, for any reason, and without repercussion.  The investigator has the right to discontinue a 
subject from the study or withdraw a subject at any time.
Reasons for subject withdrawal from the study may include:

Subject withdrawal of consent at any time

Any medical condition that the investigator determines my jeopardize the 
patient’s safety if she continues in the study or continues treatment.

The investigator determines it is in the best interest of the patient

Failure of subjects to adhere to protocol requirements 

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Every effort will be made to obtain information on subjects who withdraw from the study, 
including the reason for taking a participant off the study.  The date the participant was removed, 
must be documented.  
6.8
Follow-up
After the end of radiation treatment, each subject will be followed for 30 days ( + 2 weeks), at   
90 days and 6 months ( + 6 weeks) for serious adverse event reporting.   Assessments will 
continue with yearly ( + 8 weeks) visits for the remaining 5 years.  
7.0
METHODS & PROCEDURES
7.1
Descriptive Factors/Stratification/Randomization Scheme
This is a prospective, randomized study.  No stratification is planned.  The study schema 
describes the study design.
7.2
Randomization Scheme
Research Coordinators will randomize patients to one of the 2 arm of the study, as soon as they 
have provided informed consent and eligibility packet to participate in the research study.  The 
randomization list will be done via REDCap, a browser-based, metadata-driven EDC software 
solution for research databases and will be maintained in the department of Radiation Oncology.
. 
Table 5 Study Schema
Eligibility 
 Day 0 
Day 1-5 
(start within 90 days from last 
breast surgery) 
284 stage I or low risk-stage 0 breast 
cancer in post-menopausal women, s/p 
segmental mastectomy 
    Low risk-stage 0 criteria:

 Screen-detected

Low to intermediate nuclear grade

< 2.5cm in size

Resected with negative margins at 
>3mm
Informed consent and randomization
CT planning for determination of 
tumor bed on the prone position 
Daily IGRT, IMRT or Conformal 
Partial breast irradiation, randomly 
assigned to:

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600 cGy X 5 fractions, over 5 
consecutive days (arm 1)
or
800 cGy X 3 fractions, every other 
day, over 5 days (arm 2)

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8.0
RATIONALE FOR STUDY DESIGN
8.1 
The women in this study will receive either 5 or 3 radiation fractions to the tumor 
bed. We have chosen to study T1 or low risk-Tis post menopausal women because 
in this subset: 1) the tumor is small enough to be treated by partial breast radiation 
2) the odds of having multicentric disease are low, making it ethical to avoid whole 
breast irradiation, 3) the most benefit from reducing the radiation schedule from 5 
to 3 could be expected. 
8.2 
The Principal Investigator explains all elements of the protocol to the patients 
and answers any and all questions. Clinical procedures are performed by the 
principal investigator. The consent process takes place in the Department of 
Radiation Oncology at NYU Medical Center. 
8.3 
Once the process of eligibility has been determined, patients will be randomly 
assigned to one of the 2 arms:
Arm 1: 6 GyX5 over 5 days, on five consecutive days
Arm 2: 8 GyX3 over 5 days, every other day
8.4 
Simulation and treatment will be started within 90 days from surgery, in order to 
maximize the chances of optimal lumpectomy cavity visualization on the planning 
and cone beam CT scans. Start of treatment within 60 days from surgery is 
encouraged, but the treating physician is allowed a window up to 90 days from last 
breast surgery to start the radiation treatment, as long as clinical judgment supports 
accurate visualization of the target lumpectomy cavity at that timepoint.   
8.5
All subjects will be followed for 30 days ( + 2 weeks),  at  90 days and 6 months 
(+ 6 weeks) , then yearly for 5 years (+ 8 weeks) (see 11.0 Study calendar). 
9.0
RADIATION THERAPY/TREATMENT PLAN 
9.1 Radiation Dose Specification: The prescription dose is the dose delivered to a 
reference point within the clinical target volume. The prescription dose should 
cover at least ninety- five percent of the planning target volume. 
9.2 Target Volumes: 
9.2.1 The resection cavity should be discernible based upon architectural 
changes in the breast tissue by the CT images and is defined as the 
clinical target volume (CTV). 
9.2.2 The planning target volume (PTV) = CTV + 1.5 cm margin. 
9.2.3 PTV eval = PTV limited to be within the defined ipsilateral breast 
tissue, specifically excluding the 1st 5 mm of tissue under the skin 
and tissue beyond the chest wall, pectoralis muscles and lung. 

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9.2.4 Whole breast reference volume: all tissue encompassed within 
traditional tangent field borders, excluding tissue deep to the chest 
wall interface and using the skin surface as the superficial border. 
9.3 Imaging: A treatment planning CT of the breast will be acquired with the 
patient in the treatment position (prone), utilizing the same immobilization 
devices as will be used for treatment. CT scan thickness should be < 0.375 cm 
through the tumor bed region. These images will be used in 3D treatment 
planning of the breast in accordance with the dose specification constraints. 
9.4 Treatment Machine: A linear accelerator with > 4 MV x-rays is required. 
9.5 Immobilization Techniques: Patients will be set-up for treatment and CT 
scanning utilizing  a dedicated table designed to accommodate prone 
positioning for breast treatment [15].
9.6 Target Positioning Verification: Digitally acquired radiographic images, 
acquired prior to each fraction, will be used to verify the position of the target 
with respect to the treatment machine’s isocenter using digitally reconstructed 
radiographs (DRRs) as a reference image set. Both kV and MV images may 
be used to verify setup. 
9.7 IGRT Target Localization: Cone-beam CT (CBCT) images will be acquired 
prior to the first radiation treatment. By using IGRT to image the post-
operative tumor bed of the breast in “real-time”, the operator may 
automatically align the tumor bed with the treatment machine on the day of 
treatment. If shifts are made based upon the CBCT images, they will be 
recorded and the following day’s portal images will be taken. If the resection 
cavity is not visualized then cone-beam CT images will be used to ensure 
optimal positioning of the breast tissue. 
9.8 Treatment Planning: 3D-Conformal or Intensity Modulated Radiation Therapy 
(IMRT) treatment planning is allowed. This includes “field-in-field” beams as 
well as the use of dynamic multi-leaf collimator (MLC) derived using inverse 
planning or electronic compensator techniques. Field arrangements and 
technique should be chosen that satisfy the PTV_eval and normal tissue dose 
constraints using Dose-Volume Histogram (DVH) analysis. By carefully 
selecting the gantry and table angle combinations that do not enter or exit 
through other organs of the body, the dose can be confined to the traditional 
breast treatment volumes treated using a pair of tangent photon beams. No 
plan will be deemed acceptable if fields are directed towards the contralateral 
breast, heart or lung. Non-coplanar beam arrangements are encouraged, but 
not required. Dose calculations with tissue inhomogeneity correction must be 
used. 
9.9 Normal Tissue Dose Constraints: 

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9.9.1 Uninvolved by tumor  breast: Less than 60% of the whole 
ipsilateral breast should receive >50% of the prescription dose and 
less than 35% of the whole breast should receive the prescription 
dose. 
9.9.2 Ipsilateral lung: Less than 15% of the lung can receive 30% of the 
prescribed dose. 
9.9.3 Contralateral lung: Less than 15% of the lung can receive 5% of 
the prescribed dose. 
9.9.4 Heart: Less than 5% of the heart can receive > 5% of the 
prescription dose. 
10.0
TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS
10.1 Expected toxicities include fatigue and skin reactions within the radiation 
field. Erythema, dry and wet desquamation of the skin will be recorded 
weekly. 
10.2 In the previous study of 45 patients there were no grade 2-3 skin 
toxicities[19]. Additional experience with the same regimen in 292 patients, 
demonstrated no grade 2-3 acute toxicity.
10.3 The risks involved in using the treatment machine or the CT scanning are 
described in the regular informed consent given to all patients undergoing 
radiation therapy. 
10.4 The risks associated with venipuncture may occasionally include pain, 
bruising, fainting or a small infection at the puncture site. 

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11.0
STUDY CALENDAR
All subjects will be followed the first 30 days ( + 2 weeks), at   90 days and 6 months ( + 
6 weeks) for serious adverse event reporting.   Assessments will continue with yearly ( + 
8 weeks) visits for the remaining 5 years.  Acute and late effects will be recorded 
following the criteria described in Appendix 1 and 2.  At each post treatment follow-up 
visit, a physical exam to detect clinical recurrence will be performed.  Mammographic 
studies and/or MRI will be performed and reviewed on an annual basis.  The degree of 
fibrosis assessed by palpation will be measured as per Appendix 2, late effects.
Table 6 Flow Chart/Time and Events Schedule for Treatment and Follow up
Procedure 
Summary
Pre 
treatm
ent
Day
1
Day
2
Day
3
Day
4
Day
5
30 days 
post 
treatme
nt 
Follow Up 
- 90 day 
post 
treatment
Follow 
Up 6 
months 
post 
treatme
nt
Follo
w up -
Every 
year 
for 5 
years
Informed Consent
X
MD/NP visit: 
physical and vital 
signs/cosmesis 
assessment (you 
will be examined 
for any skin 
changes at the 
radiation site)§
X
X§*
X§*
X§*
X
X
X
X
 Medical History
X
X*
X*
X*
X*
Mammogram
X
X**
X**
Lumpectomy 
Pathology Report
X
Randomization 
(Treatment 
assignment)
X
Treatment 
simulation***
X
Baseline CBCT, 
first RT
X
Port films/ each RT 
dose after the first 
onea,b
X
X
X
X
Radiation Therapy
Xa,b
Xa
Xa,b
Xa
Xa,b
AEs
X
X
X
X
X
X
X
X
X
§MD evaluation will occur at least once during treatment visits.
§* MD evaluation will occur at least once if randomized to Arm 2
* first 30 days ( + 2 weeks)   post-treatment, then 90 days  and 6 months (+ 6 weeks) , and 
then yearly for the next 5 years (+ 8 weeks).
**  Standard annual mammogram (or MRI) for both breasts.
*** May occur before Informed Consent, as this is part of standard of care
aArm1 6Gy X 5 fractions (5 days)

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bArm2 8Gy X 3 fractions (3 days)
12.0
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS
12.1 Acute and late toxicity will be reported as scheduled in the above study calendar (10.1) 
following the criteria in Appendix 1. 
12.2 Local recurrence will be classified as it follows: 
12.2.1. Local recurrence within the field of conformal radiation is defined as TRUE 
LOCAL RECURRENCE.
12.2.2 In breast recurrence outside the treatment volume will be defined as 
LOCAL RECURRENCE OUTSIDE THE FIELD, SAME BREAST
12.2.3 Axillary/ intra-mammary or supraclavicular recurrence in the same side of 
the index lesion will be defined as REGIONAL RECURRENCE /SAME 
BREAST. 
12.3
At the time of local recurrence all patients will undergo disease assessment with 
CT of Chest/ Abdomen/ Pelvis and, if symptomatic, bone scan and/or brain MRI. 
Local/regional recurrences will be further grouped as: 
12.3.1 ISOLATED LOCAL/REGIONAL RECURRENCES 
12.3.2. CONCOMITANT LOCAL/REGIONAL AND DISTANT 
RECURRENCES 
Patients developing local recurrences after systemic recurrence has been 
documented will be classified as: 
12.3.3. METACRONOUS LOCAL/REGIONAL RECURRENCES. 
12.4 CONTRALATERAL BREAST CANCER will also be recorded and reported 
as invasive and noninvasive. 
13.0
STATISTICAL AND DATA MANAGEMENT CONSIDERATIONS
Study Design: This study is a prospective randomized controlled trial to test the hypothesis 
that 8 Gy x 3 fractions is not worse that 6 Gy X 5 fractions, with respect to the development 
of breast fibrosis.
The current 6X5 schedule results in 1% 5 year recurrence rate and 10% of grade 2 or 3 
fibrosis and approximately 32% of any induration or retraction, measured at after a 
minimum of 6 months from treatment. In other words approximately one out of 10 patients 
experience grade 2-3 fibrosis after lumpectomy and partial breast radiation. 

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Based on our prior experience, we observed a 10% rate of grade 2-3 fibrosis in these 
patients. With 142 patients randomized to each of the two treatment arms,  we can test the 
hypothesis that the rate of fibrosis with 8Gy x3 is not more than 10% worse than the 
expected rate on the 6 Gy x 5 arm with one sided alpha =0.025 and power =80% . 
The trial will have a planned interim analysis when 142 patients across both arms are 
evaluable for fibrosis assessment at 2 years from accrual. Table 7 below provides the 
stopping boundaries for the interim and final analyses. The trial will not stop while 
waiting for the results from the interim analysis.
All analyses may be stratified by whether a ppatient started treatment within 60 days from 
surgery or within 90 days from surgery. 
Table 7 Stopping Boundaries for Non-inferiority with Respect to Proportion of Patients with 
Fibrosis Treated with 8Gy x3 Compared with Control of 6GY x5 Overall 1-sided alpha = 0.025, 
power =80%, O’Brien-Fleming Boundaries Calculations from EAST V 6.2, Cytel Inc.
To Reject Ho of Non-inferiority
Analysis
Number of 
Patients 
Randomized and 
Evaluable for 
Fibrosis
Critical Value 
of z-statistic
Alpha level 
Difference in 
Proportion of 
Patients with 
Fibrosis (8Gy 
x3 -6Gyx5 )
Interim 
142
≤-2.96
≤0.0015
≤-0.0493
Final
284
≤-1.97
≤0.0245
≤0.0299
Data management will be carried out by staff of the Department of Radiation Oncology 
and the NYUCI under the direction of Drs. Perez and Goldberg. Randomization will occur 
via REDCap (Research Electronic Data Capture),  after consent is acquired, by the PI, 
research nurse, in the department of Radiation oncology. Data will be entered into Velos, 
a database management system maintained by the NYULMC PCC CTO according to the 
procedures of the NYULMC PCC CTO. Patients will be followed every 12 months to 
evaluate their status with respect to recurrence. Recurrences will be evaluated using 
standard criteria in the Dept. of Radiation Oncology that are provided in the protocol. Data 
will be transferred from the Velos database to the Division of Biostatistics for analysis. The 
Principal Investigator, Research Nurse, and Research Coordinators have access to data 
collected. 
Analysis: Patient characteristics at randomization will be summarized by treatment group 
using descriptive statistics and graphical displays. For the primary endpoint of fibrosis, the 
proportions of patients by grade of fibrosis will be compared in the two treatment arms 
using contingency table methods and chi square tests. The primary analysis will be the 
difference in proportions of patients with grade 2 or 3 fibrosis between the two treatment 
groups compared using a non inferiority z- test.  Secondary endpoints including rates of 
recurrence at 1, 2, and 3 years post randomization will be estimated with 95% confidence 
limits within treatment groups along with plots of Kaplan-Meier time to recurrence curves.  
. 

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14.0
ADVERSE EVENT REPORTING  AND DSMC
Adverse events (AEs) will be recorded in the case report form for the duration of the trial, regardless 
of whether or not the event(s) are considered related to the trial. All AEs considered related to trial 
medication will be followed until resolution even if this occurs post-trial. 
Definitions of adverse events 
Adverse event (AE) 
Any untoward medical occurrence in a clinical investigation patient administered a pharmaceutical 
product that does not necessarily have a causal relationship with this treatment. An adverse event 
(AE) can, therefore, be any unfavorable and unintended sign (including an abnormal finding), 
symptom, or disease temporally associated with the use of an investigational product, whether or 
not related to the investigational product. 
Serious adverse event (SAE) 
An adverse event occurring at any dose that results in any of the following outcomes: 
-death 
-a life-threatening adverse drug experience 
-inpatient hospitalization or prolongation of existing hospitalization excluding those for 
administration, transfusional support, disease staging/re-staging procedures, concomitant 
radiotherapy, thoracentesis/paracentesis, or placement of an indwelling catheter, unless associated 
with other serious events. 
-persistent or significant disability/incapacity, 
or 
-congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious adverse drug experiences when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
Death, regardless of cause, which occurs within 30 days of the last dose of or after 30 days and is 
a result of delayed toxicity due to administration of the , should be reported as a serious adverse 
event. 
Unexpected adverse event 
An adverse event that is not mentioned in the Investigator's Brochure or package insert or the 
specificity or severity of which is not consistent with the Investigator's brochure or package insert. 
Life-threatening 
Any adverse drug experience that places the patient or subject, in the view of the investigator, at 
immediate risk of death from the reaction as it occurred. It does not include a reaction that, had it 
occurred in a more severe form, might have caused death. 
Reporting adverse events 

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Adverse events 
Adverse events will be recorded for the duration of a patient’s participation in the trial. All adverse 
events (except grade 1 and 2 laboratory abnormalities unless a dose treatment modification, delay 
or therapeutic intervention is required), regardless of causal relationship, are to be recorded in the 
case report form and source documentation. Pre-existing conditions at baseline will be recorded. If 
a pre-existing condition does not change, it does not have to be reported on subsequent cycles. 
The investigator must determine the toxicity of adverse events according to the CTC version 2.0 
(Appendix 1) and their causal relationship. 
Serious adverse events 
Adverse events classified as serious require expeditious handling and reporting to comply with 
regulatory requirements. 
All serious adverse events, whether considered to be drug-related or not, require that a Serious 
Adverse Event Report Form be completed within 24 hours of the investigator becoming aware of 
the event. The investigator must immediately report all unexpected serious adverse events to the 
Institutional Review Board in writing. 
SAE contact information for NYULMC PCC Clinical Trials Office;
Please email all SAEs to NYUPCCsafety@nyumc.org, Dr. Carmen Perez, and the NYULMC 
PCC regulatory specialist within 24 hours of learning of the SAE.
Serious adverse events will be reported to: 
Name Carmen Perez, M.D.
Address 160 East 34th Street 
              NY, NY10016 
Phone number: (212) 731-5003 
Fax number: (212) 731-5513
The reportable events noted above will be reported to the IRB using the form: “Reportable Event 
Form” or as a written report of the event (including a description of the event with information 
regarding its fulfillment of the above criteria, follow-up/resolution and need for revision to 
consent form and/or other study documentation).
Copies of each report and documentation of IRB notification and receipt will be kept in the 
Clinical Investigator’s study file.
The Principal Investigator is responsible for reporting all unexpected problems involving risk to 
participants or others to NYU Perlmutter Cancer Center CTO.

Protocol Version 3.3 dated 10/12/2018
Clinical Research Protocol 
Federal regulations require timely reporting by investigators to the NYULMCIRB of 
unanticipated problems posing risks to subjects or others.  The following describes the NYULMC 
IRB reporting requirements, though Investigators at participating sites are responsible for meeting 
the specific requirements of their IRB of record. 
This section also specifies the NYULMC IRB requirements for investigator reporting of 
unanticipated problems posing risk to subjects or others, including adverse events.  The IRB 
requirements reflect the current guidance documents released by the Office of Human Research 
Protections (OHRP), and the Food and Drug Administration (FDA) and are respectively entitled 
“Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or 
Others and Adverse Events” and “Guidance for Clinical Investigators, Sponsors, and IRBs:  
Adverse Event Reporting – improving Human Subject Protection”.
The NYU IRB address is:
NYU School of Medicine IRB
1 Park Avenue, 6th Floor
New York, NY 10016
14.1 
MEDICAL MONITORING  It is the responsibility of the Principal Investigator to 
oversee the safety of the study at these sites.  This safety monitoring will include careful 
assessment and appropriate reporting of adverse events as noted above, as well as the 
construction and implementation of a site data and safety-monitoring plan.  The Data Safety and 
Monitoring Committee (DSMC) will review the study at least annually.  Medical monitoring will 
include a regular assessment of the number and type of serious adverse events.  
14.1.2 DATA AND SAFETY MONITORING PLAN
This study will be monitored by the Data Safety Monitoring Committee (DSMC) of the New 
York University (NYU) Perlmutter Cancer Center (PCC). The DSMC operates based on the 2011 
National Cancer Institute approved Charter.  It is an existing and multidisciplinary committee 
(consisting of clinical investigators/oncologists, biostatisticians, nurses, and research 
administration staff knowledgeable of research methodology and design and in proper conduct of 
clinical trials) that is responsible for monitoring safety, conduct and compliance in accordance 
with protocol data monitoring plans for clinical trials conducted in the NYULMC Perlmutter 
Cancer Center that are not monitored by another institution or agency. The DSMC reports to the 
Director of the NYULMC PCC.  
Per the NYU PCC Institutional Data Safety and Monitoring Plan, this study will be monitored by 
DSMC at least annually (from the date the first patient is enrolled), and at the completion of the 
study prior to study closure. This review includes accrual data, subject demographics and adverse 
events.  The Principal Investigator is required to attend the review of their study. Additional 
reviews can be scheduled based on SAE reports, investigator identified issues, and external 
information, etc. The DSMC will review safety data every 6-8 weeks.
In accordance with HIPAA and associated privacy regulations, a patient’s authorization to use 
personal identifiable health information may be required from each patient before commencement 
of research activities. This authorization document must clearly specify what parties will have 
access to a patient’s personal health information, for what purpose and for what duration.

Protocol Version 3.3 dated 10/12/2018
Clinical Research Protocol 
At the NYU Perlmutter Cancer Center, all investigator-initiated protocols are subject to a 
standardized data and safety monitoring, which includes scientific peer review, IRB review and 
DSMC review as well as internal auditing. 
The review of AEs and trial conduct for this trial occurs at several levels:
(1) Principal Investigator: Adverse events are evaluated monthly by the principal 
investigator in conjunction with the research nurses, data manager and research team. 
(2) DSMC, at least annually
(3) Institutional Review Board (IRB): An annual report to the IRB is submitted by the 
trial PI for continuation of the protocol. It includes a summary of all AEs, total 
enrollment with demographics, protocol violations, and current status of subjects as well 
as available research data.
(4) In addition, the quality assurance unit will monitor this trial every 6-8 weeks, to verify 
adherence to the protocol; the completeness, accuracy and consistency of the data; and 
adherence to ICH Good Clinical Practice guidelines.
14.2
DATA AND SOURCE DOCUMENTATION
Source documentation refers to original records of observations, clinical findings and evaluations 
that are subsequently recorded as data.  Source documentation should be consistent with data 
entered into Velos.  Relevant source documentation to be reviewed by the DSMC throughout the 
study includes:
1.
 Baseline measures to assess eligibility and disease status
2.
 Subject demographics
3.
 Treatment records
4.
  Adverse events
Velos, an electronic database capture system will be created to record the data for this trial.  
Research coordinators will input clinical trial data into the database.  This database is password 
protected and only the PI, assigned research coordinator, and CTO quality assurance specialists 
will have access to the database.  Velos is the primary data collection instrument for the study.  
All data requested in Velos must be reported.  All missing data must be explained.  The quality 
assurance specialists will monitor this trial 6-8 weeks for data entry accuracy.
15.0
STUDY FINANCES
 15.1
RESEARCH CONFLICT OF INTEREST
There are no conflicts of interest to report.

Protocol Version 3.3 dated 10/12/2018
Clinical Research Protocol 
15.2
COST TO SUBJECTS
Each subject or their insurance company will be charged and held responsible for the costs of care 
provided as part of this study. Radiotherapy is a standard treatment for breast cancer and will be 
billed to subjects and their insurance companies.
There will be no monetary compensation for participating in this study.
16.0
REFERENCES
1.
Sarin, R., Partial-breast treatment for early breast cancer: emergence of a new paradigm. 
Nat Clin Pract Oncol, 2005. 2(1): p. 40-7. 
2.
Keisch, M., 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): p. 289-93. 
3.
Prosnitz, L.R. and L.B. Marks, Partial breast irradiation: a cautionary note. Int J Radiat 
Oncol Biol Phys, 2006. 65(2): p. 319-21. 
4.
Ribeiro, G.G., et al., The Christie Hospital breast conservation trial: an update at 8 years 
from inception. Clin Oncol (R Coll Radiol), 1993. 5(5): p. 278-83. 
5.
Formenti, S.C., et al., T1 stage breast cancer: adjuvant hypofractionated conformal 
radiation therapy to tumor bed in selected postmenopausal breast cancer patients--pilot 
feasibility study. Radiology, 2002. 222(1): p. 171-8. 
6.
Vicini, F.A., et al., Ongoing clinical experience utilizing 3D conformal external beam 
radiotherapy to deliver partial-breast irradiation in patients with early-stage breast cancer 
treated with breast-conserving therapy. Int J Radiat Oncol Biol Phys, 2003. 57(5): p. 
1247-53. 
7.
Formenti, S.C., et al., Prone accelerated partial breast irradiation after breast-conserving 
surgery: preliminary clinical results and dose-volume histogram analysis. Int J Radiat 
Oncol Biol Phys, 2004. 60(2): p. 493-504. 
8.
Vicini, F., et al., A phase I/II trial to evaluate three-dimensional conformal radiation 
therapy confined to the region of the lumpectomy cavity for Stage I/II breast carcinoma: 
initial report of feasibility and reproducibility of Radiation Therapy Oncology Group 
(RTOG) Study 0319. Int J Radiat Oncol Biol Phys, 2005. 63(5): p. 1531-7. 
9.
Rosenstein, B.S., S.C. Lymberis, and S.C. Formenti, Biologic comparison of partial 
breast irradiation protocols. Int J Radiat Oncol Biol Phys, 2004. 60(5): p. 1393-404. 
10.
Owen, J.R., et al., Effect of radiotherapy fraction size on tumour control in patients with 
early-stage breast cancer after local tumour excision: long-term results of a randomised 
trial. Lancet Oncol, 2006. 7(6): p. 467-71. 
11.
Formenti, S.C., A.G. Wernicke, and J.K. DeWyngaert, External beam partial-breast 
radiotherapy: crucial differences between NYU 00-23 and RTOG 0319: in regard to 
Vicini et al. (Int J Radiat Oncol Biol Phys 2005;63:1531-1537). Int J Radiat Oncol Biol 
Phys, 2006. 66(2): p. 630; author reply 630-1. 
12.
Taghian, A.G., et al., Initial dosimetric experience using simple three-dimensional 
conformal external-beam accelerated partial-breast irradiation. Int J Radiat Oncol Biol 
Phys, 2006. 64(4): p. 1092-9. 
13.
Kader, CARO Abstract #17. Radiother Oncol, 2004(72:S6). 
14.
White, E.A., et al., Cone Beam Computed Tomography Guidance for Setup of Patients 
Receiving Accelerated Partial Breast Irradiation. International Journal of Radiation 
Oncology*Biology*Physics, 2007. 68(2): p. 547-554. 

Protocol Version 3.3 dated 10/12/2018
Clinical Research Protocol 
15.
Formenti, S.C., et al., Phase I-II Trial of Prone Accelerated Intensity Modulated 
Radiation Therapy to the Breast to Optimally Spare Normal Tissue. J Clin Oncol, 2007. 
25(16): p. 2236-2242. 
16.
Withers, H.R. and H.D. Thames, Dose fractionation and volume effects in normal tissues 
and tumors. Am J Clin Oncol, 1988. 11(3): p. 313-29. 
17.
Withers, H.R., H.D. Thames, Jr., and L.J. Peters, A new isoeffect curve for change in 
dose per fraction. Radiother Oncol, 1983. 1(2): p. 187-91. 
18.
Quarmby S, F.H., Levine E, Barber J, Wylie J, Hajeer AH, West C, Stewart A, Magee B, 
Kumar S., Association of transforming growth factor beta-1 single nucleotide 
polymorphisms with radiation-induced damage to normal tissues in breast cancer 
patients. Int J Rad Oncol Phys, 2003. 79(2): p. 137-43. 
19.
Demaria, S., et al., Ionizing radiation inhibition of distant untreated tumors (abscopal 
effect) is immune mediated. Int J Radiat Oncol Biol Phys, 2004. 58(3): p. 862-70. 
20.
Simon, R., Optimal two-stage designs for phase II clinical trials. Control Clin Trials, 
1989. 10(1): p. 1-10. 

Protocol Version 3.3 dated 10/12/2018
Clinical Research Protocol 
APPENDIX 1
Common Toxicity Criteria: Acute reactions 
0 
-1 
-2 
-3 
-4 
HAND-FOOT 
SKIN 
REACTION 
No 
change 
Skin changes 
or dermatitis 
without pain 
(e.g., 
erythema, 
peeling)
Skin changes 
with pain not 
interfering 
with function 
Skin changes 
with pain 
interfering 
with function 
RADIATION 
DERMITITIS 
No 
change 
Faint 
erythema or 
dry 
desquamatio
n 
Moderate to 
brisk 
erythema or a 
patchy moist 
desquamation
, mostly 
confined to 
skin folds and 
creases; 
moderate 
edema 
Confluent 
moist 
desquamation 
≥1.5 cm 
diameter and 
not confined 
to skin folds; 
pitting edema
Skin necrosis 
or ulceration 
of full 
thickness 
dermis; may 
include 
bleeding not 
induced by 
minor 
trauma or 
abrasion 
PNEUMONITIS 
No 
change 
Radiographic 
changes but 
asymptomatic 
or symptoms 
not requiring 
steroids 
Radiographic 
changes and 
requiring 
steroids or 
diuretics 
Radiographic 
changes and 
requiring 
oxygen 
Radiographi
c changes 
and 
requiring 
assisted 
ventilation 
FATIGUE 
No 
change 
increased 
fatigue over 
baseline, not 
altering 
normal 
activities 
Moderate 
causing 
difficulty in 
performing 
some activities 
Severe 
causing 
difficulty in 
performing 
some activities 
Bedridden or 
disabling 
ALOPECIA 
No 
change 
Mild hair loss 
Pronounced 
hair loss 
ANOREXIA 
No 
change 
Loss of 
appetite 
Oral intake 
decreased
Requires IV 
fluid 
Requires 
feeding tube 
DYSPHAGIA 
No 
change 
can eat 
regular diet 
Eats pureed 
liquids 
Requires IV 
fluid 
Requires 
feeding tube 
GASTRITIS 
No 
change 
Needs 
medication 
Uncontrolled 
by meds 
requires 
hospitalizatio
n or surgery 
Life 
threatening 
bleeding 
needing 
emergent 
surgery
NAUSEA 
No 
change 
able to eat 
Oral intake 
decreased
Requires IV 
fluid 
STOMATIITS 
No 
change 
painless 
ulcers or mild 
soreness 
without 
lesions 
Painful but 
can eat and 
swallow 
Requires IV 
fluid 
Requires 
feeding tube 
or parenteral 
nutrition 

Protocol Version 3.3 dated 10/12/2018
Clinical Research Protocol 
APPENDIX 2 
LENT/SOMA Criteria: Late Reactions