Phase I-II Study of Concurrent Adjuvant Systemic Therapy and Accelerated Radiotherapy (Over 3 Weeks)
Phase: PHASE1
Conditions: Breast Cancer
Sponsor: NYU Langone Health

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TITLE: 
 
PHASE I-II STUDY OF CONCURRENT ADJUVANT SYSTEMIC THERAPY AND 
ACCELERATED RADIOTHERAPY (OVER 3 WEEKS) 
 
Coordinating Center: 
 
New York University Cancer Institute 
160 East 34th Street 
New York, NY 10016 
 
*Principal Investigator: 
 
Carmen Perez, M.D. 
160 East 34th Street 
New York, NY 10016 
Telephone: (212) 731-5003 
Fax: (212) 731-5513 
e-mail address:  Carmen.Perez@nyumc.org  
 
Co-PI: 
 
 
                                                     Silvia. C. Formenti, M.D. 
Telephone: 212-746-6314 
 
 
e-mail address: Formenti@med.cornell.edu  
 
 
 
Yelena Novik, M.D. 
160 East 34th Street  
New York 10016 
Telephone: (212) 731-5350 
e-mail address: yelena.novik@med.nyu.edu 
 
Co-Investigators: 
 
 
 
James Speyer, M.D. 
160 East 34th Street  
New York 10016 
Telephone: (212) 731-5432 
e-mail address: James.Speyer@nyumc.org 
 
Sylvia Adams, M.D. 
Bellevue C&D Building  
462 First Avenue, 5th Floor 
New York 10016 
Telephone: (212) 263-3809 
e-mail address: Sylvia.Adams@nyumc.org 
 
 
Ruth Oratz, MD 
345 East 37th Street, Suite 202  
New York, NY 10016 
Telephone : (212) 400-4904 
e-mail address: ruth.oratz@nyumc.org 

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Nelly Huppert, M.D. 
160 East 34th Street 
New York, NY 10016 
Telephone: (212) 263-2145 
Fax: (212) 263-6274 
e-mail address: nelly.huppert@nyumc.org 
 
Joshua Silverman, M.D. 
160 East 34th Street 
New York, NY 10016 
Telephone: (212) 731-5880 
Fax: (212) 731-5512 
e-mail address: joshua.silverman2@nyumc.org 
 
Jennifer Wu, M.D. 
Bellevue C&D Building 
Bellevue Hospital 
462 First Avenue 
New York 10016 
Telephone: (212) 263-6485 
e-mail address: Jennifer.Wu@nyumc.org 
 
 
Ping Gu, M.D. 
Bellevue C&D Building 
462 First Avenue, 5th Floor 
New York 10016 
Telephone: (212) 263-6485 
e-mail address: Ping.Gu@nyumc.org 
 
 
Judith D. Goldberg, Sc.D. (Biostatistics) 
650 First Avenue, KIP 5 534 
New York NY 10016 
Telephone: (212) 263-0314 
Fax: (212) 263-8570 
e-mail address: jd.goldberg@nyumc.org 
 
Naamit Gerber, M.D. 
160 East 34th Street 
New York, NY 10016 
Telephone: (212) 731-5003 
Fax: (212)731-5512 
e-mail address: Naamit.Gerber@nyumc.org 
 

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Protocol Type / Version # / Version Date Original / Version   3.1 04/13/2015  
 

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Summary of Changes: Protocol Version 11/02/2015 
 
Revising the cover page to remove Nagashree Seetharamu and Maria Fenton-Kerimian- 
Both no longer at NYU.  Adding Dr. Naamit Gerber as a CO-Investigator on the trial 
 
Summary of Changes: protocol version 09/16/2015 
 
Revising section 15.3 further to include the reason why anonymous data will be shared with 
Weill Cornell Medical College- re-location of personnel- Dr. Encouse Golden.  Inclusion of 
statement that anonymous data will only be shared after a transfer agreement is executed. 
 
Summary of changes: protocol version 09/01/2015 
 
Removing Dr. Encouse Golden as Co-Investigaor 
Revising section 15.3 to state anonymous data will be shared with Weill Cornell Medical 
College 
 
Summary of changes: protocol version 07/02/2015 
 
Changing Dr. Carmen Perez to Principal Investigator 
Changing Dr. Encouse Golden to Co- Investigator 
 
 
Summary of changes : protocol version 04/13/2015 
 
Adding Dr. Formenti as Co-PI  
 
 
Summary of changes : Version 3.0   03/24/2015 
 
Changing the Principal Investigator to Dr. Encouse Golden 
 
Changing informed Consent to reflect new Principal investigator 
 
 
Protocol Version 2.0 03/11/2015 : 
 
• 
Increasing accrual to add two more patients in order to reach a target of 37 evaluable 
patients. 
 
• 
Removing Dr. Mathew Volm from the investigator section, as Dr. Volm is no longer at 
NYU. 
 
Section 16.3 Accrual Estimates : 

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• 
Biostatistics Section amended to reflect the new target of 37 patients.  
 
Informed consent dated 02/02/2012 : 
 
No changes have been made to the informed consent  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
 
 
Page 
PROTOCOL SYNOPSIS ............................................................................................................. 8 
SCHEMA ....................................................................................................................................... 9 
STUDY SYNOPSIS .................................................................................................................... 11 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................ 12 
1. 
OBJECTIVES ..................................................................................................................... 14 
1.1. Primary Objectives...................................................................................................... 14 
1.2. Secondary Objectives................................................................................................ 14 
1.3. Exploratory Objectives ............................................................................................. 14 
2. 
BACKGROUND ................................................................................................................. 14 
2.1. NYU research in hypo-fractionated whole breast radiotherapy ................................. 14 
2.2. NYU Experience on Accelerated Concomitant Boost Whole Breast: NYU 03-30 and 
01-51 ........................................................................................................................... 14 
2.3. Rationale for Prone Radiotherapy: NYU 05-181........................................................ 16 

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2.4. NYU 09-0300: a prospective randomized trial aimed at establishing the optimal boost 
schedule....................................................................................................................... 16 
2.5. Rationale for concurrent chemoRT in TN tumor carriers: the LABC experience ...... 17 
2.6. Background for Primary Objective ............................................................................. 21 
2.7. Correlative Studies Background ................................................................................. 21 
3. 
PATIENT SELECTION .................................................................................................... 23 
3.1. Inclusion Criteria ........................................................................................................ 23 
3.2. Exclusion Criteria ....................................................................................................... 23 
4. 
REGISTRATION PROCEDURES ................................................................................... 23 
4.1 
General Guidelines...................................................................................................... 23 
4.2 
Registration Process .................................................................................................... 24 
4.3 
Randomization Process ............................................................................................... 24 
5. 
TREATMENT PLAN ......................................................................................................... 24 
5.1. General Concomitant Medication and Supportive Care Guidelines ........................... 24 
5.2. Duration of Therapy ................................................................................................. 24 
5.3. Duration of Follow Up .............................................................................................. 24 
5.4. Alternatives ................................................................................................................ 24 
5.5. Compensation ............................................................................................................ 25 
6 
SURGERY ........................................................................................................................... 25 
7 
CHEMOTHERAPY ........................................................................................................... 25 
7.1 
Carboplatin Administration .................................................................................... 25 
7.2 
Formulation ............................................................................................................... 25 
7.3 
Pharmacokinetic information .................................................................................. 26 
7.4 
Dosing of Carboplatin............................................................................................... 26 
7.5 
Potential Drug Interactions ...................................................................................... 27 
7.6 
Adverse Effects of Carboplatin................................................................................ 28 
7.7 
Adverse Events Reporting ........................................................................................ 28 
8 
RADIOTHERAPY SPECIFICATIONS ........................................................................... 28 
8.1 
Treatment Planning Using either 3D-CRT or Hybrid IMRT Technique .................... 28 
8.2 
Radiotherapy schedule ................................................................................................ 29 
8.3 
Radiotherapy target ..................................................................................................... 29 
8.4 
Dose Specification ...................................................................................................... 29 
8.5 
Target Delineation ...................................................................................................... 29 
8.6 
Normal structure delineation ................................................................................... 30 
8.7 
Technical Factors ........................................................................................................ 30 
8.8 
Boost Technique with Image Guidance (IGRT) ......................................................... 31 
9 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................... 32 
10 ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .......................... 33 

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10.1 Adverse Events and Potential Risks List .................................................................... 33 
10.2 Expedited Adverse Event Reporting ........................................................................... 33 
10.3 Routine Adverse Event Reporting Guidelines ............................................................ 33 
11 CORRELATIVE/SPECIAL STUDIES ............................................................................ 33 
11.1 Blood collection for TGF-beta 1 polymorphism determination ........................... 33 
11.2 Coding of Samples..................................................................................................... 33 
12 INVESTIGATOR RESOURCES ...................................................................................... 33 
12.1 Qualifications............................................................................................................. 33 
12.2 Use of NYU Facilities ................................................................................................ 34 
12.3 Conflict of interest..................................................................................................... 34 
13 STUDY CALENDAR ......................................................................................................... 35 
14 MEASUREMENT OF EFFECT ....................................................................................... 35 
14.1 Response Review ........................................................................................................ 35 
15 DATA REPORTING / REGULATORY CONSIDERATIONS ..................................... 36 
15.1 Monitoring plan ........................................................................................................ 36 
15.2 Data management ..................................................................................................... 36 
15.3 Confidentiality ........................................................................................................... 36 
16. STATISTICAL CONSIDERATIONS .............................................................................. 37 
16.1 Endpoints ................................................................................................................... 37 
16.2 Analysis Populations ................................................................................................. 37 
16.3 Accrual estimates ...................................................................................................... 37 
16.4 Criteria for future studies ............................................................................................ 37 
16.5 Interim analyses ........................................................................................................ 37 
16.6 Statistical Analysis ...................................................................................................... 38 
APPENDIX 1. – COMMON TOXICITY CRITERIA ............................................................ 39 
APPENDIX 2 - INFORMED CONSENT TEMPLATE.......................................................... 41 
APPENDIX 3 - TOXICITY TRACKING FORM ................................................................... 42 
APPENDIX 4 – QUALITY OF LIFE QUESTIONNAIRES .................................................. 43 
Appendix 4.1 Quality of Life questionnaire used at baseline ............................................... 43 
Appendix 4.2 Quality of Life questionnaire used for follow-up visits ................................. 50 
Appendix 4.3 Form for missing Quality of Life information ............................................... 56 
REFERENCES ............................................................................................................................ 58 
 
 

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PROTOCOL SYNOPSIS 
 
TITLE 
PHASE I-II STUDY OF CONCURRENT 
ADJUVANT SYSTEMIC THERAPY AND 
ACCELERATED RADIOTHERAPY (OVER 3 
WEEKS)  
 
STUDY PHASE 
Feasibility 
INDICATION 
Stage I-II breast cancer 
PRIMARY OBJECTVES 
Acute toxicity 
SECONDARY OBJECTIVES 
QOL, defined by RTOG-PRO;  
Late toxicity, Fibrosis, Telangiectasia 
EXPLORATORY OBJECTIVES 
Local control; Time to Progression, 
Survival; Evaluation of Determinants of 
Breast Fibrosis 
HYPOTHESES 
FEASIBILITY OF ACCELERATED 
RADIOTHERAPY WITH 
CARBOPLATIN:  
Proportion of patients with grade II-III 
dermatitis is 0.25 vs. alternative that the 
proportion is greater than 0.25 by more 
than 0.24.  
< 10% Grade 3 (CTC 4.0) events 
chemotherapy related 
STUDY DESIGN 
Prospective, single arm  
PRIMARY ENDPOINTS AND 
SECONDARY ENDPOINTS 
Acute, effects of radiation (Grade II, III 
dermatitis 
Secondary—other acute effects of radiation, 
late effects of radiation, QOL-PRO  
Local control, DFS, OS 
SAMPLE SIZE BY TREATMENT GROUP 
37 patients 
SUMMARY OF SUBJECT ELIGIBILITY 
CRITERIA 
Newly diagnosed breast cancer patients 
after segmental mastectomy, HORMONAL 
RECEPTOR NEGATIVE, HER2 
NEGATIVE (TRIPLE NEGATIVE) 
INVESTIGATIONAL PRODUCTS 
DOSAGE AND ADMINISTRATION 
N/A 
CONTROL GROUP 
- 
PROCEDURES 
N/A 
STATISTICAL CONSIDERATIONS 
Phase I-II  
 

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SCHEMA 
 
 
ELIGIBLE PATIENTS: 
STAGE I-II BREAST CANCER PATIENTS, 
HORMONAL RECEPTOR AND HER2-neu NEGATIVE, 
TRIPLE NEGATIVE (TN) 
ELIGIBLE FOR ADJUVANT RADIOTHERAPY 
AFTER SEGMENTAL MASTECTOMY 
 
 
 
INFORMED CONSENT 
 
 
 
Carboplatin will be administered with AUC of 2.0, repeated weekly for 6 weeks 
 
 
Whole Breast 3D-RT or IMRT at 2.7 Gy X 15 fractions (40.50 Gy) 
(the second and third Friday, 3 Gy to the tumor bed only X 2 fractions) 
Total dose to tumor bed = 46.5 Gy 
 
 
WEEK 
WEEK 2 
WEEK 3 
WEEK 4 
DAY # 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 
 
M 
T 
W 
T 
F 
 
S 
M 
T 
W 
T 
F 
 
S 
M 
T 
W 
T 
F 
Tx 
wb* wb wb wb wb 
 
wb wb wb wb 
wb 
B+ 
 
wb 
wb 
wb 
wb 
wb 
B+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*wb = target is whole breast, 2.7 Gy/fraction 
+B = boost to tumor bed 3 Gy (second and third Friday) 
 
 
 
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. 
 

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Treatment Schema 
 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Additional 
Adjuvant 
Chemo 
C 
C/RT 
C/RT 
C/RT 
C 
C 
 

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STUDY SYNOPSIS 
 
Preliminary experience in the neo-adjuvant setting of Locally Advanced Breast 
Cancer has recently demonstrated that HR negative patients have approximately 
50% chance to achieve a pathological response after concurrent chemo-radiation. 
In a multi-institutional collaboration of 105 patients it was found that triple 
negative tumor carriers achieved pathological response in 54% of the cases and 
that the response reflected on 5-year DFS and OS. Our group has speculated that 
these effects on the risk of distant recurrence could depend on the recovery of anti-
tumor immunity among the patients achieving pathological response, after tumor 
cell death induced by concurrent chemo-radiation. 
 
We are proposing a novel study that translates these findings to the adjuvant 
setting of triple negative tumors (TN). TN breast cancer is a more aggressive form 
of the disease often coinciding with basal-like tumors. BRCA mutated-cancer is 
more frequently TN. 
 
The current protocol converges the experience NYU has developed in 
accelerated prone breast radiotherapy with encouraging finding from the use of 
concurrent chemoradiation in LABC. 
 
We will study the feasibility of combining weekly carboplatin with concurrent 
3-weeks prone breast radiotherapy in the adjuvant setting of 35 women with TN 
tumors, after segmental mastectomy and nodal assessment. Primary endpoint of the 
study is acute toxicity of the combined regimen, with a target of < 25% of grade II-
III dermatitis. 
 

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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 
Complete response 
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 
QOL 
Quality of Life 
RBV 
Residual Breast Volume 
RECIST 
Response evaluation criteria in solid tumors 
RR 
Response rate 
RTOG 
Radiation Therapy Oncology Group 
SAE 
Serious adverse event 

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SD 
Stable disease 
SNP 
Single Nucleotide Polymorphism 
SSCP 
Single-Strand Conformation Polymorphism 
TN 
Triple negative 
TGF-beta1 
Transforming Growth Factor beta-1  
TV 
Treatment Volume 
WBD 
Weekend Boost Dose 
 

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1. OBJECTIVES  
 
1.1. 
Primary Objectives 
1.1.1. 
To test feasibility of combining carboplatin and accelerated radiotherapy in 
patients with triple negative breast cancer (HR and Her2-neu negative) by 
evaluating the proportion of patients who experience grade II-III dermatitis 
within 60 days of the end of treatment. 
 
1.2. 
Secondary Objectives 
1.2.1. 
To assess QOL of patients at baseline and after the course of treatment. 
1.2.2. 
To compare incidence of late radiation toxicity (fibrosis and telangiectasia) 
and to examine genetic determinants of breast fibrosis by treatment regimen. 
 
1.3. 
Exploratory Objectives 
1.3.1. 
To assess local control rates, distant recurrence and overall survival of at 2, 5 
and 10 years follow up. 
1.3.2. 
To prospectively validate the data on molecular signature of BRCA 
methylation in triple negative cancers in this prospective series and examine 
possible new molecular signatures of breast cancer. 
 
 
2. 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] Analysis of two prospective randomized trials that included 2644 women, selected 
based on tumor size less than five cm, negative pathological margin of excision and negative 
lymph nodes. No difference in clinical outcome was detected. The conclusion of the review is 
that the use of unconventional fractionation regimens (> 2 Gy per fraction) does not affect breast 
appearance or toxicity and does not seem to affect 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 eight years the Breast Cancer Radiotherapy Research team at NYU has 
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-II breast cancer patients, s/p segmental mastectomy, found to have HR negative HER2 
negative tumors (TN). 
 
2.2. 
NYU Experience on Accelerated Concomitant Boost Whole Breast: NYU 03-30 
and 01-51 
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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 to 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  = 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, 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 2 (RTOG score). Most common toxicity was radiation 
dermatitis, which 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%) 
- 
- 
- 
 
Longer follow up is required to assess local control and late toxicity, likely to determine the 
cosmetic result. Because of blood collection, once sufficient time has elapsed to measure late 
effects, the study will enable to explore association between specific genomic profiles and the 
occurrence of fibrosis. [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. [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 to the trial were DCIS patients 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 it 
either, and especially for left breast DCIS, some women were initially simulated supine and 
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not always) were found to have better normal tissue sparing when prone and were then treated 
consistently. [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, NYU 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 
postmenopausal 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, be 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 received a CT simulation in the prone and 
supine position. Treatment followed in the optimal position defined as that which assured the 
smallest volume of heart and lung respectively, 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 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 (submitted for publication). 
Based on the experience gathered from NYU Protocol 05-181, it is rational for all patients to 
first undergo a CT Simulation in prone position. Again, we will be using 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. Only if found that conventional tangents in 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 
Solid radiobiological reasons supported the introduction of a larger fraction dose before a 
two-day treatment break (weekend). In the context of a Phase III randomized study, we are 
studying two different boost schemas. The standard arm is a concomitant boost protocol over 
three weeks which has previously been evaluated in over 500 patients (NYU 03-30 and NYU 05-

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181) and has shown excellent tolerance, and results. The experimental arm evaluates a Friday 
Weekly Boost Dose (FBD) regimen which may have a radiobiological advantage by 
counteracting tumor repopulation which can occur over the weekend break. Choice of the 
technique was be randomized. BED calculations for the standard arm using an alpha/beta ratio 
of 4 Gy, result in a BED for 3.2 Gy x 15 fx of 86 Gy4. By comparison, the BEDs for possible 
comparative experimental arms at 2.7 Gy X 12 fx plus 3 fractions given each Friday of either 3.7 
Gy, 4.2 Gy, 4.7 Gy or 5.2 Gy would be 76, 80, 85 and 90 Gy4, respectively. Thus, the 
experimental arm delivers 2.7 Gy four times per week (Monday-Friday) during the 3 weeks 
(i.e., 2.7 Gy x 15 fx), but with an additional 2 Gy on each of the three Fridays to the tumor bed in 
addition to the 2.7 Gy whole breast dose given on that day, with the tumor bed receiving 4.7 Gy 
on each of the three Fridays. Preliminary results of the interim analysis are presented in Table 2. 
Between March 2009 and March 2010, 126 patients have enrolled to this protocol. CTCAE v3.0 
defined radiation dermatitis was evaluated at two month follow-up demonstrating no statistical 
difference between the two arms in RT-related acute toxicity between terms of the two regimens 
P-value NS. 
Table 2 below compares rates of radiation dermatitis among the two treatment groups. 
 
Table 2. Comparison of acute radiation skin toxicities among patients in NYU 09-0030 
 
 
Grade 1 
Grade 2 
Grade 3 
Total # 
 
Arm 1 
Arm 2 
Arm 1 
Arm 2 
Arm 1 
Arm 2 
Arm 1 
Arm 2 
Dry DesQ 
3 
5 
0 
0 
0 
0 
3 
5 
Edema 
23 
21 
3 
4 
1 
0 
27 
25 
Erythema 
52 
53 
9 
5 
0 
0 
61 
58 
Wet DesQ 
0 
0 
8 
3 
0 
1 
8 
4 
 
To further reduce the risk of acute and late effects during concurrent radiosensitizing 
chemotherapy the regimen proposed consists of a total of 17 fractions over 19 days, taking 
advantage of the fact that NYU Department of Radiation Oncology is open during the weekend 
enabling radiotherapy on Sunday. Patients will be treated with 2.7 Gy per fraction to the whole 
breast, prone as per our extensive experience in > 2,000 patients. A 3 Gy boost to the tumor bed 
will be given by IGRT on the 2nd and 3rd Friday. 
 
2.5. 
Rationale for concurrent chemoRT in TN tumor carriers: the LABC experience 
Triple-negative breast cancers (TNBCs) are characterized by the lack of expression of 
estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 
2 (HER-2). [6-7] These cancers occur in approximately 20% to 25% of all patients with breast 
cancer, and are associated with an unfavorable prognosis. [7-9] Patients with TNBC derive no 
benefit from molecularly targeted treatments such as endocrine therapy or trastuzumab, because 
they lack the appropriate targets for these drugs. 

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Liedke et al compared the outcome 255 triple negative carriers out of 1118 treated with 
neoadjuvant chemotherapy at MD Anderson cancer center (23%). [10] Patients with TNBC 
compared with non-TNBC had significantly higher pCR rates (22% vs. 11%; P <.034), but 
decreased 3-year progression-free survival rates (P < .0001) and 3-year Overall Survival (OS) 
rates (P < .0001). TNBC was associated with increased risk for visceral metastases (P < 0.0005), 
lower risk for bone recurrence (P < 0.027), and shorter post-recurrence survival (P < 0.0001). 
Recurrence and death rates were higher for TNBC only in the first 3 years. If pCR was achieved, 
patients with TNBC and non-TNBC had similar survival (P < 0.24). In contrast, patients with 
residual disease (RD) had worse OS if they had TNBC compared with non-TNBC (P <.0001). In 
their experience patients with TNBC had increased pCR rates compared with non-TNBC, and 
those with pCR had excellent survival. However, patients with RD after neoadjuvant 
chemotherapy had significantly worse survival if they have TNBC compared with non-TNBC, 
particularly in the first 3 years. 
Derived from a protocol of concurrent paclitaxel and radiation originally developed by Dr. 
Formenti at USC, three institutions, USC, NYU and Vanderbilt reported the five years 
experience on 105 patients with LABC (White 46%, Non-White 54%) treated with paclitaxel (30 
mg/m2 intravenously twice a week) for 10-12 weeks. Daily radiotherapy was delivered to the 
breast, axillary and supraclavicular lymph nodes during weeks 2-7, at 1.8 Gy per fraction to a 
total dose of 45 Gy with a tumor boost of 14 Gy at 2 Gy/fraction. Post-operative treatment was 
left to the discretion of the treating physician. Pathological response (pCR and pPR) after 
neoadjuvant chemoradiation was achieved in 36/105 patients (34%, 95% CI: 25%-44%). 
Achievement of pathologic response was associated with significantly better DFS and OS. 
Patients with pathologic response had a lower risk of recurrence or death compared with non-
responders (hazard ratio =0.35, 95% CI: 0.15-0.80, log-rank p-value=0.01). At a median follow-
up of 60 months, the median survival for the entire group has not been reached. The estimated 5-
year disease-free (DFS) and overall survival (OS) are 61.4% (95% CI: 50.1-70.8%) and 71.6% 
(95% CI: 60.5-80.1%), respectively.  

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Table 3. Pathological response and Receptor status 
Subtype  
Total 
 
Proportion of patients who received 
trastuzumab 
Proportion of patients 
with pathologic response 
(pCR+pPR)  
Entire Cohort (n = 105) 
HR positive 
57 
5/57 (2 with pathologic response) 
10/57 (17.5%) 
HR negative 
48 
3/48 (3 with pathologic response) 
26/48 (54.2%)  
Cohort with Her2 status available (n = 85) 
HR positive/Her2 negative  
34 
N/A 
6/34 (17.7%) 
HR positive/Her2 positive  
13 
5/13 (2 with pathologic response) 
3/13 (23.1%) 
HR negative/Her2 positive  
14 
3/14 (3 with pathologic response) 
7/14 (50.0%) 
HR negative/Her2 negative 
(triple negative) 
24 
N/A 
13/24 (54.2%) 
Abbreviations: HR: hormone receptor, Her2: human epidermal growth factor receptor,  
pCR: pathologic complete response, pPR: pathologic partial response 
 
Figure 1. Outcome at five years of 105 LABC patients treated pre-operatively by concurrent 
paclitaxel and radiation: DFS and OS results based on pathological response and HR status  
 
Approximately half of HR negative 
tumor carriers achieved a pathological 
response: the incidence of pathological 
response was 54% in TN tumor carriers. 
Importantly, in this study the 5 year 
outcome of the patients was plotted based 
on 
receptor 
status 
and 
pathological 
response. As demonstrated in figure 1, HR 
negative tumor carriers achieving a 
pathological response did as well at 5 
years as the HR positive tumor carriers 
who had achieved a pathological response. 
However, the main insight from 
the results of this multi-institutional trial is 
the fact that a pathological response after 
single agent concurrent chemo-radiation is 
prognostically similar to that achieved 
with protocols of much more intense 
multi-agent, dose-dense chemotherapy. 
We 
speculated 
that 
that 
the 
recruitment of an effective immune 
response may reflect in the survival 

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benefit that some patients gain after a pathologic response following chemoradiation, supported 
by the fact that response to therapy was associated with certain immune signatures. [11] A 
superior outcome after concurrent versus sequential chemotherapy and radiation has been 
demonstrated in other settings. [12-16] Standard anti-cancer modalities such as certain 
chemotherapy agents and radiotherapy are thought to generate an immunogenic cell death, 
converting the original tumor into an in situ immunogenic hub. [17-21] The consequent anti-
tumor immune response might also control micro-metastatic foci. Alternatively, it is possible that 
in patients achieving a pathologic response, concurrent chemoradiation successfully eradicated 
CD44+/CD24-/low or aldehyde dehydrogenase 1 (ALDH1)+ tumor cells, shown to possess 
tumor-initiating potential if they persist after treatment. [22-23] RT and chemotherapy when 
given alone can enrich the population of breast cancer stem- like cells, which are resistant to 
either single modality [23-26], suggesting that perhaps they are sensitive to concurrent 
chemoradiation. Finally, the concurrent combination of chemoradiation could have successfully 
eliminated the subset of cancer cells later destined to become circulating cells with seeding 
potential. [27] The relevance of these findings to TN tumors, found to be potentially more 
immunogenic than the other subtypes of breast cancer, has justified the design of this 
protocol. 
 
2.5.1. 
Rationale for carboplatin and radiation 
Triple negative breast cancer represents approximately 15% of breast cancer of all 
breast cancer cases. [28] Though the sensitivity of these tumors to platinum drugs was 
debated for a number of years only recently the abundance of both basic science and limited 
clinical data lead to a consensus that these drugs play a crucial role in the treatment of these 
tumors both as management of metastatic and locally advanced disease. Patients with TN 
tumors have demonstrated sensitivity to platinum compounds, possibly because of their 
inherent chromosomal fragility and impairment of DNA repair pathways. [29] 
The possible interaction of platinum agents and PARP inhibitors especially in cancers 
related to the BRCA mutation. So far there is paucity of data investigating the role of 
platinums in the adjuvant management of breast cancer.  
The main platinum agent established in the management of triple negative breast 
cancer is Cisplatin, fewer clinical studies utilized carboplatin in the setting of triple negative 
disease. 
Over the last decade the difference between the 2 platinum drugs have been debated. 
The carboplatin toxicity especially vis-a vis nephrotoxicity and gastrointestinal (nausea and 
vomiting) is significantly less pronounced compared to equivalent doses of cisplatin. In other 
malignancies (testicular, ovarian cancer etc) the equivalency in efficacy are well established. 
The role of adjuvant chemoradiation in breast cancer has been studied mostly in small 
studies and in combinations with CMF, anthracyclines and taxanes. The possibility of better 
locoregional control is debated as well as higher toxicities (fatigue, skin toxicity). 
In the current protocol we propose the combination of platinum containing 
chemoradiation as adjuvant therapy for patients with triple negative breast cancer. 
The 3 week radiation extensively studied in the adjuvant regimens will be combined 
with weekly carboplatin at a dose of AUC of 2 per week. 

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2.6. 
Background for Primary Objective 
2.6.1. 
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 v3.0 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 pain. 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 v3.0 (see Appendix 1). 
 
2.7. 
Correlative Studies Background 
2.7.1. 
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. [30] 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, 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. [31-32] 
 
2.7.2. 
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%. [33-34] 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 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. [35] 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 

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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). 
The Delfin MoistureMeter D is a portable, non-invasive device that measures the 
dielectric constant of the skin and subcutaneous fat that can be used to provide a quantitative 
assessment of radiation-induced breast fibrosis. A report by Nuutinen et al. demonstrates that 
two years post irradiation, the dielectric constant of the irradiated skin increases with 
increasing clinical findings of subcutaneous ﬁbrosis. Since the dielectric constant of 
biological tissues is related to tissue water content, these results demonstrate that the free 
water content and thus the extracellular fluid increases in irradiated skin. [36] 
The LENT/SOMA scoring system will be used in the reporting of late radiation 
morbidity in this protocol as well as quantifiable measurements using the MoistureD device. 
Patients will be assessed with the MoistureD device, as part of their physical examination at 
baseline and during the follow up visits.  
Measurements will be obtained at the tumor bed (B1) and at the indexed breast (B2) 
away from the surgical bed and at the two symmetrical, corresponding areas in the 
contralateral breast (CB1 and CB2), with a total of four areas of assessment per patient. For 
each area, the measurement will be repeated three times, and the average value and standard 
deviation calculated. We will obtain measurement of breast fibrosis at baseline (prior to 
treatment) and at each subsequent follow-up after completing radiotherapy. 
 
2.7.3. 
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. [37] 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.  
 

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2.7.4. 
Blood collection for genomic studies 
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-1 polymorphisms that have been reported to be correlated 
with the development of fibrosis following radiotherapy for treatment of breast cancer. [37] 
 
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 data office of New York University School of Medicine (NYUSM). When the study 
information is disclosed outside of NYUSM 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. NYUSM will not disclose the code key, except as required by law. 
 
 
3. PATIENT SELECTION 
 
3.1. Inclusion Criteria 
3.1.1. 
Age older than 18. 
3.1.2. 
Pre- or post-menopausal women with Stage I and II breast cancer, triple 
negative tumors (upper limit of positivity <10% for estrogen receptors, <20% 
for progesterone receptors) 
3.1.3. 
Biopsy-proven invasive breast cancer, excised with negative margins of at 
least 1 mm 
3.1.4. 
Status post segmental mastectomy, after sentinel node biopsy and/or axillary 
node dissection (Tumors < 5 mm in size do not require nodal assessment) or 
after mastectomy. 
3.1.5. 
No previous chemotherapy 
3.1.6. 
Patient needs to be able to understand and demonstrate willingness to sign a 
written informed consent document 
 
3.2. Exclusion Criteria 
3.2.1. 
Previous radiation therapy to the ipsilateral breast 
3.2.2. 
Active connective tissue disorders, such as lupus or scleroderma 
3.2.3. 
Pregnant or lactating women 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
Patients will have completed all breast surgical procedures 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 (< 1 mm). If the patient meets the eligibility criteria after re-excision, she may be 

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entered into the left or right breast cancer strata. AJCC staging criteria will be used to identify 
Clinical Stage I, II breast cancer patients eligible to this study. All eligible women who are 
referred to the Radiation Oncology Department at NYU School of Medicine for radiation 
following surgery for breast cancer will be offered the opportunity to participate in this 
experimental protocol. 
 
4.2 
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. 
 
4.3 
Randomization Process 
This study is a Phase I-II non-randomized trial. Patients will be registered within strata 
defined by menopausal status (pre/post) and by nodal status (yes/no). 
 
 
5. TREATMENT PLAN  
 
5.1. 
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. 
 
5.2. 
Duration of Therapy 
The treatment will consist of 17 fractions, Monday to Friday, week 2, Sunday to Friday week 
3 and Sunday to Friday week 4, for 3 weeks total time (over a total of 19 days), see study 
calendar in Section 13. 
 
5.3. 
Duration of Follow Up 
Patients will be seen for follow-up at day 45-60 and then yearly thereafter, see study calendar 
in Section 13. 
 
5.4. 
Alternatives 

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At the time of study accrual all patients will be offered access to standard six weeks 
radiotherapy. If patients are stage I and are carrier of node negative breast cancer they will be 
offered the option to be treated with an established accelerated whole breast radiotherapy 
regimen (3 weeks Canadian trial). [2]  
 
5.5. 
Compensation 
No compensation is available for participating in the study. 
 
 
6 SURGERY 
 
Patients will have completed all breast surgical procedures 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. All patients with tumors > 5 mm in diameter require nodal assessment, by 
sentinel node biopsy and/or axillary dissection. 
 
 
7 CHEMOTHERAPY 
 
7.1 
Carboplatin Administration 
Carboplatin will be administered with AUC of 2.0 which will be repeated weekly for 6 
weeks. Carboplatin (NSC 241240), other names: Paraplatin® 
 
7.2 
Formulation 
Carboplatin Injection is a premixed aqueous solution of 10 mg/mL Carboplatin. 
Carboplatin Injection, 10 mg/mL can be further diluted to concentrations as low as 0.5 
mg/mL with 5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection, USP. 
When prepared as directed, Carboplatin aqueous solutions are stable for 8 hours at room 
temperature (25°C). Since no antibacterial preservative is contained in the formulation, it is 
recommended that Carboplatin aqueous solutions be discarded 8 hours after dilution. 
How Carboplatin is Supplied 
Carboplatin Injection, 10 mg/mL is available in multi-dose vials, individually carton: 
NDC 0703-4244-01 
10 mg/mL, 5 mL Vial 
NDC 0703-4246-01 
10 mg/mL, 15 mL Vial 
NDC 0703-4248-01 
10 mg/mL, 45 mL Vial 
NDC 61703-0339-56 
10 mg/mL, 60 mL Vial 
 

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Storage 
Unopened vials of Carboplatin Injection, 10 mg/mL are stable to the date indicated on the 
package when stored at 25°C (77°F) excursions permitted from 15°–30°C (59°–86°) [see USP 
Controlled Room Temperature] Protect from light. 
Carboplatin injection, 10 mg/mL multidose vials maintain microbial, chemical, and physical 
stability for up to 14 days at 25°C following multiple needle entries. 
Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration. Solutions for infusion should be discarded 8 hours after preparation. 
Handling and Disposal 
Procedures for proper handling and disposal of anti-cancer drugs should be considered. 
Several guidelines on this subject have been published. There is no general agreement that all of 
the procedures recommended in the guidelines are necessary or appropriate. NOTE: Aluminum 
reacts with Carboplatin causing precipitate formation and loss of potency, therefore, needles or 
intravenous sets containing aluminum parts that may come in contact with the drug must not be 
used for the preparation or administration of Carboplatin. 
 
7.3 
Pharmacokinetic information 
Carboplatin is an alkylating agent which covalently binds to DNA; possible crosslinking and 
interference with the function of DNA. Distribution: Vd: 16 L/kg; into liver, kidney, skin, and 
tumor tissue. Protein binding: 0%; however the platinum from carboplatin becomes 30% 
irreversibly bound. Metabolism: Minimally hepatic to aquated and hydroxylated compounds. 
Half-life elimination: Terminal: 22 – 40 hours. In patients with creatinine clearance 
> 60 mL/minute: 2.5-5.9 hours. Excretion: Urine (~60% - 90%) within 24 hours.  
 
7.4 
Dosing of Carboplatin 
The dose will be calculated to reach a target area under the curve (AUC) of concentration x 
time according to the Calvert formula using an estimated glomerular filtration rate (GFR) from 
Cockcroft‐ Gault formula. 
• 
The initial dose of carboplatin must be calculated using GFR. In the absence of new 
renal obstruction or other renal toxicity greater than or equal to CTCAE grade 2 
(serum creatinine 1.5 x ULN), the dose of carboplatin will not be recalculated for 
subsequent cycles, but will be subject to dose modification as noted. 
• 
In patients with an abnormally low serum creatinine (less than or equal to 0.6 mg/dl), 
due to reduced protein intake and/or low muscle mass, the creatinine clearance should 
be estimated using a minimum value of 0.7 mg/dl. If a more appropriate baseline 
creatinine value is available within 4 weeks of treatment that may also be used for the 
initial estimation of GFR. 
• 
Calvert Formula: Carboplatin dose (mg)= target AUC x (GFR +25) 
• 
NOTE: the GFR used in the Calvert formula to calculate AUC-based dosing 
should be capped at 125 mL/min for patients with normal renal function. No 
higher estimated GFR values should be used. 
• 
Maximum carboplatin dose (mg) = target AUC(mg·min/mL) x 150 mL/min 

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• 
The maximum carboplatin dose should not exceed target AUC(mg·min/mL) x 150 
mL/min, but it may be less. Many trials have a target carboplatin AUC of 6 which 
would result in a maximum dose of 900 mg.  Highly specific settings like bone 
marrow transplant or pediatric studies may target a higher AUC (see table below). 
 
Maximum AUC-based Carboplatin Dose 
AUC 
Maximum Carboplatin Dose 
6 
900 mg 
5 
750 mg 
4 
600 mg 
 
• For the purposes of this protocol, the GFR is considered to be equivalent to the estimated 
creatinine clearance. The estimated creatinine clearance (ml/min) is calculated by the 
method of Cockcroft‐ Gault using the following formula:  
 
Creatinine Clearance (mL/min) = [140‐Age (years)] x Weight (kg) x 0.85 
72 x serum creatinine (mg/dl) 
Notes: 
Weight in kilograms (kg): In general, actual weight should be used for estimation of 
GFR. However, it is also acceptable to utilize adjusted weight, when concerned about 
safety in a specific patient, in accordance with local institutional policy. Suggested ideal 
and adjusted weight calculations:  
Ideal weight (kg) = (((Height (cm)/2.54) – 60) x 2.3) + 45.5 
Adjusted weight (kg) = ((Actual weight – Ideal weight) x 0.40) + Ideal weight 
 
The Cockcroft‐Gault formula above is specifically for women (it includes the 0.85 
factor). 
 
At the time of a dose modification for toxicity:  
If the creatinine at the time of a dose modification is lower than the creatinine used to 
calculate the previous dose, use the previous (higher) creatinine; if the creatinine at the 
time of a dose modification is higher than the creatinine used to calculate the previous 
dose, use the current (higher) creatinine. This will ensure that the patient is actually 
receiving a dose reduction.  
 
If the dose of carboplatin (mg) at the time of dose modification, is higher than the previous 
dose due to the use of the Cockcroft‐Gault formula [when the previous dose was 
calculated using the Jelliffe formula and IDMS to “non‐IDMS” conversion (if 
applicable)], use the same method that was used to calculate the previous dose [Jelliffe 
formula and IDMS to “non‐IDMS” conversion (if applicable)], to calculate the dose of 
carboplatin (mg) at the time of dose reduction. This will ensure that the patient is actually 
receiving a dose reduction. 
 
7.5 
Potential Drug Interactions 
Increased 
Effect/Toxicity: 
Aminoglycosides 
increase 
risk 
of 
ototoxicity 
and/or 
nephrotoxicity. When administered as sequential infusions, observational studies indicate a 

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potential for increased toxicity when platinum derivatives (carboplatin, cisplatin) are 
administered before taxane derivatives (docetaxel, paclitaxel). 
 
7.6 
Adverse Effects of Carboplatin 
Common known potential adverse events: >10%: Central nervous system: Pain. 
Endocrine & metabolic: Hyponatremia, hypomagnesemia, hypocalcemia, hypokalemia. 
Gastrointestinal: Nausea, vomiting, abdominal pain. Hematologic: Myelosuppression is dose 
related, schedule related, and infusion-rate dependent (increased incidences with higher doses, 
more frequent doses, and longer infusion times) and, in general, rapidly reversible upon 
discontinuation. (dose related and dose limiting; nadir at ~21 days with q 3 weeks dosing 
recovery by ~28 days), leukopenia, anemia, neutropenia, thrombocytopenia. Hepatic: Alkaline 
phosphatase increased, AST increased. Neuromuscular & skeletal: Weakness. Renal: Creatinine 
clearance decreased, BUN increased. 
 
Less common known potential adverse events, 1% - 10%: Central nervous system: Neurotoxicity 
Dermatologic: Alopecia. Gastrointestinal: Constipation, diarrhea, stomatitis/mucositis, taste 
dysgeusia. Hematologic: Hemorrhagic complications. Hepatic: Bilirubin increased. Local: Pain 
at the injection site. Neuromuscular & skeletal: Peripheral neuropathy. Ocular: Visual 
disturbance. Otic: Ototoxicity. Renal: Creatinine increased. Miscellaneous: Infection, 
hypersensitivity. 
 
Rare known potential adverse events, <1% (Limited to important or life-threatening): 
Anaphylaxis, anorexia, bronchospasm, cardiac failure, cerebrovascular accident, embolism, 
Erythema, fever, hemolytic uremic syndrome, hyper-/hypotension, malaise, necrosis (associated 
with extravasation), nephrotoxicity, neurotoxicity, pruritus, rash, secondary malignancies, 
urticaria, vision loss. 
 
7.7 
Adverse Events Reporting 
Adverse events to be reported based on CTC AE 4.0 version and RTOG toxicity criteria and 
reported to the NYU IRB as well as medwatch based on the NYU SAE reporting guidelines. 
The Study will be monitored by NYU Cancer Institute Data Monitoring and Safety Committee 
as per DSMC chapter and Internal Audit Committee as per institutional SOPs. 
 
8 RADIOTHERAPY SPECIFICATIONS 
 
8.1 
Treatment Planning Using either 3D-CRT or Hybrid IMRT Technique 
In the context of this study, this protocol will implement accelerated whole breast 
radiotherapy using either 3D-CRT or a hybrid IMRT approach.  
 
 
 
 
 

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8.2 
Radiotherapy schedule 
WEEK 
WEEK 2 
WEEK 3 
WEEK 4 
DAY # 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 
 
M 
T 
W 
T 
F 
 
S 
M 
T 
W 
T 
F 
 
S 
M 
T 
W 
T 
F 
Tx 
wb* wb wb wb wb 
 
wb wb wb wb 
wb 
B+ 
 
wb 
wb 
wb 
wb 
wb 
B+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*wb = target is whole breast, 2.7 Gy/fraction 
+B = target is the original tumor bed, 3 Gy/fraction  
 
8.3 
Radiotherapy target 
Defined above. 
 
8.4 
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 2 daily radiation fractions of 3.0 Gy to the tumor bed to a total dose 
of 6.0 Gy to the tumor bed.  The whole breast will be treated for five consecutive fractions 
Monday to Friday the first week of RT, then for an additional five fractions from Sunday to 
Thursday the second week of RT and finally for another five fractions Sunday to Thursday the 
last week of RT. The second and third Fridays of RT the patient will be treated only to the tumor 
bed with a 3 Gy fraction. Consequently, the tumor bed will receive a total dose of 46.5 Gy. 
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 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. 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) 
 
8.5 
Target Delineation 
8.5.1 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% 
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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.  
8.5.2 The GTV is the tumor bed, as identified on CT. 
8.5.3 The PTVTumor is the GTV with an additional 1.0 cm 3D margin. PTVTumor 
will not extend outside of the breast tissue and, if necessary, will be consistently 
modified (“clipped”) to be confined within PTVBreast. 
 
8.6 
Normal structure delineation 
The following structures will be contoured: contralateral breast, thyroid, 
ipsilateral lung, contralateral lung, heart, and LAD 
 
8.7 
Technical Factors 
8.7.1 Dose calculation with heterogeneity corrections must be used. 
8.7.2 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. 
8.7.3 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. 
8.7.4 Hybrid Whole Breast planning - IMRT (intensity modulated radiation therapy)  
tangents plus non-IMRT tangents 
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. 
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. 
 
8.7.5 3D-CRT Whole Breast Planning 
1. 3D-CRT tangents will be used to obtain a uniform dose distribution. 
2. Wedges and/or field within fields can be used. 
8.7.6 Boost plan 
1. Non-coplanar beam arrangement is encouraged, but not required 
2. Electrons, 3D-CRT or IMRT may be used 
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) 
4. No photon beam will be directed toward heart, lung, contralateral breast, 
or thyroid 
5. Inclusion of soft tissue not irradiated by the whole breast tangents is 
allowed to aid in target coverage 
8.7.7 Composite plan is created with all fields. 
 

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8.7.8 Dose Constraints 
 
1. Target volume dose constraints for Whole Breast Plans: 
 
a. Whole breast IMRT hybrid tangents 
 
• 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. 
• PTVBreast: ≥95% of the volume must receive ≥100% of the whole 
breast dose. 
• PTVTumor: ≥98% of the volume must receive ≥100% of the whole 
breast dose. 
 
b. Whole breast 3D-CRT tangents 
• PTVBreast max 112% (to >1cc) of the whole breast dose. 
• PTVBreast: ≥95% of the volume must receive ≥100% of the whole 
breast dose. 
• PTVTumor: >98% of the volume must receive >100% of the whole 
breast dose. 
 
2. Target volume dose constraints for Boost Plans: 
 
a. IMRT Boost 
 
• 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. 
• PTVTumor: >98% of the volume must receive >100% of the total boost 
dose. 
• >60% of the PTVBreast volume must not receive >50% of the total 
boost dose. 
b. 3D-CRT Boost 
• Breast max 112% (to>1cc) of the boost dose. This can be  achieved with 
6 MV, 16 MV, or 6MV/16 MV photons. 
• PTVTumor: ≥98% of the volume must receive ≥100% of the total boost 
dose. 
• > 60% of the PTVBreast volume must not receive >50% of the total 
boost dose 
 
3. Composite of tangents and boost fields 
a. PTVTumor: >98% of the volume must receive >100% of the total dose, where 
total dose is the whole breast dose plus boost dose. 
b. PTVBreast: >95% of the volume must receive >100% of the whole breast dose. 
c. PTVBreast: no more than 60% of PTVBreast should receive > 4455 cGy 
 
4. Normal tissue dose constraints: 
 
a. Heart: <5% of the heart receives >5 Gy. 
 
b. Ipsilateral lung: <15% of the ipsilateral lung receives >10 Gy. 
 
c. Contralateral lung: <15% of the contralateral lung receives >5 Gy. 
 
d. LAD: maximum <1800cGy, mean <1000 cGy. 
 
8.8 
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 

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“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 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. 
For Carboplatin toxicity, please see table below: 
 
Criteria for Dose Modification of carboplatin 
Toxicity 
Actions 
 
Non-hematological Toxicity 
Grade 3 
Decrease Carboplatin to AUC 1. 5.  If grade 3 toxicity 
continues with an AUC of 1.5, decrease Carboplatin to 
AUC of 1.  If grade 3 toxicity continues with an AUC of 
1, discontinue study regimen. 
Grade 4 
Decrease Carboplatin to AUC of 1.5.  If grade 4 toxicity 
continues with an AUC of 1.5, decrease Carboplatin to 
AUC of 1.   If grade 4 toxicity continues with an AUC 
of 1, discontinue study regimen. 
 
Hematological Toxicity 
Grade 2 Thrombocytopenia (platelets < 75.0- 50.0 x 
109/L) 
Hold until platelet recovers to 100 x109/L and decrease 
Carboplatin to AUC of 1.5.  If grade 2 toxicity continues 
with an AUC of 1.5, decrease Carboplatin to AUC of 1.  
If grade 2 toxicity continues with an AUC of 1, 
discontinue study regimen. 
Grade 3 Thrombocytopenia (platelets < 50.0 – 25.0 x 
109/L) 
Hold until platelet recovers to 100 x109/L and decrease 
Carboplatin to AUC of 1.5.  If grade 3 toxicity continues 
with an AUC of 1.5, decrease Carboplatin to AUC of 1.  
If grade 3 toxicity continues with an AUC of 1, 
discontinue study regimen.    
Grade 4 Thrombocytopenia (platelets < 25.0 x 109/L) 
Hold until platelet recovers to 100 x109/L and decrease 
Carboplatin to AUC of 1.5.  If grade 4 toxicity continues 
with an AUC of 1.5, decrease Carboplatin to AUC of 1.  
If grade 4 toxicity continues with an AUC of 1, 
discontinue study regimen. 
Grade 3 Neutropenia (neutrophils < 1.0 – 0.5 x 109/L) 
Hold the treatment until ANC < 1.5 – 1.0 x109/L. 
Grade 4 Neutropenia (neutrophils < 0.5 x 109/L) 
Use GMCSF per treating physician discretion. 
 
Any hematological or non-hematological toxicity 
requiring interruption for ≥ 3 weeks 
Discontinue carboplatin. 
 

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10 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. 
 
10.2 Expedited Adverse Event Reporting 
Expedited AE reporting will utilize the descriptions and grading scales as presented in 
Appendix 1. SAEs that occur in this study must be promptly reported to the study P.I. (Dr. 
Carmen Perez) as well as to the NYU IRB, if they fall under the policy of reportable events to 
IRB (see 10.3) (550 First Avenue, Veteran’s Administration Hospital, 10th floor, West Wing, 
New York, NY 10016) and to the NYU Clinical Trials Office (462 First Avenue, New York, NY 
10016) for reporting to the NYUCI Data Safety Monitoring Committee. The rest of the events 
(SAE or any other) will be brought to attention of the DSMP. The IRB would need to see their 
regular reports as a result of analysis of all SAEs and AEs.  
 
10.3 Routine Adverse Event Reporting Guidelines 
The IRB Reportable Events Forms (available electronically at 
http://irb.med.nyu.edu/files/irb/attachments/Reportable_event_11-09_0.doc) should be used for 
all adverse events 
 
 
11 CORRELATIVE/SPECIAL STUDIES 
 
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.” 
 
 
 
11.2 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. 
 
 
12 INVESTIGATOR RESOURCES 
 
12.1 Qualifications 
Drs. Adams, Novick, Speyer, Volm and Tiersten and Huppert will be responsible for the 

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accrual and care of study patients. Maria Fenton-Kerimian, N.P. will be in charge of study 
screening, eligibility checklist and will participate in the process of acquisition of an informed 
consent, after the faculty has discussed the trial with the patient. Ms. Fenton-Kerimian will also 
provide the research nursing component of the study, including supervising the QOL assessment 
of the patients. 
Drs. DeWyngaert and Joszef provide the necessary expertise in physics to conduct the 
proposed study. Dr. Goldberg will participate in the design of the study and oversee the 
statistical analysis and interpretation of the data. Linda Rolnitzky will participate in the 
development of the study data collection forms and the ongoing data review and monitoring as 
well as conduct the analyses as required. Martin Donach will be the study coordinator for the 
study. 
 
12.2 Use of NYU Facilities 
Therapy will be administered in the Department of Radiation Oncology at the Clinical 
Cancer Center and at Tisch Hospital. 
 
12.3 Conflict of interest 
There are no conflicts of interest to declare. 

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13 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 
Moisture-D assessment 
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 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 DATA REPORTING / REGULATORY CONSIDERATIONS 
 
15.1 Monitoring plan 
The NYU PRMC Data and Safety Monitoring Committee (DSMC) is the monitoring board 
for this study. The Committee will review safety at scheduled intervals (not less than once/year) 
and at the time of the final analysis according to the NYU Data Safety Monitoring Plan Charter.  
Stopping rules - 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. 
 
15.2 Data management 
Data will be entered into the NYUCI Oracle Clinical database and maintained at NYUSOM 
by trained Radiation Oncology data managers.  
The Oracle 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 
NYU 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 
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. 
 
15.3 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 

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auditing agencies to satisfy regulatory requirements.  Anonymous data will be shared with Weill 
Cornell Medical College due to the relocation of study personnel so that a paper may be 
published on the findings of this study.  The anonymous data will only be shared with Weill 
Cornell Medical College after a transfer agreement is fully executed. 
 
16.  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 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 
Estimated number of eligible patients for the trial is 3-5/month. Therefore, we estimate that 
the required 35 patients will be recruited within 12 months. With 35 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%. If we observe 14 or more events among these 35 patients, the null 
hypothesis that the rate is 25% will be rejected.  
Amendment: 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  

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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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APPENDICIES and Informed Consent Template 
APPENDIX 1. – Common Toxicity Criteria  
Acute Toxicity from Common Terminology Criteria for Adverse Events v3.0 (CTCAE), Published: August 9, 2006 
  
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 - Informed Consent Template  
 
Attach a copy of the protocol informed consent form.  
 
 

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APPENDIX 3 - Toxicity Tracking Form 
. 
 
 

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APPENDIX 4 – Quality of Life Questionnaires  
 
Appendix 4.1 Quality of Life questionnaire used at baseline  

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Appendix 4.2 Quality of Life questionnaire used for follow-up visits  
 

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Appendix 4.3 Form for missing Quality of Life information 
 

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NYU Comprehensive Cancer Center  
Fibrosis Measurement Device: Moisture meter D 
 
 
Date:____________  
 
 
 
Treatment Site:_________________ 
Treatment Completion Date:_______________ 
Treatment Dose:________________ 
Protocol___________ 
 
 
 
 
 
 
 
 
 
 
Area of Fibrosis:_____________________ 
 
Grade of Fibrosis:____________________ 
 
 
 
 
 
Moisture Meter D Measurement 
Location 
Right Breast 
Left Breast 
Upper Outer Quadrant 
 
 
Upper Inner Quadrant 
 
 
Lower Outer Quadrant 
 
 
Lower Inner Quadrant 
 
 
Nipple/ Areola Complex 
 
 
 
 
 

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