Accelerated Radiation Therapy (ART) To The Breast And Nodal Stations After Neo-Adjuvant Systemic Therapy And Surgery: A Feasibility Study
Phase: PHASE1
Conditions: Breast Cancer
Sponsor: Weill Medical College of Cornell University

Identifiers: NCT 02917421   
Unique Protocol ID: 1602017017 
Brief Title: 
Accelerated Radiation Therapy (ART) To The 
Breast And Nodal Stations After Neo-Adjuvant 
Systemic Therapy And Surgery: A Feasibility 
Study 
 
Version 6.0  
 
Version date: 24MAR2021 
 
IRB approval: 07FEB2024 
 
 
Document History 
 
 
Protocol  
Version Number 
Version Date 
Amendment 6 
6.0 
24MAR2021 
Amendment 5 
5.0 
12JAN2021 
Amendment 4 
4.0 
06.30.2020 
Amendment 3 
3.0 
10.11.2019 
Amendment 2 
2.1 
05.04.2018 
Amendment 1 
2.0 
10.09.2017 
Initial Protocol 
1.0 
07.25.2016 
 

 
ACCELERATED RADIATION THERAPY (ART) TO THE BREAST AND NODAL STATIONS 
AFTER NEO-ADJUVANT SYSTEMIC THERAPY AND SURGERY: A FEASIBILITY STUDY 
 
IRB Protocol #: 1602017017 
Version Date: - 24MAR2021 
Version:  6.0 
 
Principal Investigator: 
 
Silvia C. Formenti, M.D. 
 
  
 
 
 
 
Co-Investigators: 
 
 
 
 
 
 
 
      
 
                                               

Protocol 1602017017 version 6.0 date 24MAR2021 
                                                     
 
                                                                
  
                                                     
 
 
     
 
                                                    
 
 
 
                                                    
 
                                                    
 
 
  
  
  
 
 
  
  
  
 
  
  
  
  
 
 
 
 
 
Nurse Practitioner:  
       
 
 
       
 
  
                                                      
 
                                                      
 
                                                      
 
 
 
 
 
 
 
Statistician: 
                                    
 
 
 
 
                                                    
                                              
                                                             
  
 
                        
                                                                
                                          
 
 
Study Coordinators: 
 
 
 
 
 
 
 
 
 

Protocol 1602017017 version 6.0 date 24MAR2021 
 
 
 
 
 
 
 
 
 
Participating Sites:   
 
1. New York-Presbyterian Weill Cornell Medical College Stich Radiation N-046 525 
East 68th street, New York, NY – 10065 
2. New York-Presbyterian Weill Cornell Medical College, 1283 York Avenue,4th floor, 
David H, Koch Building New York, NY-10065 
3. New York-Presbyterian - Brooklyn Methodist Hospital 506 Sixth Street, Brooklyn, 
NY - 11215 
4. New York Presbyterian - Queens Radiation Oncology 56-45 Main Street, Flushing, 
NY – 11355  
 
 
 
  
 
 

Protocol 1602017017 version 6.0 date 24MAR2021 
 
 
 
Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or institutional 
review boards. The contents of this document shall not be disclosed to others without written 
authorization from WCMC. 
 
 

Protocol 1602017017 version 6.0 date 24MAR2021 
TABLE OF CONTENTS 
Protocol Summary .......................................................................................................... 12 
SCHEMA .......................................................................................................................... 14 
Treatment Schema .......................................................................................................... 15 
STUDY SYNOPSIS .......................................................................................................... 15 
1.0 OBJECTIVES ............................................................................................................. 16 
1.1 Primary Objectives ......................................................................................................... 16 
1.2 Secondary Objectives .................................................................................................... 16 
1.3 Exploratory Objectives ................................................................................................... 16 
2.0 BACKGROUND .......................................................................................................... 16 
2.1 NYU research in hypo-fractionated whole breast radiotherapy ....................................... 16 
2.2 Experience On Accelerated Concomitant Boost Whole Breast: NYU 03-30 and 01-51 ... 16 
2.3 Rationale For Prone Radiotherapy: Nyu 05-181 ............................................................. 18 
2.4 NYU 09-0300: A Prospective Randomized Trial Aimed At Establishing The Optimal Boost 
Schedule .................................................................................................................... 18 
2.5 Prone Breast And Nodal Radiotherapy ........................................................................... 19 
2.6 Benefit Of Post-Operative Radiotherapy In The Adjuvant Setting ................................... 19 
2.7 Post-Operative Radiotherapy After Neo-Adjuvant Chemotherapy .................................. 20 
3.0 Background For Primary Objective ......................................................................... 21 
3.1 Measuring Acute Toxicity ................................................................................................ 21 
4.0 Correlative Studies Background ............................................................................. 21 
4.1 Quality of Life Assessment ............................................................................................. 21 
4.2 Measuring The Late Toxicities Of Breast Radiation ........................................................ 21 
4.3 Genetics Of Radiation-Induced Breast Fibrosis .............................................................. 22 
4.4 Blood Collection For Genomic Studies ............................................................................ 22 
5.0 Patient Eligibility ....................................................................................................... 23 
5.1 
Inclusion Criteria ......................................................................................................... 23 
5.2 
Exclusion Criteria ........................................................................................................ 23 
6.0 Registration Procedures .......................................................................................... 23 
6.1 General Guidelines......................................................................................................... 23 
6.2 Registration Process ...................................................................................................... 24 
6.3 Randomization Process .................................................................................................. 24 
7.0 Treatment Plan .......................................................................................................... 24 
7.1 General Concomitant Medication and Supportive Care Guidelines ................................ 24 
7.2 Duration of Therapy ........................................................................................................ 24 
7.3 Duration of Follow Up ..................................................................................................... 24 
7.4 Alternatives .................................................................................................................... 24 
7.5 Compensation ................................................................................................................ 24 
8.0 Surgery ...................................................................................................................... 25 

Protocol 1602017017 version 6.0 date 24MAR2021 
9.0 Radiotherapy ............................................................................................................. 25 
Radiotherapy schedule for Cohort 1 and Cohort 2 ................................................................ 25 
9.1 Radiotherapy target ........................................................................................................ 25 
9.2 Dose Specification.......................................................................................................... 25 
9.3 Target Delineation .......................................................................................................... 26 
9.4 Normal structure delineation ........................................................................................... 27 
Technical Factors ................................................................................................................. 27 
9.6 
Boost Technique with Image Guidance (IGRT) ........................................................... 28 
9.7 Dosing Delays/Dose Modifications ................................................................................. 28 
10.0 Adverse Events: List And Reporting Requirements ............................................ 29 
10.1 Adverse Events and Potential Risks List ...................................................................... 29 
10.2 Medical Monitor .......................................................................................................... 30 
10.3 DSMB safety Review .................................................................................................. 30 
10.4 Expedited Adverse Event Reporting ........................................................................... 30 
11.0 Correlative/Special Studies .................................................................................... 30 
11.1 Blood collection for TGF-beta 1 polymorphism determination ..................................... 31 
12.0 Storage Of Samples ................................................................................................... 31 
12.1 Research Conflict Of Interest ...................................................................................... 31 
12.3 Cost To Subjects ........................................................................................................ 31 
12.4 Optional Genetic Research ......................................................................................... 31 
12.5 Coding of Samples ....................................................................................................... 32 
13.0 Study Calendar ........................................................................................................ 33 
14.0 Measurement Of Effect ........................................................................................... 33 
14.1 Response Review ........................................................................................................ 33 
15.0 Data Reporting / Regulatory Considerations ........................................................ 34 
15.1 Monitoring plan ............................................................................................................. 34 
15.2 Stopping rules ............................................................................................................... 34 
15.3 Data management ........................................................................................................ 34 
15.4 Confidentiality ............................................................................................................... 35 
16.0 Statistical Considerations ...................................................................................... 35 
16.1 Endpoints ..................................................................................................................... 35 
16.1.2 
Secondary endpoints ............................................................................................ 35 
16.1.3 
Exploratory endpoints ............................................................................................ 35 
16.2 Analysis Populations .................................................................................................... 35 
Statistical Considerations Sample Size and Interim Analysis Plans ....................................... 35 
16.3 Accrual estimates ......................................................................................................... 35 
16.4 Criteria for future studies ............................................................................................... 36 
16.5 Interim analyses ........................................................................................................... 36 
16.6 Statistical Analysis ...................................................................................................... 36 
16.6.2 
Secondary Endpoints ............................................................................................ 36 
16.6.3 
Exploratory Endpoints ........................................................................................... 36 
Appendix 1. – Common Toxicity Criteria ....................................................................... 37 
Appendix 2 - Toxicity Tracking Form ............................................................................ 39 

Protocol 1602017017 version 6.0 date 24MAR2021 
Appendix 3 – Quality Of Life Questionnaires ................................................................ 40 
Appendix 3.1 Quality of Life questionnaire used at baseline ................................................. 40 
Appendix 3.2 Quality of Life questionnaire used for follow-up visits ....................................... 47 
Appendix 3.3 Form for missing Quality of Life information ..................................................... 53 
REFERENCES ................................................................................................................. 54 
 
 
 
 
 
 
 
 

Protocol 1602017017 version 6.0 date 24MAR2021 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ADL 
Activities of daily living 
AE 
Adverse event 
AIMRT 
Accelerated Intensity Modulated Radiation Therapy 
ATM 
Ataxia Telangiectasia Mutated 
BED 
Biologically Effective Dose 
CBC 
Complete blood count 
CI 
Confidence interval 
CBCT 
Cone-Beam CT 
CRF 
Case report/Record form 
CR 
3D-CRT 
Complete response 
3 Dimensional Conformal Radiotherapy 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTV 
Clinical target volume 
DCIS 
Ductal Carcinoma In Situ 
DHPLC 
Denaturing High Performance Liquid 
Chromatography 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
FBD 
Friday Boost Dose 
GI 
Gastrointestinal 
Gy 
Gray 
Hgb 
Hemoglobin 
IBV 
Ipsilateral Breast Volume 
IGRT 
Image Guided RadioTherapy 
IMRT 
Intensity Modulated RadioTherapy 
IRB 
Institutional Review Board 
LENT/SOMA 
Late Effects Normal Tissues / Subjective, 
Objective, Management criteria with Analytic 
laboratory and imaging procedures 
LLN 
Lower limit of normal 
OS 
Overall survival 
PCR 
Polymerase Chain Reaction 
PCR-RFLP 
Polymerase Chain Reaction-Restriction Fragment 
Length Polymorphism 
PD 
Progressive Disease 
PFS 
Progression free survival 
PLT 
Platelet 
PR 
Partial response 
PTT 
Protein Truncation Test 
PTV 
Planning Target Volume 
RBV 
Residual Breast Volume 
RECIST 
Response evaluation criteria in solid tumors 
RR 
Response rate 
RTOG 
                 Radiation Therapy Oncology Group 
SAE 
                 Serious adverse event 

Protocol 1602017017 version 6.0 date 24MAR2021 
SD 
Stable disease 
TGF-beta1 
Transforming Growth Factor beta-1 
TV 
Treatment Volume 
WBD 
Weekend Boost Dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 1602017017 version 6.0 date 24MAR2021 
Protocol  
Version Number 
Version Date 
Amendment 6 
6.0 
24MAR2021 
Amendment 5 
5.0 
12JAN2021 
Amendment 4 
4.0 
06.30.2020 
Amendment 3 
3.0 
10.11.2019 
Amendment 2 
2.1 
05.04.2018 
Amendment 1 
2.0 
10.09.2017 
Initial Protocol 
1.0 
07.25.2016 
 
 
Summary of changes: Version 6.0 dated 24MAR2021 
 
Section(s) 
Changes 
Rationale 
Inclusion Criteria 5.1 
Criteria 5.1.5 : Expanding inclusion to allow patients with 
a focally positive margin. 
Expanding 
inclusion criteria. 
Changes to the Informed consent document  
Footer changes 
Updating the footer to match the protocol version 
date. Updated consent version date 24MAR2021. 
Admin changes 
only. 
 
 
Summary of changes: Version 5.0 dated 12JAN2021 
 
Section(s) 
Changes 
Rationale 
Adding Network sites 
Adding NYP-BMH, NYP-Q as addition sites for patient 
enrollments 
Adding sites. 
Personnel section 
Adding Jessica Richman (admin amendment approved 
10/19/2020) 
Adding Co investigators:  
Dr. Andrew Brandmaier, Dr. Hani Ashamalla, Dr. Steven 
DiBiase and Dr. Akkamma Ravi  
 
Removing : Sally Sa  
Personnel changes 
Informed consent document changes 
Adding network sites  
Adding NYP-BMH, NYP-Q as addition sites for patient 
enrollments 
Adding sites 
 
 
Summary of changes: Version 4.0 dated 06.30.2020  
 
Adding to the eligibility criteria:  
 
1. To include patients who because of COVID had undergone up to 3 months neoadjuvant 
hormonal therapy before surgery for clinical T1/T2 BC  
2. Video visits will be included as part of patient follow up.  
3. Removing Viji Nagaraj from the study as she is no longer working in WCM Radiation 
Oncology.  
 

Protocol 1602017017 version 6.0 date 24MAR2021 
Rationale for the changes: NCI wants to assure most patients who had modifications 
during COVID are still eligible to clinical trials. 
 
 
 
Summary of changes: Version 3.0 dated 10.11.2019 
 
1. Adding Dr. Encouse Golden to the study.  
2. Formatting the protocol as the index is not correctly formatted.  
3. Making the protocol version date consistent on the header text.  
 
No Changes to the informed consent.  
 
Summary of changes: Version 2.1 dated 05.04.2018 
 
1. Making the investigators’ list consistent with eIRB. 
2. Changing study coordinator to Pragya Yadav 
 
Exclusion Criteria Section 5.2:  
 
1. Adding: Patients with more than 5 nodes involved at axillary dissection will be excluded 
from this study since they will be eligible to receive radiotherapy to level I and II axilla. 
 
This was already written in the body of the protocol (section (9.0 Radiotherapy) but was not 
included in the exclusion Criteria section 5.2.  
 
 
 
Summary of Changes: Version 2.0 Dated 10.09.2017.  
 
 
1. Title Change :  Accelerated Radiation Therapy (Art) To The Breast And Nodal Stations After 
Neo-Adjuvant Systemic Therapy And Surgery: A Feasibility Study 
 
➢ Rationale  for title change :  To include neoadjuvant hormone therapy 
 
2. Cohort 2 to include:  If clinically indicated, internal mammary nodes will also be treated and 
a supine set up will be used 
 
➢ Rationale - To follow the most recent NCCN indications to irradiate internal 
mammary nodes for inner quadrants and central cancers, particularly if axillary 
nodes are also involved 

Protocol 1602017017 version 6.0 date 24MAR2021 
 
12 
 
PROTOCOL SUMMARY 
 
Full Title: 
ACCELERATED RADIATION THERAPY (ART) TO THE BREAST AND 
NODAL STATIONS AFTER NEO-ADJUVANT SYSTEMIC THERAPY 
AND SURGERY: A FEASIBILITY STUDY 
 
Short Title: 
                       ART Protocol   
 
Clinical Phase: 
 
Phase I-II 
 
Principal Investigator: 
Dr. Silvia. C. Formenti 
 
Sample Size: 
 
N= 74 (37 per Arm) 
 
Accrual Ceiling: 
 
100 
 
Rate of subject accrual:        Approximately 3 subjects per month or 36 patients per year 
 
Study Population: 
 
Newly diagnosed breast cancer patients with an indication for 
post-operative radiotherapy after neo-adjuvant chemotherapy and 
surgery 
 
Accrual Period: 
 
2-3 years 
 
Study Design: 
 
Prospective two cohorts study in newly diagnosed breast cancer 
patients. Cohort 1 patients will receive Radiation to breast and chest wall. 
Cohort 2 patients will receive Radiation to Breast, chest wall and Level 
III/SCV nodes.  
 
Study Duration: 
 
Patients will complete treatment in three weeks (15 fractions). All patients 
will be followed at 3 months after the completion of treatment then yearly 
for the next 5 years. 
Study Agent/  
Intervention Description: Cohort 1 (Post-segmental Mastectomy, post-mastectomy and Post-
mastectomy with expanders or final reconstruction): 
Prone whole breast or chest wall 3D-CRT or IMRT at 2.7 Gy X 15 fractions 
(40.50 Gy) with a concomitant boost of 0.50 Gy (7.5 Gy) to the original 
tumor bed in post-segmental mastectomy patients or mastectomy scar in 
post-mastectomy patients. Patients who have undergone reconstruction 
will not receive concomitant boost. 
 
 
Cohort 2:  In addition to receiving radiation to the original tumor bed, 
patients will also receive radiation to Level III axillary nodes and 
Supraclavicular nodes: 3D-CRT or IMRT at 2.7 Gy X 15 fraction (40.50 
Gy) If clinically indicated, internal mammary nodes will also be treated 
and a supine set up will be used 
 

Protocol 1602017017 version 6.0 date 24MAR2021 
 
13 
 
Primary Objective:  
Acute Toxicity: Grade 2-3 dermatitis <25% in each cohort 
 
 
Secondary Objective:        QOL, defined by RTOG-PRO; Late toxicity, Fibrosis, Telangiectasia, Brachial  
                                              Plexopathy.  
 
Exploratory Objectives:     Local control; Time to Progression, Survival; Evaluation of                                 
                                                Determinants of Breast Fibrosis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 1602017017 version 6.0 date 24MAR2021 
 
14 
 
 
SCHEMA 
 
 
 
Stage I-III Breast Cancer Patients, Eligible For Post-Surgical Radiotherapy After Neo-adjuvant 
Chemotherapy And/Or Hormonal Therapy Followed By Segmental Mastectomy Or Mastectomy 
 
 
 
             INFORMED CONSENT  
and assignment to clinically indicated cohort 
 
Cohort 1                                        Cohort 2 
RT target: Breast/chest wall*  
RT target: Breast/chest wall 
+Level III/SCV nodes* 
 
* Radiation fields and doses: 
 
Cohort 1 
a) Post segmental mastectomy:  Prone whole breast 3D-CRT or IMRT at 2.7 Gy X 15 
fractions (40.50 Gy) with a concomitant boost of 0.50 Gy (7.5 Gy) to the tumor bed. 
b) Post-mastectomy: Prone whole breast 3D-CRT or IMRT at 2.7 Gy X 15 fractions (40.50 
Gy) with a concomitant boost of 0.50 Gy (7.5 Gy) to the mastectomy scar on the chest 
wall. 
c) Post-mastectomy with expanders or final reconstruction: Prone whole breast 3D-CRT 
or IMRT at 2.7 Gy X 15 fractions (40.50 Gy). 
 
Cohort 2 
Either a, b, c + 
d) Level III axillary nodes and Supraclavicular nodes: 3D-CRT or IMRT at 2.7 Gy X 15    
fractions (40.50 Gy) -If clinically indicated, internal mammary nodes will also be treated 
and a supine set up will be used. 
 
 
 
 
All patients will be followed for toxicity and outcome (local and systemic recurrence, survival) In 
addition, patients will complete a self-assessment of QOL at baseline, completion of radiation 
treatment, at 45-60 day follow-up and at 2 year follow-up. 

Protocol 1602017017 version 6.0 date 24MAR2021 
 
15 
 
 
TREATMENT SCHEMA 
 
 
Within a month 
from initiation  
Week 1 
Week 2 
Week 3 
Months 3 
Months 12-24-36-48-
60 
simulation 
RT 
RT 
RT 
Follow up 
Follow up 
Patient education  - 
baseline QOL 
Blood sample 
 
 
QOL 
assessment 
Blood sample 
QOL 
assessment 
QOL assessment 
 
 
 
 
 
 
STUDY SYNOPSIS 
 
Patients undergoing primary systemic therapy, followed by surgery often receive post-operative 
radiation. While the targets treated post-operatively vary and depend on the initial and post-surgical 
stage, patients generally undergo 6-7 weeks of daily (Monday to Friday) post-operative radiation. 
This approach is long and draining, particular in this population of breast cancer patients who often 
experience chemotherapy-induced fatigue. Our group has developed and tested a combined 
positioning and hypo-fractionated regimen of post-operative radiotherapy that may be particularly 
convenient and indicated for these women. 
Specifically a prone set-up has enabled safe sparing of heart and lung while targeting the breast and, 
more recently, level III and supraclavicular nodes. 
While we have extensively tested this approach in the classical adjuvant setting of breast cancer, 
until now we have not tested it after neo-adjuvant chemotherapy. 
We are proposing a prospective study to test feasibility of prone breast and nodal radiotherapy in 
women who have undergone surgery after preoperative systemic therapy. Primary study endpoint 
will be acute toxicity and secondary will be late effects (with focus on radiation fibrosis) and patient’s 
assessment of QOL with this approach.  Exploratory endpoints will be 5y local control and survival. 

Protocol 1602017017 version 6.0 date 24MAR2021 
 
16 
 
 
 
1.0 OBJECTIVES 
 
1.1 Primary Objectives 
1.1.1. 
To test feasibility of accelerated radiotherapy in the post-operative setting of 
breast cancer patients treated by neo-adjuvant chemotherapy and 
surgery, by evaluating the proportion of patients who experience grade II-III 
dermatitis within 60 days of the end of treatment. 
 
1.2 Secondary Objectives 
1.1.2. 
To assess QOL of patients at baseline and after the course of treatment. 
1.1.3. 
To assess incidence of late radiation toxicity (brachial plexopathy, fibrosis and 
telangiectasia) and to examine genetic determinants of breast fibrosis 
 
1.3 Exploratory Objectives 
1.1.4. 
To assess local control rates, distant recurrence and overall survival of at 2, 5 and 
10 years follow up. 
1.1.5. 
To prospectively validate the data on molecular signature of f i b r o s i s .  
 
2.0 BACKGROUND 
 
2.1 NYU research in hypo-fractionated whole breast radiotherapy 
A recent Cochrane Collaboration Intervention Review has addressed the effects of altered 
fractionation size on women with early breast cancer who have undergone breast conservation 
surgery. [1] Four prospective randomized trials that included 7095 women, selected based on tumor 
size less than five cm, negative pathological margin of excision and negative lymph nodes were 
analyzed. No difference in clinical outcome was observed when comparing traditional 6 
weeks to shorter 3 weeks treatment courses. The conclusion of the review is that the use of 
unconventional fractionation regimens (> 2 Gy per fraction) does not affect breast appearance or late 
toxicity and does not adversely impact local recurrence or five-year survival rates. 
Hypo-fractionation regimens enable shortening of the duration of therapy; the findings are quite 
relevant, since changing the standard recommendation of 30 fractions over six weeks to a 3-week 
regimen could result in higher compliance and cost saving. 
During the past 12 years we have conducted a series of consecutive studies to optimize the safe 
delivery of accelerated radiotherapy to partial and whole breast. A review of whole breast radiation 
research conducted so far is detailed below, as a background for the current study that targets 
Stage I-III breast cancer patients after neoadjuvant chemotherapy and segmental 
mastectomy or mastectomy. 
 
2.2 Experience On Accelerated Concomitant Boost Whole Breast: NYU 03-30 and 01-51 
NYU 03-30. Inspired by the hypo-fractionated Canadian trial, [2] we developed a technique 

 Protocol 1602017017 version 6.0 date 24MAR2021 
 
17 
 
that utilizes IMRT to deliver accelerated prone whole breast radiotherapy with a concomitant 
boost to the tumor bed. Patients with stage I or II breast cancer, excised by breast conserving 
surgery with negative margins, and either sentinel node biopsy or axillary dissection were 
eligible for this IRB-approved protocol. All patients underwent an informed consent procedure. 
CT simulation was performed with the patient on a dedicated prone breast board, in the exact 
position used for treatment. Relevant volumes contoured included the post-operative tumor bed 
(CTV), the ipsilateral breast volume (IBV), the heart, and the lungs. The Planning Target 
Volume (PTV) was defined as CTV + 1 cm. The residual breast volume (RBV) was defined as 
the IBV - PTV. A dose of 40.5 Gy in 15 fractions was prescribed to the IBV. An additional 0.5 
Gy was delivered concomitantly to the PTV for a total dose of 48 Gy. The dose was determined 
by radiobiological modeling of the Biologically Effective Dose (BED), to match tumor control and 
risk of late effects of a standard schedule of 46 Gy to the whole breast plus a sequential 
boost dose of 14 Gy to the tumor bed. A value for tumor α/β = 4 was used and the impact of cell 
proliferation during the course of treatment was taken into account. For each patient accrued to 
the study, blood was collected for radiation genomic studies, to explore markers predictive of late 
breast complications (fibrosis, retraction, and telangiectasia). 
From September 2003 to August 2004, the planned accrual was completed, with 90 patients 
treated in the protocol (mean follow-up of 13 months, range 1-23 months). Median age was 58 
(range 28-80). Median tumor size was 13 mm (range 1-40 mm). Acute toxicity was generally 
mild and is summarized in Table 1 using the RTOG score. Radiation dermatitis was the most 
common toxicity and tended to occur the week after completion of treatment. 
 
Table 1. Acute Toxicity NYU 03-30 
 
Grade 1 
Grade2 
Grade 3 
Grade 4 
Dermatitis 
38 (42%) 
9 (10%) 
2 (2%) 
- 
Fatigue 
15 (17%) - 
- 
- 
Breast edema 
7 (8%) 
- 
- 
- 
Breast pain 
4 (4%) 
- 
- 
- 
 
Because of blood collection, the study also started an annotated repository to enable 
exploration of the association between specific genomic profiles and the occurrence of fibrosis, 
once there has been sufficient follow up to assess late effects. [3] In addition, this trial has 
generated an invaluable repository of physics information from the planning and volume 
inclusion by the technique adopted, offering the opportunity for an in-depth investigation of 
the effect of laterality when patients are treated prone.  This information is relevant in terms of 
optimization of normal tissue sparing, particularly the heart and lung, both organs susceptible to risk of 
fatal late effects of radiation [4]. 
 
01-51: Accelerated Radiotherapy for DCIS 
This protocol aimed at testing the use of accelerated whole breast radiotherapy in women 
with ductal carcinoma in situ. Eligible patients were women with DCIS who refused conventional 
5-week radiotherapy. The trial consisted of 15 daily fractions of 2.8 Gy, over three weeks, to a 
total dose of 42 Gy. While the protocol did not require prone positioning it did not exclude this 
technique either. In some instances, women who were initially simulated supine were re-simulated 
in the prone position due t o  the large extent of lung and heart in the field. They were often (but 
not always) found to have better normal tissue sparing when prone and were then treated in 

 Protocol 1602017017 version 6.0 date 24MAR2021 
 
18 
 
that position. [5] 
 
 
2.3 Rationale For Prone Radiotherapy: Nyu 05-181 
Despite the demonstrated feasibility and advantages of a prone set up, in our experience of 
more than 3,000 cases, occasional patients appear to be better treated supine, in order  to 
optimally spare heart and lung. Since no obvious clinical characteristics predict for this exception, 
we led an organized prospective effort of comparing supine versus prone breast setup in a 
consecutive cohort of 200 right and 200 left breast cancer patients. Again, intensity modulated 
radiotherapy with an accelerated, daily concomitant boost approach was used, the same 
regimen originally pilot-tested for prone IMRT. NYU Protocol #05-181, “Accelerated Intensity 
Modulated Radiation Therapy (AIMRT) to the Breast after Segmental Mastectomy: Identification 
of Optimal Individual Positioning” was opened in 2005 to pre- and post-menopausal women with 
stage 0-IIB breast cancer who had received breast conserving surgery. Patient eligibility 
criteria included the requirement of at least 1mm of margin, no more than 3 positive lymph 
nodes for breast cancer, at least two weeks post chemotherapy (if indicated), with no history 
of prior or concurrent malignancy (within 3 years), and with no history of active connective 
tissue disorders. Patients underwent CT simulation in the prone and supine positions. Treatment 
followed in the optimal position defined as that which assured the smallest volume of heart and 
lung in the target field. 
Among right breast cancer patients, the prone position was optimal in sparing lung volume in 
all women, reducing the in-field lung volume by a mean 104.6cc (95%CI: 94.01 – 115.16) 
compared to supine set-up. For left breast cancer patients, the prone position was optimal in 
85%, with in-field heart volume reduced by a mean of 9.9cc (95%CI: 7.37 – 12.45) and in-field 
lung volume reduced by a mean of 95.2cc (95%CI: 84.27 – 106.13). In the 30 left breast patients 
best treated supine, the in-field heart volume was reduced by a mean of 6.2cc (95%CI: 2.97 – 
9.33). Only 32% of the women with breast volume <750 cc were better treated supine. Prone 
set-up reduced the amount of lung volume irradiated in all patients and reduced the amount of 
heart volume irradiated in 85% of left breast cancer patients. Prone positioning was also superior 
to supine treatment for the majority of small-breasted women, contrary to the common opinion 
that it should be reserved for large breast size patients (6). 
Based on the experience gathered from NYU Protocol 05-181, it is rational for all patients to 
first undergo a CT Simulation in the prone position. In this protocol, we will again use 2.5 mm slice 
thickness with the patient positioned on a dedicated breast mattress that allows the index breast 
to freely fall through an opening. If it is found that conventional tangents in the prone position 
include any volume of heart and/or > 5% of lung volume, a second simulation will be required 
in supine position to assess which position best minimizes the amount of heart and lung in the 
treatment fields to be chosen for treatment. 
 
2.4 NYU 09-0300: A Prospective Randomized Trial Aimed At Establishing The Optimal 
Boost Schedule 
Radiobiological evidence supported the introduction of a larger fraction dose before a two-
day treatment break (weekend). We studied two different boost schemas in a randomized trial 
of 400 patients. The standard arm was a concomitant boost protocol over three weeks which 
had previously been evaluated in over 500 patients (NYU 03-30 and NYU 05-16 of 60

 Protocol 1602017017 version 6.0 date 24MAR2021 
 
19 
 
181) and had shown excellent tolerance, and results. In addition to the 2.7 Gy whole breast 
dose, an additional 2 Gy was delivered to the tumor bed on each of the three Fridays, with the tumor 
bed receiving 4.7 Gy on each of the three Fridays.  
At a median follow-up of 45 months, there were no deaths related to breast cancer. The weekly 
boost regimen produced no more grade ≥ 2 acute toxicity than the daily boost regimen (8.1% vs 
10.4%; non-inferiority Z = -2.52; p = 0.006). There was no statistical difference in cumulative 
incidences of long term fibrosis or telangiectasia grade ≥2 between the two arms (log-rank p=0.923). 
There were 2 local and 2 distant recurrences in the daily boost arm.  There were 3 local and 1 distant 
recurrences in the weekly arm, with no difference in 4-year RFS between the two arms (98% in both 
arms). In addition, extensive QOL assessment between the 2 arms demonstrated comparable 
results with regard to the patient’s experience during and after radiotherapy.  In conclusion, the trial 
demonstrated that a tumor bed boost delivered either daily or weekly is similarly tolerated during 
accelerated prone breast radiotherapy, with excellent control of disease and comparable cosmetic 
results (7). 
 
2.5 Prone Breast And Nodal Radiotherapy 
 
The results of NYU- 09– 0623, a prospective trial of prone breast radiotherapy with inclusion of level 
III axillary and supraclavicular nodes was recently reported (8). Eligibility required surgical dissection 
of ≥ 8 axillary lymph nodes and negative surgical margins of ≥ 1 mm at the primary site. An interval 
of 60 days from surgery was allowed. RT started ≥ 2 weeks and <60 days following completion of 
chemotherapy. Exclusion criteria included pregnancy, prior ipsilateral breast RT, or >5 involved 
nodes at dissection. Following either segmental or total mastectomy with axillary node dissection, 
patients were treated to a dose of 40.5 Gy/15 fractions with a concomitant daily boost to the tumor 
bed of 0.5 Gy (total dose, 48 Gy). In post-mastectomy patients, the same treatment was prescribed, 
but without a tumor bed boost. The primary endpoint was incidence of grade 2 acute skin toxicity. 
The secondary endpoints were feasibility of treatment using prone set-up, compliance with protocol-
defined dosimetric constraints, and incidence of late toxicity.  
Sixty nine patients accrued to the study (one with bilateral breast cancer), for a total of 70 prone 
treatments of breast/chest wall, level III and supraclavicular nodes: 54/70 breast cancers were 
staged as N1 and 16 as N2. Fifty-five of the 69 patients (79%) underwent adjuvant chemotherapy, 
usually after radiotherapy was completed. 
The results of this trial are encouraging, since no patients experienced grade >2 acute skin toxicity 
according to the Common Terminology Criteria for Adverse Events, version 3.0, meeting the primary 
endpoint.  At a median follow up of 36 months, no ipsilateral breast local recurrence, regional nodal 
recurrence, or contralateral breast cancer have developed. Three patients have developed distant 
failures, 1 after 9 months and 2 after 18 months post-treatment. Currently, there have been 4 deaths, 
2 from breast cancer, resulting in a 3-year breast cancer–specific survival of 95.6%. 
The results of this trial warrant testing of the same approach after neo-adjuvant chemotherapy and 
surgery, the scope of this protocol. 
 
2.6 Benefit Of Post-Operative Radiotherapy In The Adjuvant Setting 
  
Several consecutive meta-analyses have demonstrated the additional benefits of post-
operative/adjuvant radiotherapy distinct from those of systemic therapy (9) in both the breast 
conservation and post-mastectomy settings (10,11,12). Noticeably, for node positive patients, 
adding radiotherapy confers a statistically significant survival advantage that is comparable to that 
derived from the addition of anthracycline-based chemotherapy (figure 1). The data from the meta-
analyses have changed the practice of oncology by establishing a central role for post-operative  
 

 Protocol 1602017017 version 6.0 date 24MAR2021 
 
20 
 
breast cancer radiotherapy. 
 
 
Figure 1 (from references 9-12) 
 
 
 
2.7 Post-Operative Radiotherapy After Neo-Adjuvant Chemotherapy  
 
Neo-adjuvant/preoperative chemotherapy is usually reserved for high-risk breast cancer patients, 
whether because of locally advanced stage, an inflammatory breast cancer diagnosis or aggressive 
tumor biology. In such settings neo-adjuvant chemotherapy is considered standard care. 
Alternatively, a preoperative investigational approach can be tried as part of a “window of 
opportunity” clinical protocol, testing the effect of a novel targeted therapy. The latter choice is 
commonly offered in the setting of biologically more aggressive breast cancers, like triple negative 
breast cancer, tumors overexpressing HER2 positivity or in oestrogen receptor-positive tumors with 
clinically positive nodes. The majority of patients given preoperative chemotherapy subsequently 
undergo a mastectomy (13). Generally these patients are offered the choice of breast reconstruction 
and most North American patients elect to undergo reconstructive surgery. However, nowadays 
approximately a third of patients treated with preoperative systemic therapy undergo breast 
conservation surgery (BCS).  
 
Based on the evidence for a benefit in the adjuvant setting, radiotherapy is often offered to women 
treated neo-adjuvantly, after surgery. Traditionally, women are treated with a supine set up that 
includes the breast (or chest wall / reconstructed breast) and draining nodes, over 6-7 weeks of 
daily visits (Monday-Friday). 
 
Recently, the concept that the pathological response to neoadjuvant chemotherapy might be used 
to exclude patients from postoperative RT or to at least reduce the fields of radiotherapy has 
emerged. NSABP B-51/RTOG 1304 is an Intergroup clinical trial currently exploring the effects of 
excluding post-operative radiation or reducing the radiotherapy fields among patients who present 
with involved axillary nodes (documented by fine needle aspiration or core needle biopsy) and are 
found to have a negative sentinel node or axillary dissection after chemotherapy. The trial 

 Protocol 1602017017 version 6.0 date 24MAR2021 
 
21 
 
randomizes patients treated with preoperative chemotherapy and mastectomy to receive or not 
receive post-mastectomy chest wall and regional nodal RT. Those who have been treated with 
segmental mastectomy are randomized to receive post-segmental mastectomy radiation to the 
breast alone versus breast and regional nodal RT. 
 
 In conclusion, at this time, most breast cancer patients who have undergone neo-adjuvant 
radiotherapy are offered post-operative radiotherapy with standard dose and fractionation resulting 
in a course duration of approximately 6-7 weeks. We propose testing the feasibility of 
accelerated radiotherapy after neo-adjuvant systemic therapy and surgery. We will utilize the 
same 3 weeks accelerated regimen used to treat the breast and draining nodes in the prone 
position that we have extensively tested in the adjuvant setting of breast cancer (6, 8)  
 
3.0 Background For Primary Objective 
 
3.1 Measuring Acute Toxicity 
The Cancer Therapy Evaluation Program (CTEP), National Cancer Institute (NCI) 
Common Toxicity Criteria (CTC) was developed in 1982 for use in adverse drug experience 
reporting, study AE summaries, Investigational New Drug (IND) reports to the Food and 
Drug Administration (FDA), and publications. The CTCAE v4.0 is the first uniform and 
comprehensive dictionary of AE grading criteria available for use by all modalities used in 
the treatment of cancer. A grading (severity) scale is provided for each AE term. 
The terms considered in this trial are specific to radiation toxicity and include fatigue, 
radiation dermatitis and brachial plexopathy. This information will be collected by the treating 
physician using a specific tracking form (see appendix 3). Acute Toxicity will be scored 
using the CTCAE v4.0 (see Appendix 1). 
 
4.0 Correlative Studies Background 
 
4.1 Quality of Life Assessment 
Patients’ quality of life assessments will be performed at regular intervals (baseline, 
last week of radiation treatment, 45-60 days from starting radiotherapy and 2-year follow- 
up). QOL will be evaluated in several ways. 
First, cosmetic results will be examined using the Breast Cancer Treatment Outcome 
Scale (BCTOS) using patient self-reports. This brief self-report instrument has high reliability 
and validity, and has been used in a variety of previous studies on recovery from breast 
cancer treatment. [14] The BCTOS also will be used as a primary measure to assess breast-
related symptoms and treatment effects. Specifically, the BCTOS will be augmented with a 
brief set of additional items that focus on radiotherapy-relevant symptoms (e.g., reports 
of skin problems, tenderness/pain in the breast, and hardness in the breast due to enhanced 
fibrosis). Second, we will use the MOS SF-36 Vitality Scale, a widely used measure with 
high reliability and validity, will assess fatigue. [15-16] 
 
4.2 Measuring The Late Toxicities Of Breast Radiation 
 
Radiation-induced breast fibrosis is another important late effect of radiotherapy with 
a commonly reported incidence of 5-15% [17-18]. Manifestations of radiation-induced breast 
fibrosis include pain, cosmetic deformities, and diminished quality of life. Clinically, radiation-
induced breast fibrosis is characterized by skin retraction, atrophy, toughness to palpation, 
and decreased tissue compliance with associated functional limitations. Visual assessment 
and palpation are the most important clinical investigations of the skin in radiotherapy but they 

 Protocol 1602017017 version 6.0 date 24MAR2021 
 
22 
 
are subjective and unquantitative. 
Hoeller et al. recently reported a careful comparison of The Radiation Therapy 
Oncology Group (RTOG) and Late Effects Normal Tissue Task Force subjective, objective, 
management, and analytic (LENT/SOMA) scores for late breast toxicity after radiation in a 
group of breast cancer patients. [19] In comparison, when LENT/SOMA criteria were used, 
telangiectasia and pigmentation were upgraded in 34% and 36%, respectively, and 
telangiectasia was downgraded in 45%. Inter-observer variability was similar for both 
classification systems and ranged from Cohen's kappa 0.3 (retraction) to 0.91 
(telangiectasia). The authors concluded that LENT/SOMA criteria seem to be the better in 
grading and recording late radiation toxicity compared with the RTOG scale. Specifically, 
fibrosis scores correlated well with the LENT/SOMA scoring system (Spearman's rho 0.78, 
p = 0.01). 
Brachial plexopathy is a potential toxicity associated with nodal irradiation. This side 
effect can significantly impair arm/shoulder function and worsen quality of life due to pain and 
paresthesia. Early trials of hypofractionated nodal irradiation conducted in Australia and 
Sweden in the 1960s revealed a 73% and 63% rate of neuropathy, respectively. However, the 
Australian regimen consisted of 63 Gy delivered in 12 fractions while the Swedish trial used 
44 Gy in 11 fractions. Decades of experience have improved our understanding of the 
relationships between the volume of a critical structure treated, dose, fractionation and 
subsequent brachial plexus injury. We will also report this adverse effect using the 
LENT/SOMA scoring system. 
 
4.3 Genetics Of Radiation-Induced Breast Fibrosis 
 
Since the most likely long-term toxicity of accelerated radiation is soft tissue fibrosis 
and skin telangiectasia the preliminary recognition of genetic predispositions to these 
complications enables the exclusion of high-risk carriers from the trials of accelerated/hypo- 
fractionated radiation. In other words, similar to the impact of pharmacogenomics in medical 
oncology, the field of radiation-genomics is also rapidly emerging, permitting to identify 
individuals with genetic predisposition to inferior repair of the damage caused by ionizing 
radiation. 
A recent study from Quarmby et al has shed some light on the genetic risk of developing 
breast 
fibrosis 
post-ionizing 
radiation. To 
investigate 
whether 
single 
nucleotide 
polymorphisms (SNP) of transforming growth factor beta-1 (TGF-beta1) were associated 
with the susceptibility of breast cancer patients to severe radiation-induced normal tissue 
damage Quarmby et al performed Polymerase Chain Reaction-Restriction Fragment Length 
Polymorphism- (PCR-RFLP) assays for TGF-beta1 gene polymorphisms on DNA obtained 
from 103 breast cancer patients who received radiotherapy. [21] The G-800A, C–509T, 
T+869C and G+915C polymorphic sites were examined, and genotype and allele frequencies 
of two subgroups of patients were calculated and compared. The investigators found that the 
less prevalent –509T and +869C alleles were significantly associated with a subgroup of 
patients who developed severe radiation-induced normal tissue fibrosis (n=15) when 
compared with those who did not (n=88) (odds ratio=3.4, p=0.0036, and 2.37, p=0.035, 
respectively). Furthermore, patients with the –509TT or +869CC genotypes were between 
seven and 15 times more likely to develop severe fibrosis. These findings imply a role for the 
-509T and +869C alleles in the biological mechanisms underlying susceptibility to radiation- 
induced fibrosis. 
 
4.4 Blood Collection For Genomic Studies 
 

 Protocol 1602017017 version 6.0 date 24MAR2021 
 
23 
 
The purpose of this portion of the study will be to collect blood from each subject 
accrued to the study and willing to donate a specimen of blood for research, to study the – 
509C T and +869T C TGF-β1 polymorphisms that have been reported to be correlated 
with the development of fibrosis following radiotherapy for treatment of breast cancer. [21] 
 
For the purpose of this trial blood will be collected to enable genomic analysis for this 
polymorphism to explore association with the incidence of grade 3 and 4 late complications 
at 3 years follow up. Results of the blood test will be de-identified and will not be part of the 
patient’s care. It will not be included in the medical record, but it will be maintained at the 
research office of the Department of Radiation Oncology at WCMC. When the study 
information is disclosed outside of WCMC as part of the research, the information that can 
identify the patient will be removed and the patient’s records will be assigned a unique 
number. WCMC will not disclose the code key, except as required by law. 
 
 
 
 
5.0 Patient Eligibility 
 
5.1 Inclusion Criteria 
 
5.1.1 Age older than 18 
5.1.2 Pre- or post-menopausal women with Stage I-III breast cancer 
5.1.3 Status post neoadjuvant systemic therapy  
5.1.4 Status post-chemotherapy breast surgery 
5.1.5 Original biopsy-proven invasive breast cancer, excised with negative margins of at least 1 
mm (patients with focally positive margin are not excluded). 
5.1.6 Status post segmental mastectomy or mastectomy, with either negative sentinel node 
biopsy and/or axillary node dissection (at least 6 nodes removed). 
5.1.7 Patient needs to be able to understand and demonstrate willingness to sign a written 
informed consent document 
 
5.2 Exclusion Criteria 
 
5.2.1 Previous radiation therapy to the ipsilateral breast and/or nodal area 
5.2.2 Active connective tissue disorders, such as lupus or scleroderma requiring flare therapy 
5.2.3 Pregnant or lactating women 
5.2.4 Concurrent chemotherapy, with the exception of anti HER2neu therapies 
5.2.5 Inadequate axillary dissection in a setting of positive sentinel node 
5.2.6 
Patients with more than 5 nodes involved at axillary dissection will be excluded from this 
study since they will be eligible to receive radiotherapy to level I and II axilla. 
 
 
6.0 Registration Procedures 
 
6.1 General Guidelines 
Patients will have completed breast cancer surgery prior to accrual into this protocol in order 
to establish eligibility criteria. Final pathology margins must be at least 1 mm in all directions 
to be eligible. The patient may undergo re-excision if the initial margins are involved or close (< 

 Protocol 1602017017 version 6.0 date 24MAR2021 
 
24 
 
1 mm).  
AJCC staging criteria will be used to identify original Clinical Stage of breast cancer patients 
eligible to this study. All eligible women who are referred to the Radiation Oncology Department 
at Weill Cornell Medicine for radiation following neo-adjuvant systemic therapy and surgery 
for breast cancer will be offered the opportunity to participate in this experimental protocol. 
 
6.2 Registration Process 
Before any protocol specific procedures can be carried out, investigators/staff will fully 
explain the details of the protocol, the study procedures and the aspects of patient privacy 
regarding research information. Patients will be provided a comprehensive explanation of the 
proposed treatment including the type of therapy, the rationale for treatment on the protocol, 
alternative treatments that are available, any known adverse events, the investigational nature of 
the study and the potential risks and benefits of the treatment. The Informed Consent document 
will meet all requirements of the Institutional Review Board. All subjects/patients are informed in 
the Consent that participation or refusal to participate in the research study will not affect any of 
the clinical treatment or services to which they would otherwise be entitled. 
The physicians who may obtain informed consent are listed on the title page of this protocol. 
The Informed Consent form will be signed by the participant and the registering physician. Once 
signed, a copy will be given to the patient and one will be maintained with the patient’s medical 
record. Once eligibility is confirmed and Informed Consent is documented, the patient will be 
registered by the study coordinator/data manager. 
 
6.3 Randomization Process 
This study is a Phase I-II non-randomized trial. Patients will be registered within 2 cohorts 
defined by requirement for nodal radiation (yes =Cohort 2/no= Cohort 1). 
 
 
7.0 Treatment Plan 
 
  7.1 General Concomitant Medication and Supportive Care Guidelines 
During radiation treatment, all patients will be prescribed daily application of Calendula 
lotion, to prevent skin dryness and reduce erythema. 
 
7.2 Duration of Therapy 
The treatment will consist of 15 fractions, Monday to Friday, for 3 weeks total time (over a total 
of 19-21 days, depending on the start day), see study calendar in Section 13. 
 
7.3 Duration of Follow Up 
Patients will be seen for follow-up at day 45-60 and then yearly thereafter for 5 years, see study 
calendar in Section 13. 
 
7.4 Alternatives 
At the time of study accrual, all patients will be offered access to the standard six weeks 
of radiotherapy.  
 
7.5 Compensation 
No compensation is available for participating in the study. 

 Protocol 1602017017 version 6.0 date 24MAR2021 
 
25 
 
 
 
8.0 Surgery 
 
Patients will have completed all surgical procedures related to breast cancer surgery prior to 
accrual into this protocol in order to establish eligibility criteria. Final pathology margins must 
be at least 1 mm in all directions to be eligible. The patient may undergo re-excision if the initial 
margins are involved or close (< 1mm). If the patient meets the eligibility criteria after re-excision, 
she may be entered onto the study. Patients undergoing reconstructive surgery are eligible either 
after maximum expansion of tissue expanders or after completion of breast reconstruction. 
While currently women with a variety of clinical presentations of breast cancer are offered a 
neo-adjuvant systemic approach (stage I-III), eligibility to this protocol will require assessment of 
nodal status at surgery, either by sentinel node and/or axillary dissection (minimum 6 nodes). 
 
 
9.0 Radiotherapy 
 
 
Radiotherapy schedule for Cohort 1 and Cohort 2 
 
WEEK 
WEEK 2 
WEEK 3 
WEEK 4 
DAY # 
Tx 
1 
M 
wb/c
w* 
TB+ 
2 
T 
wb/c
w 
TB 
3 
W 
wb 
TB 
4 
T 
wb 
TB 
5 
F 
wb 
TB 
6 
7 
 
8 
M 
wb 
TB 
 
9 
T 
wb 
TB 
10 
W 
wb 
TB 
11 
T 
wb 
TB 
 
12 
F
wb 
TBB
BBb
13 14 
 
15 
M 
wb 
TB 
16 
T 
wb 
TB 
17 
W 
wb 
TB 
18 
T 
wb 
TB 
19 
F 
wb 
TB 
B
 
*wb = target is whole breast, chest wall or reconstructed breast, 2.7 Gy/fraction 
+TB = target is the original tumor bed or mastectomy scar in post-mastectomy patients 
without reconstruction, 3.2 Gy/fraction 
 
   
Cohort 2 will follow the same schedule like Cohort 1 but level III axillary and SCV nodes will 
also be treated daily, at 2.7 Gy per fraction, to a total dose of 40.50 Gy.  
 
 
9.1 Radiotherapy target 
Patients with sentinel node negative or axillary node dissection negative results will be assigned to 
cohort 1. Patients with sentinel node positive or axillary node dissection positive results will be 
assigned to cohort 2. Patients with more than 5 nodes involved at axillary dissection will be excluded 
from this study since they will be eligible to receive radiotherapy to level I and II axilla. 
 
9.2 Dose Specification 
Patients will receive 15 daily radiation fractions of 2.7 Gy, to the entire breast, to a total dose 
of 40.5 Gy to the breast, and an additional .50 Gy to the tumor bed or chest wall scar daily to a 
total dose of 48 Gy to the tumor bed or chest wall scar. The whole breast or chest walland 
boost v o l u m e will be treated for five consecutive fractions Monday to Friday for 3 weeks. 
Patients undergoing nodal RT will also receive 2.7 Gy to the nodal targets, daily, Monday to Friday 
to a total dose of 40.50 Gy. 

 Protocol 1602017017 version 6.0 date 24MAR2021 
 
26 
 
All patients will be CT scanned in the prone position on a specially designed board that 
allows the indexed breast tissue to fall freely below the board, granting unobstructed access to 
the breast and lymph nodes through radiation ports from multiple beam angles. CT slice thickness 
should be 5 mm or less. Prior to the patient lying prone on the table for scanning, the borders of 
the field will be marked with radio-opaque CT fiducial markers. The chest wall scar will also 
be delineated using radio-opaque fiducial markers. 
 These markers will be used to outline the treatment volume according to conventional 
treatment guidelines. Borders of the fields will be set medially at mid-sternum, laterally at the 
anterior edge of latissimus dorsi, superiorly at the bottom of the clavicular heads and inferiorly 2 
cm from the infra-mammary fold. Patients will be tattooed with leveling marks for setup 
alignment with room lasers and for positioning the isocenter of the beams. A tattoo will be 
placed on the lateral breast tissue as a landmark for planning and positioning. 
Contouring of tumor bed, indexed and contralateral breast tissue, thyroid, ipsilateral 
and contralateral lung, heart and left anterior descending artery (LAD) will be performed in 
order to guide beam arrangement and optimal normal tissue avoidance. The patient will be CT 
scanned in the supine position if the patient cannot lie prone, or if the prone plan is 
not acceptable. Specifically supine set up will be attempted if the dosimetry information 
derived from prone planning reveals exceeding normal tissue dose constraints for heart, 
LAD, ipsilateral lung, or contralateral lung (see section 8.7.8.4) 
 
9.3 Target Delineation 
The PTVBreast is the entire breast volume acquired in prone or supine position based on 
physician’s delineated fields. The PTVBreast is derived from the 50% isodose line associated 
with clinically determined opposed tangent fields. This is accomplished by converting the 50% 
isodose level to a structure, smoothing and then removing parts extending outside the 50% 
isodose structure with an additional 0.7 cm margin within the field borders. The lung and the heart 
are also excluded from the PTVBreast volume. 3-dimensional/intensity modulated RT (IMRT) 
tangents will include the breast/chest wall, and coverage of breast will be ensured by placing the 
posterior edge of the field on a plane connecting the midline to the anterior extent of the latissimus 
dorsi. Planning target volume (PTV) of the breast/chest wall will be created from the volume 
contained in the tangent fields with an additional 6 mm subtracted in all directions. The tumor 
bed/boost volume will be contoured with a 10-mm expansion. The regional nodal clinical target 
volume includes ipsilateral supraclavicular and level III axillary lymph nodes, with a 5-mm 
expansion (PTV nodes), but cropped 6 mm from the skin. We anticipate that coverage will require 
3 IMRT fields (2 anterior/1 posterior). All target volume and normal tissue constraints are shown in 
Table 1. Portal images of orthogonal set-up fields will be acquired on days 1 through 3, then weekly. 
Portal imaging of each treatment field will occur once during the first 3 days of treatment. Cone 
beam computed tomography of PTV nodes is acquired on days 1 through 3. 
 
9.3.1 
The GTV is the tumor bed, as identified on CT. 
9.3.2 The PTVTumor is the GTV with an additional 1.0 cm3D margin.    
9.3.3 PTVTumor will not extend outside of the breast tissue and,    Table 3. 

 Protocol 1602017017 version 6.0 date 24MAR2021 
 
27 
 
 if necessary, will be consistently   modified  
(“clipped”) to be confined  within PTVBreast. 
 
9.4 Normal structure delineation 
The following structures will be contoured: contralateral 
breast, thyroid, ipsilateral lung, contralateral lung, heart, 
and LAD. If nodes are treated spinal cord, esophagus 
and brachial plexus will also be contoured Table 3 
describes the constraints. 
 
 
 
 
 
 
Technical Factors 
 
9.5.1 Dose calculation with heterogeneity 
corrections must be used. 
9.5.2 Nominal photon energies greater than or equal to 6 MV must be used. 16 MV 
photons may be used mixed with 6 MV photons in a ratio not to exceed 3:1 
(16 MV: 6 MV). However, 16 MV photons may not be used for any beam in 
which the superficial extent of the GTV is within 0.5 cm of the skin. 
9.5.3 Prone positioning requires the isocenter to be placed approx 1.5 cm from medial 
edge of the breast to allow clearance between the gantry and the couch/board. 
9.5.4 Hybrid Whole Breast planning - IMRT (intensity modulated radiation therapy) 
tangents plus non-IMRT tangents 
 
9.5.4.1 Non-IMRT tangents deliver  nominally  67%  of  prescribed  dose  using 6 MV or 
6MV/16MV photons and include 3 cm anterior flash. The fields are wedged and 
weighted to obtain a uniform dose distribution, normalized to allow approximately 105% 
dose max. 
9.5.4.2 IMRT tangents deliver nominally 33% of prescribed dose using 6 MV photons and 
include 3 cm anterior flash, and use the non-IMRT tangent plan as a base for 
optimization. 
 
9.5.5 3D-CRT Whole Breast Planning 
 
9.5.5.1 3D-CRT tangents will be used to obtain a uniform dose distribution. 
              Wedges 
and/or 
field 
within 
fields 
can 
be 
used. 
 
9.5.6 
Boost plan 
 
9.5.6.1 Non-coplanar beam arrangement is encouraged, but not required 
9.5.6.2 Electrons, 3D-CRT or IMRT may be used 
9.5.6.3 If the tumor bed, as visualized in the BEV (beams-eye-view), is within 1cm of the body 
surface, 1 cm of flash will be added to the field(s) 
9.5.6.4 No photon beam will be directed toward heart, lung, contralateral breast, or thyroid 
9.5.6.5 Inclusion of soft tissue not irradiated by the whole breast tangents is allowed to aid 
in target coverage 
 
9.5.7 Composite plan is created with all fields.  Dose Constraints  
 

 Protocol 1602017017 version 6.0 date 24MAR2021 
 
28 
 
9.5.7.1 Target volume dose constraints for Whole Breast Plans: 
9.5.7.2 Whole breast IMRT hybrid tangents 
9.5.7.3 PTVBreast max 108% (to ≥1cc) of the whole breast dose. This can be achieved with 6 MV, 
or 6 MV/16 MV (IMRT/3D) photons. 
9.5.7.4 PTVBreast: ≥95% of the volume must receive ≥100% of the whole breast dose. 
9.5.7.5 PTVTumor: ≥98% of the volume must receive ≥100% of the whole breast dose. 
9.5.7.6 Whole breast 3D-CRT tangents 
9.5.7.7 PTVBreast max 112% (to >1cc) of the whole breast dose. 
9.5.7.8 PTVBreast: ≥95% of the volume must receive ≥100% of the whole breast dose. 
9.5.7.9 PTVTumor: >98% of the volume must receive >100% of the whole breast dose. 
9.5.7.10 Target volume dose constraints for Boost Plans: 
9.5.7.11 IMRT Boost 
9.5.7.12 Breast max 108% (to >1cc) of the boost dose. This can be achieved with 6   MV IMRT, 
or a hybrid approach using 6 MV/16MV (IMRT/3D) photons. 
9.5.7.13 PTVTumor: >98% of the volume must receive >100% of the total boost dose. 
9.5.7.14 >60% of the PTVBreast volume must not receive >50% of the total boost dose. 
9.5.7.15 3D-CRT Boost 
9.5.7.16 Breast max 112% (to>1cc) of the boost dose. This can be achieved with 6MV, 16 MV, or 
6MV/16 MV photons. 
9.5.7.17 PTVTumor: ≥98% of the volume must receive ≥100% of the total boost dose. 
9.5.7.18 > 60% of the PTVBreast volume must not receive >50% of the total boost   
      dose 
9.5.7.19 
Composite of tangents and boost fields 
 
 
   
9.5.7.20 
PTVTumor: >98% of the volume must receive >100% of the total dose,  
          where total dose is the whole breast dose plus boost dose. 
9.5.7.21 
PTVBreast: >95% of the volume must receive >100% of the whole breast   
                    dose. 
9.5.7.22 
PTVBreast: no more than 60% of PTVBreast should receive > 4455 cGy 
9.5.7.23 
Normal tissue dose constraints: 
9.5.7.24 
Heart: <5% of the heart receives >5 Gy. 
9.5.7.25 
Ipsilateral lung: <15% of the ipsilateral lung receives >10 Gy. 
9.5.7.26 
Contralateral lung: <15% of the contralateral lung receives >5 Gy. 
9.5.7.27 
LAD: maximum <1800cGy, mean <1000 cGy. 
 
 
9.6 
Boost Technique with Image Guidance (IGRT) 
IGRT Target Localization: Cone-beam CT (CBCT) images will be acquired weekly prior to 
each boost 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 
each day of treatment of the tumor bed. If the resection cavity is not visualized then cone-beam 
CT images will be used to ensure optimal positioning of the breast tissue. A portal image of each 
boost treatment field will be acquired following CBCT. 
 
9.7 Dosing Delays/Dose Modifications 
 
For radiation toxicity: In case of grade 3 acute skin toxicity occurring during the course of 
the 3 weeks radiotherapy treatment, the dose per fraction of the remaining treatment fractions 
will be reduced to 2 Gy/fraction to the whole breast (and 2 Gy to the boost area on boost 
days) until completion of the total prescribed dose. No interruptions are planned. No other 
grade 3 toxicity is expected. 

 Protocol 1602017017 version 6.0 date 24MAR2021 
 
29 
 
 
 
10.0 Adverse Events: List And Reporting Requirements 
 
10.1 Adverse Events and Potential Risks List 
Expected toxicities include fatigue and skin reactions within the radiation field. Erythema, dry 
and moist desquamation of the skin will be recorded weekly as described in Appendix 1. Breast 
edema and tenderness are additional possible acute side effects. Acute and late toxicity will be 
reported as scheduled in the study calendar. 
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 treatment 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 procedure, whether or not related 
to the investigational procedure.  
 
Serious adverse event (SAE)  
An adverse event occurring at any dose that results in any of the following outcomes:  
-death  
-a life-threatening adverse experience  
-inpatient hospitalization or prolongation of existing hospitalization excluding those for 
administration, 
transfusional 
support, 
disease 
staging/re-staging 
procedures, 
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 informed consent or the specificity or severity of which 
is not consistent with the study’s informed consent.  
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  
Adverse events  
Adverse events will be recorded for the duration of a patient’s participation in the trial. All adverse 

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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 4.0 
(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 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.  
 
 
Serious adverse events will be reported to:  
 
 
Name Silvia C. Formenti, M.D.  
525 East 68th Street, Box 169, 
New York, NY - 10065 
Phone number: (212) 746-3608  
Fax number: (212) 746-8068 
 
 
10.2 Medical Monitor   
 
This study will be monitored by the WCMC Data Safety Monitoring Committee according to the 
procedures of the WCMC Data Safety Monitoring Plan. The WCMC DSMB committee will be the 
medical monitor of the study.  
 
10.3 DSMB safety Review 
 
The protocol will be reviewed by the Data Safety Monitoring Board (DSMB) on a Semi-annual basis. 
Safety reports will be submitted to the DSMB every six months. 
 
 
10.4 Expedited Adverse Event Reporting 
 
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. Expedited AE reporting will utilize the descriptions and grading 
scales as presented in Appendix 1. The rest of the events (SAE or any other) will be brought to 
attention of the Data Safety Monitoring Committee. The IRB would need to see their regular reports 
as a result of analysis of all SAEs and AEs. 
 
 
11.0 Correlative/Special Studies 

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11.1 Blood collection for TGF-beta 1 polymorphism determination 
Approximately 30 cc of blood will be obtained by venipuncture once before starting 
treatment and once on the last day of treatment, after the last dose of radiation. The 
specimens will be aliquoted to store part of them for future testing of other 
polymorphisms and other related research studies. 
 
12.0 Storage Of Samples 
 
All blood samples will be processed immediately and stored indefinitely for later analysis in a locked 
-80°C freezer in WCMC for research purposes only. These specimens will not be linked to any 
clinical data and will be de-identified in the clinical research database, only the Principal investigator 
and the data manager will have access to the master list with the patient name and an identification 
number. This master list will be secured in a locked cabinet at the WCMC. Only the investigators 
listed on this protocol will have access to these samples. After blood samples are analyzed at a later 
date, any unutilized samples will be preserved indefinitely in WCMC for potential future research. 
 
All patients enrolled will be given a unique identifier (study ID number). Only the data manager will 
know the code linking patient and study ID number. Patients will be assigned a unique code number. 
All specimens collected will be de-identified and assigned the same unique study number of the 
corresponding patient and will also be marked with the collection time point. Clinical information 
regarding toxicities and response will likewise be stored in a de-identified database using only the 
unique identifier (study ID number). 
 
All blood samples will be stored indefinitely until appropriate funding has been obtained to perform 
correlative studies or until subject withdraws consent for banking of study specimens. If consent is 
withdrawn by the study subject, samples will be destroyed as per standard practices. 
The storage of blood is optional and subject may withdraw consent for the banking of these 
specimens at any time. The subject may make this request by writing to the Principal Investigator 
Silvia C. Formenti, M.D. at New York –Presbyterian Weill Cornell Medical Center, Stich Radiation 
N-046, 525 East 68th Street, New York, NY- 10065.  
 
 
 12.1 Research Conflict Of Interest 
 
There are no conflicts of interest to report. 
 
 
12.3 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. 
 
 
 
12.4 Optional Genetic Research 
 

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Part of the blood samples will be stored for DNA/RNA related studies. As with all research samples 
obtained in this study, patient samples will be de-identified and coded with a unique # that allows 
only the researchers of this study to gather information about patients if necessary.  
 
The Principal Investigator and the data manager will know the code linking patients and study ID 
number through a master list; this master list will be kept in a secured, locked cabinet at the WCMC. 
No one outside of this study will have access to the patients’ samples. 
  
Patients will not be notified of the results of the future research. The results of the future research 
might be used in presentations and publications without any identifiers that might link results directly 
to patients.   
 
Patients may choose to withdraw their permission to use the samples in the future research, and 
may do so at any time by writing to the Principal Investigator Silvia C. Formenti, M.D. at New York 
–Presbyterian Weill Cornell Medical Center, Department of Radiation Oncology, 525 East 68th 
Street, Box 169, New York, NY- 10065. 
 
 
12.5 Coding of Samples 
Specimens will be given a Study ID number and will be otherwise de-identified for privacy 
protection. The study data manager will keep the list of samples. 

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13.0 Study Calendar 
 
Study 
Pre 
Treatment 
Weekly 
Last week 
Post Treatment 
(day 45-60 ) 
Post Treatment 
(once/year) 
History & Physical 
X 
 
 
 
 
Toxicity evaluation 
X 
X 
 
X 
X 
CBC with differential 
X 
X 
 
 
 
Comprehensive metabolic 
X 
as 
clinically 
indicated 
 
 
 
Mammogram and/or breast 
MRIa 
X 
 
 
 
X 
Lumpectomy 
pathology report 
X 
 
 
 
 
BREAST-focused exam, KPS 
X 
X 
 
X 
X 
Blood for TGF-BETA 
polymorphisms 
X 
 
Xb 
 
 
Quality of Life Questionnairesc 
X 
 
X 
X 
X 
LENT/SOMA assessmentd 
 
 
 
Xc 
a. Standard mammogram or MRI for both breasts. 
b. Last day of treatment, after last dose of radiation 
c. QOL will be assessed using the Breast Cancer Treatment Outcome Scale (BCTOS) [30] 
MOS SF- 36 Vitality Scale (see appendix 4) at baseline, last week of radiation treatment, 
45-60 days from starting radiotherapy and 2 year follow-up. 
d. Patients will be seen after completion of treatment (at day 45-60) and then yearly for five 
years to assess long term sequelae by LENT/SOMA scale. 
 
 
14.0 Measurement Of Effect 
 
14.1 Response Review 
Since the first main endpoint of this study is to compare the toxicity profile of the regimen, 
the study nurse will assess the acute toxicity for radiation by recording the findings on the form 
attached in Appendix 3. 

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15.0 Data Reporting / Regulatory Considerations 
 
 
The WCMC Data and Safety Monitoring Committee (DSMC) is the central monitoring board for this 
study. The WCMC Cancer Institute Data and Safety Monitoring Committee (DSMC) is the local 
monitoring board for WCMC patients. 
 
15.1 Monitoring plan 
 
This study will be conducted in accordance with the guidelines in the 2001 NCI approved data Safety 
and Monitoring plan for the WCMC Cancer Institute and with the WCMC approved data Safety and 
Monitoring plan for the WCMC Cancer Institute. Monitoring will occur on a yearly basis from the 
date the first patient is enrolled. Reports to the Data Safety and Monitoring Committee will include 
the following information: accruals, targets, responses, adverse events and evidence of reporting 
to appropriate review committees. The WCMC Data and Safety Monitoring Board (DSMB) will 
review the IRB approved protocol, the data and safety monitoring plan and any stopping guidelines 
during protocol initiation. During the course of the study, the DSMB will review cumulative study 
data twice a year to evaluate safety, efficacy, study conduct, and scientific validity and integrity of 
the trial. The WCMC DSMB may also convene as needed if stopping criteria are met or other safety 
issues arise that the Principal Investigator and/or IRB would like the WCMC DSMB to address. 
 
15.2 Stopping rules  
 
Treatment will be held if patients experience > Grade 2 radiation dermatitis. Patients will be 
monitored until the resolution of the adverse event. Based on PI’s discretion, patients will resume 
or be withdrawn from the study. Adverse Events will be recorded based on CTCAE v4.03.  
 
 If safety concerns arise, the DSMC will identify these concerns and recommend modification 
or termination of the clinical trial. There is no formal interim analysis for this trial. 
 
15.3 Data management 
Data will be entered into the REDCap database and maintained at WCM by trained Radiation 
Oncology data managers. 
The system provides audit trails that track creation and modification of records that include 
user ID and timestamp. Once entered, the data is subjected to validation procedures that are 
executed either immediately or upon saving the eCRF page or during the batch validation 
process. Validation failures that are identified before the page is saved can be corrected 
immediately. Validation failures during saving of the eCRF page and during batch validation 
processes will generate a discrepancy. Depending on the database account privileges, the 
data managers may be able to correct a discrepancy or if not, route it to the project data 
manager at WCM who can take appropriate action to correct the problem. Data clarification 
forms can also be printed out when necessary to be sent to the project data manager. Once 
the discrepancy is closed, by marking “resolved” or “irresolvable”, the data is marked clean 
and an audit trail is generated by the system. 
All key end points will be source verified by a second person and errors will be corrected. 
Once the data is verified and all discrepancies are closed, the data can be locked/frozen. Locking 

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and freezing can be done at different granular levels and will follow institutional SOPs and any 
specific requirements for the project. 
Security measures that will be taken in order to protect patient data will include firewall 
technology and database level security which will be achieved by assigning roles and privileges 
to different levels of users and by requiring that the users authenticate themselves using user ID 
and password. Additional security for data transfer between remote clients and servers will be 
achieved by using digital certificates/SSL. All data will be backed-up to tape periodically 
according to the Institutional SOPs. All data will be stored for at least 5 years following the 
termination of this study. 
 
15.4 Confidentiality 
The medical, hospital and research records associated with this study are considered 
confidential. Members of the treating team and designated study assistants will have access to 
the records as required to administer treatment and comply with the protocol. Neither the name 
nor any other identifying information for an individual will be used for reporting or publication 
regarding this study. All laboratory and baseline data will be de-identified and transferred via 
secure links to the Study Biostatisticians. Patient records will be made available for inspection to 
auditing agencies to satisfy regulatory requirements. 
 
16.0 Statistical Considerations 
 
This trial is designed to test the feasibility of the combined regimen, defined as limitation of 
the acute effects to < 10% Grade 3 events. 
 
16.1 Endpoints 
16.1.1 Primary endpoint 
The primary endpoint for the study is acute toxicity occurring within 60 days after 
treatment; the proportion of patients with grade II or III acute skin toxicity. 
 
16.1.2 Secondary endpoints 
Acute toxicities, Quality of Life of patients before during and after treatment 
Late toxicity 60 days post treatment including brachial plexopathy, fibrosis and 
telangiectasia; the proportion of patients with grades 2 or higher toxicity 
 
16.1.3 Exploratory endpoints 
Local recurrence 
Distant   recurrence/metastases 
Survival 
 
 
16.2 Analysis Populations 
All registered patients will be included in these analyses (intent to treat). 
 
 
Statistical Considerations Sample Size and Interim Analysis Plans 
 
16.3 Accrual estimates 
Two distinct cohorts will be tested in this study. Based on the algorithm presented in study 
design (Page 9) some patients will need post-operative radiation to the breast/chest wall alone 

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(cohort 1) or to the breast and level III /SCV nodes (cohort 2). Since the fields of accelerated 
radiation are different the 2 cohorts will be accrued separately and analyzed separately. 
Estimated number of eligible patients for the trial is 2-4/month. Therefore, we estimate that 
the required 74 patients (37 per cohort) will be recruited within 24-36 months.  
With 37 patients, we can detect a difference of 18% from a baseline rate of 25% (grade II-
III acute dermatitis) with a 2-sided α = 0.05 and power of 80% using an exact binomial test. If 
we observe 15 or more events among these 37 patients, the null hypothesis that the rate is 25% 
will be rejected. Calculations from PASS 2008, NCSS. 
 
16.4 Criteria for future studies 
N/A 
 
16.5 Interim analyses 
None planned 
 
16.6 Statistical Analysis 
16.6.1 Primary Endpoint 
The primary endpoint is the occurrence of grade II or greater dermatitis within 60 days 
of the end of the treatment. The proportion of patients who experience this grade II or greater 
dermatitis will be estimated with exact 95% confidence intervals. 
Patient demographic and disease characteristics at registration will be summarized 
using frequency distributions for qualitative data and summary statistics (means, medians, 
standard deviations, etc.) and graphical displays (e.g., Boxplots). Treatment data will be 
summarized similarly. Descriptive analyses will report the primary endpoint in subgroups 
defined by radiation regimen and other characteristics. 
 
16.6.2 Secondary Endpoints 
See primary endpoint. 
 
16.6.3 Exploratory Endpoints 
Local recurrence rates will be reported along with 95% confidence intervals. Kaplan 
Meier curves will be used to estimate recurrence free and overall survival. 

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Appendix 1. – Common Toxicity Criteria 
Acute Toxicity from Common Terminology Criteria for Adverse Events v4.0 (CTCAE), Published: May 28, 
2009 
 
 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
 
 
FATIGUE 
No change 
Mild 
fatigue 
over 
baseline 
Moderate or causing 
difficulty 
performing 
some ADL 
Severe fatigue 
interfering 
with ADL 
Disabling 
 
 
 
RADIATION 
DERMATITIS 
No change 
Faint 
erythema 
or 
dry 
desquamation 
Moderate 
to 
brisk 
erythema; 
patchy 
moist desquamation, 
mostly confined to 
skin 
folds 
and 
creases; 
moderate 
edema 
Moist 
desquamation 
other than skin 
folds 
and 
creases; 
bleeding 
induced 
by 
minor trauma 
or abrasion 
Skin necrosis 
or ulceration 
of 
full 
thickness 
dermis; 
spontaneous 
bleeding from 
involved site 
 
 
 
PAIN 
No pain 
Mild 
pain 
not 
Interfering 
with 
function 
Moderate pain; pain 
or 
analgesics 
interfering 
with 
function, but 
not interfering with ADL 
Severe pain; 
pain 
or 
analgesics 
severely 
interfering 
with ADL 
Disabling 

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Appendix 2 - Toxicity Tracking Form 
 
 
 

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Appendix 3 – Quality Of Life Questionnaires 
 
Appendix 3.1 Quality of Life questionnaire used at baseline 
 

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Appendix 3.2 Quality of Life questionnaire used for follow-up visits 
 
 

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Appendix 3.3 Form for missing Quality of Life information 
 
 

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