PHASE I - II STUDY OF PRONE ACCELERATED BREAST AND NODAL IMRT(Intensity-Modulated Radiation Therapy)
Phase: NA
Conditions: Lymphedema
Sponsor: NYU Langone Health

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TITLE 
 
PHASE I - II STUDY OF PRONE ACCELERATED BREAST 
AND NODAL IMRT 
 
 
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. 
 
 
160 East 34th street 
 
 
New York, NY – 10016 
  
 
Telephone : 212-731-5003 
Fax: (212) 731-5513 
E-mail address: silvia.formenti@nyumc.org 
 
 
 
Co-Investigators:  
Nelly Huppert, M.D. 
160 East 34th Street 
New York, NY 10016 
Telephone: (212) 731-5030 
Fax: (212) 731-5512 
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 
 
 
 
Brian Yeh, M.D. 
160 East 34th Street 

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New York, NY 10016 
Telephone: 
(212) 731-5044 
Fax: (212) 731-5512 
E-mail address:brian.yeh@nyumc.org 
 
Linda Moy, M.D. 
560 First Avenue 
New York, NY 10016 
Telephone:  (212) 731-5353 
E-mail: Linda.Moy@nyumc.org 
 
Adrienne Newburg, M.D. 
550 First Avenue 
New York, NY 10016 
Telephone: (212) 263-7300 
E-mail: Adrienne.Newburg@nyumc.org 
 
Barry Rosenstein, Ph.D. 
1 Gustave L. Levy Place 
New York, NY 10029 
Telephone: (212) 241 9408 
Fax: (212) 996 8927 
E-mail address: barry.rosenstein@mssm.edu 
 
 
 
 
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 
 
Olivier Maisonet, N.P. 
160 East 34th Street 
New York, NY 10016 
Telephone: (212) 731-5035 
Fax: (212) 731-5512 
E-mail address:Olivier.Maisonet@nyumc.org 
 
Judith D. Goldberg, Sc.D. (Biostatistics) 
650 First Avenue, KIP 5 534 

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New York NY 10016 
Telephone: (212) 263 0314 
Fax: (212) 263 8570 
E-mail address: jd.goldberg@nyumc.org 
 
 
 
 
 

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TABLE OF CONTENTS 
 
Page 
SCHEMA ....................................................................................................................................... 7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................. 8 
1. 
OBJECTIVES ....................................................................................................................... 9 
1.1 
Primary Objectives........................................................................................................ 9 
1.2 
Secondary Objectives.................................................................................................... 9 
2. 
BACKGROUND ................................................................................................................... 9 
2.1 
NYU Research in Hypofractionated Whole Breast Radiotherapy ................................ 9 
2.2 
NYU Experience on Accelerated Concomitant Boost Whole Breast: NYU 03-30 .... 10 
2.3 
Rationale for Prone Radiotherapy: NYU 05-181........................................................ 11 
2.4 
Rationale for Treating Axillary Level III and Supraclavicular Nodes ....................... 12 
2.5 
Late Radiation Effects and Assessment of Risk ......................................................... 13 
2.6 
Dose Selection for Treating Breast and Nodal Stations.............................................. 16 
2.7 
Quality of Life Assessment ......................................................................................... 21 
2.8 
Measuring the Late Toxicities of Breast and Nodal Radiation ................................... 21 
3 
PATIENT SELECTION .................................................................................................... 23 
FOR COHORT A : INCLUDE PATIENTS WHO HAVE UNDERGONE SLNB 
WITHOUT COMPLETION ALND) ........................................................................................ 23 
3.1 
Inclusion Criteria ........................................................................................................ 23 
3.2 
Exclusion Criteria ....................................................................................................... 24 
4 
REGISTRATION PROCEDURES ................................................................................... 24 
4.1 
General Guidelines...................................................................................................... 24 
4.2 
Registration Process .................................................................................................... 24 
5  
TREATMENT PLAN ......................................................................................................... 25 
5.1 
General Concomitant Medication and Supportive Care Guidelines ........................... 25 
5.2 
Duration of Therapy .................................................................................................... 25 
5.3 
Duration of Follow-up ................................................................................................ 25 
5.4 
Alternatives ................................................................................................................. 25 
5.5 
Compensation ............................................................................................................. 25 
6 
SURGERY ........................................................................................................................... 25 
7 
RADIOTHERAPY SPECIFICATIONS ........................................................................... 26 
7.1 
Treatment Planning using Hybrid IMRT Technique .................................................. 26 
7.2 
Dose Specification ...................................................................................................... 26 
7.3 
CT Simulation ............................................................................................................. 26 

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7.4 
Target Delineation ...................................................................................................... 27 
7.5 
Technical Factors ........................................................................................................ 27 
7.6 
Portal Imaging ............................................................................................................. 29 
8 
DOSE MODIFICATIONS AND STOPPING CRITERIA ............................................. 29 
8.1 
Dose Modification ...................................................................................................... 29 
8.2 
Stopping Criteria ......................................................................................................... 29 
9 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .......................... 29 
9.1 
Adverse Events and Potential Risks List .................................................................... 29 
9.2 
Expedited Adverse Event Reporting ........................................................................... 30 
9.3 
Routine Adverse Event Reporting Guidelines ............................................................ 30 
10 CORRELATIVE/SPECIAL STUDIES ............................................................................ 30 
10.1 Blood Collection for TGF-beta 1 Polymorphism Determination ............................... 30 
10.2 Lymphocyte Isolation, DNA Extraction, PCR Amplification and DNA Sequencing 30 
10.3 Test Method ................................................................................................................ 30 
10.4 Denaturing High Performance Liquid Chromatography (DHPLC) ............................ 32 
10.5 Coding of Samples ...................................................................................................... 32 
11 INVESTIGATOR RESOURCES ...................................................................................... 32 
11.1 Qualifications .............................................................................................................. 32 
11.2 Use of NYU Facilities ................................................................................................. 33 
11.3 Conflict of Interest ...................................................................................................... 33 
12 STUDY CALENDAR ......................................................................................................... 34 
13 DATA REPORTING / REGULATORY CONSIDERATIONS ..................................... 34 
13.1 Monitoring Plan .......................................................................................................... 34 
13.2 Stopping Rules (for the individual patient and for the study as a whole) ................... 35 
13.3 Data Management ....................................................................................................... 35 
13.4 Confidentiality ............................................................................................................ 35 
14 STATISTICAL CONSIDERATIONS .............................................................................. 36 
14.1 Endpoints/Objectives: ................................................................................................. 36 
14.2 Statistical Considerations, Sample Size and Interim Analysis Plans .......................... 36 
14.3 Statistical Analysis ...................................................................................................... 36 
14.4 Accrual estimates ........................................................................................................ 37 
14.5 Sample Size Considerations/Interim Analysis ............................................................ 37 
REFERENCES ............................................................................................................................ 39 
APPENDIX 1 – COMMON TOXICITY CRITERIA ............................................................. 43 
APPENDIX 2 – TOXICITY TRACKING FORM .................................................................. 45 

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APPENDIX 3 – QUALITY OF LIFE QUESTIONNAIRES .................................................. 46 
PROTOCOL SYNOPSIS 
 
TITLE 
Phase I - II Study of Prone Accelerated Breast 
and Nodal IMRT 
STUDY PHASE 
I - II  
INDICATION 
Stage II - III breast cancer (AJCC 2002) 
PRIMARY OBJECTIVES 
Feasibility, Acute toxicity 
SECONDARY OBJECTIVES 
Incidence of re-simulation supine, 
QOL (defined by RTOG-PRO), 
Late toxicity: e.g., fibrosis, telangiectasia,  
Local control: Time to Progression, 
EXPLORATORY OBJECTIVES 
Survival and evaluation of genetic 
determinants of breast fibrosis 
HYPOTHESES 
Prone IMRT to breast, level III and SCV 
nodes is feasible and well tolerated in a 3-
week regimen 
STUDY DESIGN 
Prospective, single arm uncontrolled 
PRIMARY ENDPOINTS 
Acute, late effects, QOL-PRO 
SECONDARY ENDPOINTS 
Local control, DFS, OS 
SAMPLE SIZE BY TREATMENT GROUP 104 patients. Cohort A – 30 patients 
SUMMARY OF SUBJECT ELIGIBILITY 
CRITERIA 
Newly diagnosed breast cancer patients after 
segmental mastectomy, and axillary dissection 
of at least 8 lymph nodes.  
INVESTIGATIONAL PRODUCTS 
DOSAGE AND ADMINISTRATION 
N/A 
CONTROL GROUP 
N/A 
PROCEDURES 
N/A 
STATISTICAL CONSIDERATIONS 
Phase I - II  
 

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SCHEMA 
 
 
ELIGIBLE PATIENTS 
 
 
INFORMED CONSENT 
 
 
Whole breast/chest wall, level 1- III (includes Cohort A) and SCV nodes 
IMRT at 2.7 Gy x 15 fractions 
 
Total dose to the indexed breast = 40.50 Gy 
 
Daily 0.5 Gy boost to the tumor bed (15 fractions) 
 
Total dose to tumor bed = 48 Gy 
 
 
 
All patients will be followed for toxicity and outcome (i.e., local and systemic recurrence, 
survival). In addition, patients will complete a Quality of Life (QOL) self-assessment at 
baseline, week 3, day 45-60 and 2-yr follow-ups. 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ADL 
Activities of daily living 
AE 
Adverse event 
ATM 
Ataxia Telangiectasia Mutated 
BED 
Biologically Effective Dose 
CBC 
Complete blood count 
CI 
Confidence interval 
CBCT 
Cone-Beam CT 
CRF 
Case report/Record form 
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 
Gy 
Gray 
Hgb 
Hemoglobin 
IBV 
Ipsilateral Breast Volume 
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 
RIF 
Radiation-Induced Fibrosis 
RR 
Response rate 
RTOG 
Radiation Therapy Oncology Group 
SAE 
Serious adverse event 
SD 
Stable disease 
SNP 
Single Nucleotide Polymorphism 
SSCP 
Single-Strand Conformation Polymorphism 
TGF-beta1 
Transforming Growth Factor beta-1  
TV 
Treatment Volume 

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1. OBJECTIVES 
 
1.1 
Primary Objectives 
1.1.1 
To evaluate feasibility of prone IMRT to breast, level III and supraclavicular 
nodes (physics and dosimetry parameters) 
1.1.2 
To estimate acute toxicity of prone IMRT to breast, level III and 
supraclavicular nodes 
 
1.2 
Secondary Objectives 
1.2.1 
To estimate the incidence of re-simulation to improve dosimetry after initial 
prone set-up 
1.2.2 
To evaluate changes in QOL of patients assessed at baseline and after 
treatment 
1.2.3 
To estimate incidence of late radiation toxicity (e.g., lymphedema, fibrosis 
and telangiectasia) and to examine genetic determinants of breast fibrosis 
 
1.3 
Exploratory Objectives 
1.3.1 
To estimate local recurrence rates  
1.3.2 
To estimate median Disease Free Survival (DFS) 
1.3.3 
To estimate median Time to Progression 
1.3.4 
To estimate median Overall Survival (OS) 
 
1.4 
Cohort A Objectives 
1.4.1   To explore feasibility of treating in the prone position a comprehensive nodal 
volume, that includes axillary nodal levels I and II in addition to the fields already 
treated per this protocol (i.e., axillary nodal levels III, supraclavicular fossa and 
breast or chest wall tangents, depending on whether the patient has undergone 
segmental mastectomy or mastectomy, respectively) 
 
       
 
2. BACKGROUND 
 
2.1 
NYU Research in Hypofractionated 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 (James Melissa, Lehman et al. 2008). 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 (greater 
than 2 Gy per fraction) does not affect breast appearance or toxicity, and does not seem to affect 
local recurrence or five years survival rates. 
 

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Hypofractionation 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. As background for the proposed study that will test a 
novel technique to target the breast and level III/SCV nodes in the prone position for women 
with 1 - 5 involved nodes, a review of the whole breast radiation research studies conducted 
thus far is detailed below. 
2.2 
NYU Experience on Accelerated Concomitant Boost Whole Breast: NYU 03-30 
 
Inspired by the hypo-fractionated Canadian trial (Whelan, MacKenzie et al. 2002) we developed 
a technique that utilizes IMRT to deliver accelerated prone whole breast radiotherapy with a 
concomitant boost to the tumor bed. The rationale for adding a boost to the tumor cavity derived 
from the results of a prospective randomized trial conducted by the EORTC (Bartelink, Horiot 
et al. 2001). A recent update of the trial demonstrated a 10-year cumulative incidence of local 
recurrence of 10.2% versus 6.2% for the no boost and the boost group respectively 
(p < 0.0001) (Bartelink, Horiot et al. 2007). 
 
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 study NYU 03-
30. CT simulation was performed with the patient on a dedicated prone breast board, in the 
exact position used for treatment.  
 
From September 2003 to August 2004, the planned accrual was completed, with 90 patients 
treated in the protocol (mean follow-up of 39 months, range 1 - 72 months). Median age was 58 
years old (range 28 – 80 yo). Median tumor size was 13 mm (range 1 - 40 mm). Acute toxicity 
was generally mild and is summarized in Table 1 (RTOG score). Most common toxicity was 
radiation dermatitis, which tended to occur the week after completion of treatment. 
 
Table 1 - Acute Toxicity Observed from Study 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, late toxicity, and to determine cosmetic 
results. Because of blood collection, once sufficient time has elapsed to measure late effects, the 
study will enable us to explore associations between specific genomic profiles and the 

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occurrence of fibrosis (Formenti 2005). In addition, this trial generated preliminary data on dose 
sparing to the heart and lung when patients are treated prone (Darby, McGale et al. 2005). 
 
2.3 
Rationale for Prone Radiotherapy: NYU 05-181  
 
Despite the demonstrated feasibility and advantages of the 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 the heart and lung. Since no obvious clinical characteristics predict for this 
exception, NYU led a subsequent 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 1 mm of margin, no more 
than 3 positive lymph nodes for breast cancer, at least two weeks post chemotherapy (if 
indicated), no history of prior or concurrent malignancy (within 3 years), and no history of 
active connective tissue disorders. Patients underwent CT simulation in both the prone and 
supine positions. Treatment followed in the optimal position that ensured the smallest volume of 
heart and lung respectively, in the target field.  
 
From 2006 to 2009 the study met the planned accrual of 400 patients: 200 with left and 200 
with right breast cancer. Results are summarized in Table 2. Among right breast cancer patients, 
the prone position was optimal in sparing lung volume in 98% (195/200), reducing the volume 
of lung in the treatment field by a mean 107 cc (SD 75, range 463,0). In the five patients treated 
supine, the choice for supine treatment was based on patient’s preference since there was no 
significant difference in lung sparing between the two positions. For left breast cancer patients, 
the prone position was optimal in 85% (170/200), with lung volume reduced by a mean of 93 cc 
(SD 72, range 334, 9) and heart volume reduced by a mean of 11 cc (SD 23, range 0,220).  
However, in 15% of left breast patients, the best position was supine reducing the amount of 
heart in the treatment field by a mean of 6 cc (SD 8, range 0,41). 
 
Table 2 - Protocol 05-181 - Interim Results: Left/Right Breast Cancer by Supine/Prone 
Positioning  
 
Supine 
Prone 
Total 
Left 
30 
170 
200 
Right 
5 
195 
200 
 
The experience gathered from the NYU 05-181 study provides support for all patients to first 
undergo a CT simulation in the prone position when the breast is to be irradiated. An additional 
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reveals that it exceeds the following normal tissue dose constraints: 
 
a. 
Heart: > 5% of the heart volume receives greater than 5 Gy. 
b. 
Ipsilateral lung: >15% of the ipsilateral lung receives greater than 10 Gy. 
c. 
Contralateral lung: >15% of the contralateral lung receives greater than 5 Gy. 
 
2.4 
Rationale for Treating Axillary Level III and Supraclavicular Nodes 
 
After breast surgery and an adequate axillary dissection (i.e., at least 8 nodes retrieved in the 
axillary dissection specimen from level I and II) it is possible to identify patients with 1 - 5 
positive nodes who require radiotherapy to both the indexed breast/chest wall and the draining 
nodal stations that the surgeon did not include in the traditional level I - II axillary dissection, 
i.e., level III and supraclavicular stations. We are proposing to test a new technique that 
extends prone set up to also include these lymph node regions. 
 
Limiting treatment to the supraclavicular fossa and level III axilla in patients with an adequately 
dissected axilla is supported by several published studies. Regional nodal recurrences are rare 
(occurring in 1 - 5%) in patients with early stage invasive breast cancer who have undergone 
breast conserving therapy (Fisher, Anderson et al. 2002; Moran and Haffty 2002; Harris, Hwang 
et al. 2003). Several institutions choose to treat only the level III axilla and supraclavicular 
nodal stations in patients who have undergone surgical treatment of level I/II axilla. This 
technique was documented recently by Liengsawangwong, who utilized CT-delineated nodal 
stations to improve target coverage of SCV and level III axillary nodes (Liengsawangwong, Yu 
et al. 2007) in patients who had undergone axillary level I/II dissection and were found to have 
positive lymph nodes. 
 
Locoregional recurrences have been extensively studied in post-mastectomy patients as well. 
After chest wall recurrences, nodal failures in the undissected axillary level III or 
supraclavicular fossa are the second most common type of regional recurrence and occur more 
commonly in patients with four or more positive lymph nodes (Table 3) (Taghian, Jeong et al. 
2004). 
 
Table 3 - Locoregional Recurrence Rates in Post-mastectomy Patients without Radiotherapy 

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The impact of extracapsular extension on outcome of post-mastectomy patients is controversial. 
Some studies report higher risk of distant recurrence, but no change in locoregional recurrence 
(Donegan, Stine et al. 1993) while others document higher rates of locoregional recurrence in 
patients with extracapsular extension (Garg, Strom et al. 2004; Huang, Tucker et al. 2005). 
 
There may be a subset of high-risk patients who would benefit from adjuvant radiotherapy to 
the entire previously-dissected axilla. For example, an axillary boost to treat levels I/II 
decreased nodal recurrence, although it did not affect overall survival in a cohort of breast 
cancer patients with ten or more positive lymph nodes treated with breast conservation 
therapy (Chang, Feigenberg et al. 2007). 
 
In summary, for some patients, the toxicity of any nodal radiotherapy will outweigh the benefit, 
while other patients have superior outcomes when the entire axilla and supraclavicular fossa are 
treated. There is likely a subset of breast cancer patients who could benefit from the advantage 
of limiting nodal radiotherapy to axillary level III and supraclavicular nodes after adequate 
axillary level I/II lymph node dissection, without impairing their chances of loco-regional 
control. Based on the previously referenced studies, we propose utilizing an approach of limited 
nodal treatment in patients with invasive breast cancer treated by breast conservation therapy or 
mastectomy with one to five involved lymph nodes after adequate dissection of level I/II axilla. 
These patients could also be studied to explore the feasibility and safety of an accelerated 
regimen of 3 weeks to the prone breast (or chest wall), and level III and supraclavicular nodes. 
 
2.5 
Late Radiation Effects and Assessment of Risk 
 
For patients who require regional nodal irradiation, an accelerated regimen of three weeks is 
very appealing, but in the past it has generally been discouraged because of concerns regarding 
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injury.  The current protocol is likely to overcome some concerns of lymphedema by avoiding 
irradiation of the axillary stations where a surgical dissection was performed. Nevertheless, a 
field that includes axillary level III and the supraclavicular nodes will also include most of the 
ipsilateral brachial plexus, warranting cautious radiobiological modeling of late effects of 
radiotherapy to this target. 
 
The severity of late effects is known to be dependent on both total dose and fraction size. In the 
linear-quadratic model, sensitivity to fraction size is expressed by the alpha/beta ratio, with a 
lower ratio indicating increased sensitivity. In a recent review, Kurtz summarized known 
alpha/beta values for tissues irradiated in breast cancer treatment (Table 4) (Kurtz 2005). 

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Table 4 - A Review of Results Summarized by Kurtz et al. 
 
Due to low alpha/beta ratios for most of these tissues, it is possible that higher rates of late 
complications could be observed with an accelerated regimen. To clinically evaluate the impact 
of hypofractionation on brachial plexus injury, Powell et al. reported their experience with an 
accelerated schedule in a seminal paper published in 1990, describing the late effects of a group 
of 449 patients irradiated to the breast and regional lymph nodes with mean brachial plexus 
dose 45.9 Gy in 15 fractions (3 Gy per fraction) versus 54 Gy in 30 fractions (1.8 Gy per 
fraction) (Powell, Cooke et al. 1990). He noted a cumulative actuarial incidence of radiation-
induced brachial plexus injury at 5.5 years of 5.9% versus 1.0% for the large and small fraction 
size group, respectively. It is important to note that the dose was higher than our proposed dose 
of 40.50 Gy given in 2.7 Gy daily fractions and that the fields included the entire axilla. 
 
Lymphedema is another late complication sensitive to fraction size. Hayes documented rates of 
lymphedema in 2,579 patients followed at a single institution who underwent breast 
conservation therapy between 1970 and 2005. In patients receiving radiotherapy to the breast, 
breast + SCV, and breast + SCV + axillary boost, lymphedema occurred in 16%, 23%, and 
31%, respectively (Hayes, Freedman et al. 2008). In a large phase III randomized trial, 46% of 
mastectomy patients experienced arm swelling at some point after radiotherapy (Deutsch, Land 
et al. 2008). For radical mastectomy patients, total mastectomy and radiotherapy patients, and 
total mastectomy patients in this trial, arm edema was recorded at least once in 58.1%, 38.2%, 
and 39.1% of patients, respectively (p < 0.001) and at last recorded measurement in 30.7%, 
14.8%, and 15.5%, respectively (p ≤ 0.001). We anticipate that reduction of the size of the field 
for nodal radiation will reduce rates of lymphedema despite an accelerated treatment regimen. 
 
Most patients experience lymphedema within the first years after treatment, but it can continue 
to increase in severity for more than five years after treatment in over 50% of patients (Bar Ad, 
Cheville et al. 2009). Therefore, subjects will need to be carefully followed for progressive 
lymphedema, for at least five years after radiotherapy is completed. 
 

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2.6 
Dose Selection for Treating Breast and Nodal Stations  
 
The linear-quadratic model (Lea 1942) can be used to determine whether the proposed IMRT 
protocol should result in a roughly equal probability of tumor control compared with a standard 
schedule, but without increasing the potential for normal tissue damage. The equation 
describing the single dose survival curve (Douglas and Fowler 1976) using this model is  
 
-lnS = (D + D2) 
 
where S is the surviving fraction, D is the total dose and  and  are tissue specific parameters. 
If the total radiation dose is delivered in a series of n fractions of dose d, rather than a single 
exposure, then the surviving fraction can be described as  
 
-lnS = n(d + d2) 
 
which can be called the biological effect E. This equation can be rewritten as  
 
E = (nd)(+d) = ()(nd)(1+d//) 
 
If this equation is divided through by , then E/ = (nd)(1+d//). The quantity E/ has been 
termed the biologically effective dose (15) or BED that is similar to the previously suggested 
extrapolated response dose (Barendsen 1982).  
 
Hence, 
BED = (nd)(1+d//) 
 
This equation was used to calculate the BEDs for early and late responses, and tumor control for 
a standard schedule representing twenty-three 2 Gy fractions delivered once per day to the 
whole breast plus seven 2 Gy boost fractions to the tumor bed over a 39 day period. The 
proposed AIMRT schedule consists of fifteen IMRT fractions of 2.7 Gy to the whole breast and 
regional nodes and 3.2 Gy to the tumor bed delivered over an 18-day period. These calculations 
assume full repair takes place during the 24-hour or greater interval between fractions. Table 5 
lists the BEDs for tumor control in addition to the early responses, erythema and desquamation, 
as well as the late responses, telangiectasia and fibrosis. The / values used for these 
computations were reported in previous studies (Steel, Deacon et al. 1987; Matthews, Meeker et 
al. 1989; Turesson and Thames 1989; Thames, Bentzen et al. 1990; Archambeau, Pezner et al. 
1995; Yamada, Ackerman et al. 1999). 
 

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Table 5 - Biologically Effective Doses 
Normal Tissue Responses 
 
/ 
(Gy) 
Standard 
Schedule 
Standard 
Schedule 
AIMRT 
Schedule 
 
 
(2 Gy x 23 
in 39 days) 
(2 Gy x 25 
in 39 days) 
(2.7 Gy x 15 
in 18 days) 
Brachial plexus injury 
2 
92 Gy2 
100 Gy2 
95 Gy2 
Fibrosis 
2 
92 Gy2 
100 Gy2 
95 Gy2 
Telangiectasia 
4 
69 Gy4 
75 Gy4 
68 Gy4 
Erythema 
8 
58 Gy8 
63 Gy8 
54 Gy8 
Desquamation 
11 
54 Gy11 
59 Gy11 
50 Gy11 
 
Tumor Control 
 
/ 
(Gy) 
Standard 
Schedule 
AIMRT 
Schedule 
AIMRT 
Schedule 
 
 
(2 Gy x 30 
in 44 days) 
(3.2 Gy x 15 
in 18 days) 
(2.7 Gy x 15 
in 18 days) 
Tumor 
2 
120 Gy2 
125 Gy2 
95 Gy2 
Tumor* 
2 
116 Gy2 
125 Gy2 
95 Gy2 
Tumor 
4 
90 Gy4 
86 Gy4 
68 Gy4 
Tumor* 
4 
86 Gy4 
86 Gy4 
68 Gy4 
Tumor 
10 
72 Gy10 
63 Gy10 
51 Gy10 
Tumor* 
10 
68 Gy10 
63 Gy10 
51 Gy10 
*Taking into account cell proliferation during the course of treatment. 
 
In terms of normal tissue responses, it can be observed from Table 5 that the BED values for the 
IMRT treatment are generally lower than the BEDs for the standard treatment for the early 
responses of erythema and desquamation. In addition, the BEDs are similar for the late 
responses of telangiectasia and fibrosis and brachial plexus injury. Hence, it would appear 
unlikely that the IMRT treatment will result in a greater risk of complications compared with 
the standard protocol. 
 
With respect to tumor control, the classic dilemma typically encountered when a hypo-
fractionated protocol is substituted for a standard treatment plan, is either a reduced probability 
of tumor control or an increased risk for late complications. This is due to the observation that 
fractionation generally results in greater sparing of late responding tissues compared with 
tumors. This finding is reflected in the relatively large / values derived for tumors and small 
/ values for late responses (Thames and Hendry 1987). 
 
In contrast to this generalization, evidence exists that breast cancer cells display a relatively low 
/. This comes from in vitro studies in which / values determined for breast cancer cell 
lines were generally about 4 Gy (Steel, Deacon et al. 1987; Matthews, Meeker et al. 1989; 
Yamada, Ackerman et al. 1999). The way in which this problem is diminished for this study is 

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through the use IMRT to limit the dose to the whole breast. Therefore, for the AIMRT protocol, 
the tumor bed will receive 3.2 Gy per fraction, whereas the breast and level III and 
supraclavicular will receive 2.7 Gy per fraction. 
 
An even lower / of 2 Gy can be calculated using the results of a prospective randomized trial 
(Baillet, Housset et al. 1990) in which a standard treatment of twenty-five 1.8 Gy fractions 
resulted in approximately the same level of tumor recurrence as a hypo-fractionated protocol of 
two 4.5 Gy plus two 6.5 Gy fractions. Therefore, if it is assumed that the BEDs for the two 
treatments were roughly equal, this yields an / value of 2 Gy. Although there is evidence in 
the papers cited to support the use of these relatively low / values for BED calculations, 
tumors on average exhibit greater / values in the range of 10 Gy (Williams, Denekamp et al. 
1985; Thames and Hendry 1987).  
 
Viewing the results of the BED calculations for tumor control presented in Table 5, if the / 
values are assumed to be in the range of 4 - 10 Gy, then there would appear to be only a small 
loss in BED for the AIMRT treatment, while for the 2 Gy / value, the BED value for the 
alternate treatment actually is greater than the standard. In addition, it should be noted that the 
hypo-fractionated treatment also represents an accelerated protocol in which the total dose is 
delivered in only 18 days. Therefore, little or no tumor proliferation is likely to occur during the 
course of this proposed treatment as opposed to the standard treatment in which it is probable 
that tumor proliferation will take place thereby decreasing the chances for tumor control.  
 
In order to take into account tumor proliferation for the BED calculation, it can be estimated 
that the number of clonogenic cells in the tumor (N) is related to the initial number of clonogens 
(N0) by the expression  
 
ln(N/N0 ) = (T-Tk) 
 
where  is a constant related to the potential doubling time Tpot of the tumor by the expression, 
 = ln2/Tpot, T is the total treatment time, and Tk (the "kick-off" time) is the time at which 
accelerated repopulation begins (15,26) (Travis and Tucker 1987; Fowler 1989). Note, this 
relationship is only valid for values of T greater than Tk. Therefore,  
 
ln(N/N0 ) = (ln2/Tpot )(T-Tk) 
 
Hence, the biological effect for a fractionated treatment should be decreased to take into 
account the increase in the number of cells due to repopulation and becomes:  
 
E = n (d+d2) - (ln2/Tpot )(T-Tk) 
 
If this equation is divided through by , then the BED equation results and is given by 
 
E/ = [(nd) (1 + d//)] – [ln2(T-Tk)/(Tpot)] 

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Hence, it is necessary to determine values for , the initial slope of the cell survival curve, as 
well as for Tpot and Tk. However, this may be either difficult or impossible to accomplish. 
Therefore, estimates are often made for these values in order to calculate the BED. For the 
purpose of these calculations, values of 0.3 for , (Steel, Deacon et al. 1987; Matthews, Meeker 
et al. 1989) 13 days for Tpot (Stanton, Cooke et al. 1996; Haustermans, Fowler et al. 1998) and 
21 days for Tk were used. However, it must be stressed that the actual values for any given 
patient may differ significantly. Nevertheless, an effort was made to correct for tumor 
proliferation even though these calculations may be somewhat imprecise, as they still provide a 
better estimate of BED than a determination of this parameter performed in the absence of any 
cell proliferation correction factor.  
 
As presented in Table 5, the equation above which incorporates a cell proliferation correction 
factor produces small decreases in the BEDs for the standard treatment. Therefore, taking into 
consideration tumor proliferation during treatment, the IMRT schedule results in BED values 
greater to or equal to the standard treatment for / values of either 2 or 4 Gy and is only 
slightly lower when a 10 Gy / value is used. In addition, it must be kept in mind that there is 
a range of Tpot values for a population of tumors. Therefore, the accelerated nature of the 
AIMRT treatment may have a particularly beneficial effect for those patients whose tumors are 
characterized by relatively short Tpot values.  
 
Of course, if cell proliferation is taken into account, this also diminishes the BEDs and lessens 
the severity of the anticipated early responses for the standard schedule compared with the 
AIMRT schedule. This should not affect late responses because the Tk is generally greater than 
the total treatment time for late responding tissues as compensatory proliferation usually does 
not begin until after completion of a standard protocol. However, even if the BEDs were 
decreased to take into account cell proliferation, this would probably result in only slightly 
diminished BEDs for erythema and desquamation for the standard schedule, resulting in BEDs 
comparable to the AIMRT schedule.  
 
2.6.1  
Rationale for this Approach 
 
The proposed treatment approach entails radiotherapy to axillary level III and SCV, defined by 
CT imaging obtained in a prone position using IMRT technique. We anticipate that this will 
improve target coverage, toxicity, and tolerability for several reasons.  First, by avoiding 
radiotherapy to level I and II axillary lymph nodes in a previously dissected axilla, we anticipate 
reduced risk of lymphedema.  Additionally, treatment in the prone position has been shown to 
reduce dose to heart and lungs (Formenti, Gidea-Addeo et al. 2007), which may decrease late 
toxicity to these organs. Finally, while standard 3-field and 4-field techniques provide 
inadequate lymph node coverage in the prone position (refer to preliminary data in Section 
2.6.2), use of IMRT technique will enable prone target coverage while maintaining low doses to 
normal tissues.  
 
2.6.2  
Preliminary Data 
 

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To evaluate the dosimetric feasibility of the prone IMRT treatment approach and to compare its 
dosimetric performance compared to other standard techniques, we explored six treatment 
planning techniques to target the breast and axillary level III and supraclavicular nodes.  
 
The CT images of 10 breast cancer patients (7 left, 3 right) who underwent simulation in both 
prone and supine positions were used for planning. Supraclavicular and level III axillary lymph 
node regions, breast tissue, tumor bed, heart, and ipsilateral lung were manually contoured. Six 
treatment plans were created for each patient; all utilized tangential fields to target breast tissue. 
A three-dimensional conformal radiotherapy (3DCRT) plan with a single anterior-oblique field, 
a 3DCRT plan with anterior-oblique and posterior axillary boost fields, and an intensity-
modulated radiotherapy (IMRT) plan were utilized to target regional nodes in both prone and 
supine positions. Dose-volume histograms were compared to evaluate lymph node coverage and 
normal tissue dose. Two-tailed student t-test was used to identify statistically significant 
differences between planning techniques. Nodal target and normal tissue doses from the six 
techniques are summarized below in Tables 6 - 8. 
 
Table 6 - Prone Compared to Supine Positioning 
 
 
  
mean (st dev, range) 
mean (st dev, range) 
p-value 
 
3-field supine 
3-field prone 
 
PTV-V50  
53.96% (18.20, 25.70-75.00) 
34.10% (21.91, 4.50-73.10) 
0.0407559 
Lung-V40 
14.70% (4.84, 8.30-24.40) 
3.81% (4.41, 0.10-14.40) 
0.0000530 
Lung-V20  
22.98% (5.23, 16.50-33.80) 
9.52% (5.98, 2.10-21.20) 
0.0000434 
Lung-V5  
31.57% (5.82, 24.00-42.10) 
13.57% (6.83, 4.90-27.90) 
0.0000056 
Heart-V20 
0.15% (0.30, 0.00-0.80) 
0.04% (0.08, 0.00-0.20) 
0.2687512 
Heart-V5 
0.72% (1.07, 0.00-2.70) 
0.38% (0.44, 0.00-1.20) 
0.3436903 
Spinal 
cord-
Dmax  
1131.90 cGy (333.38, 782.00-1712.00) 
889.60 cGy (273.04, 263.00-1258.00) 
0.0922816 
 
IMRT supine 
IMRT prone 
 
PTV-V50  
94.59% (0.32, 94.00-95.00) 
95.48% (0.69, 94.80-97.00) 
0.0016879 
Lung-V40 
15.28% (3.06, 11.90-21.80) 
6.54% (1.98, 3.50-9.00) 
0.0000005 
Lung-V20  
27.22% (6.88, 18.60-37.80) 
12.48% (3.29, 8.20-17.90) 
0.0000089 
Lung-V5  
43.73% (7.47, 32.30-56.90) 
24.18% ( 5.09, 19.50-33.40) 
0.0000021 
Heart-V20 
0.12% (0.26, 0.00-0.70) 
0.37 (0.72, 0.00-2.00) 
0.3011538 
Heart-V5 
0.62% (0.93, 0.00-2.40) 
0.93% (1.08, 0.00-3.70) 
0.6524424 
Spinal 
cord-
Dmax  
3490.70 cGy (765.64, 1963.00-4266.00) 
2805.20 cGy (953.84, 1762.00-4112.00) 
0.0932683 
 
4-field supine 
4-field prone 
 
PTV-V50  
60.77% (12.56, 36.90-83.50) 
38.93% (20.65, 1.80-78.60) 
0.0104802 
Lung-V40 
12.29% (7.38, 0.70-25.30) 
5.59% (4.70, 0.00-15.60) 
0.0262689 
Lung-V20  
20.53% (8.34, 2.20-34.10) 
10.93% (6.65, 2.10-26.30) 
0.0107219 
Lung-V5  
29.78% (10.27, 5.60-43.70) 
16.40% (8.19, 5.90-36.50) 
0.0047406 
Heart-V20 
0.50% (1.05, 0.00-2.80) 
0.06% (0.10, 0.00-0.20) 
0.2870816 
Heart-V5 
1.84% (3.09, 0.10-8.50) 
0.53% (0.42, 0.20-1.20) 
0.2864321 
Spinal 
cord-
Dmax  
836.20 cGy (225.60, 560.00-1258.00) 
739.10 cGy (134.95, 418.00-872.00) 
0.2580200 
 
These results indicate that all 3DCRT plans had inadequate lymph node coverage, with mean 
planning target volume (PTV) V50 Gy 54% supine and 34% prone (3-field 3DCRT), and 61% 
supine and 39% prone (4-field 3DCRT). Compared to these techniques, IMRT significantly 
improved nodal coverage, with mean PTV V50 Gy 95% supine and 95% prone (p < 0.001, two-

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tailed t-test). Prone positioning resulted in significantly lower ipsilateral lung doses: mean V20 
Gy was 10% prone versus 23% supine (3-field 3DCRT, p < 0.001, two-  
tailed t-test); 21% supine versus 11% prone (4-field 3DCRT, p = 0.01, two-tailed t-test); and 
12% prone versus 27% supine (IMRT, p < 0.001, two-tailed t-test). Among the 7 left breast 
cancer patients, there was no statistically 
significant difference in mean heart V20 Gy or V5 Gy (p > 0.05, two-tailed t test). 
 
2.7 
Quality of Life Assessment 
 
Quality of life (QOL) assessments will be performed by patients at regular intervals (i.e., 
baseline, last week of treatment, 45 - 60 days from starting radiotherapy and 2-year follow-up). 
Patients status post mastectomy will be asked to answer applicable questions only in the QOL 
assessment. This trial will use the QLB and QLF questionnaires from the RTOG. 
 
The QLB and QLF questionnaires are derived from a validated integration of parts of the 
BCTOS and MOS SF 36. BCTOS is a validated questionnaire that measures cosmetic results 
based on 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 
(Stanton, Krishnan et al. 2001). MOS SF36 is a common QOL questionnaire used in cancer 
patients (Shelbourne 1992; Ware and Sherbourne 1992). 
 
2.8 
Measuring the Late Toxicities of Breast and Nodal Radiation 
 
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 (Hoeller, Tribius et al. 2003). In comparison, when LENT/SOMA criteria were used, 
telangiectasia and pigmentation were upgraded in 34% and 36% of patients, respectively, and 
Table 7 - Supine IMRT Compared to  Supine 3F/4F 
 
mean 
mean 
p-value 
 
3-field supine 
IMRT supine 
 
PTV-V50  
53.96 
94.59 
0.0000014 
Lung-V40 
14.70 
15.28 
0.7525528 
Lung-V20  
22.98 
27.22 
0.1382071 
Lung-V5  
31.57 
43.73 
0.0007318 
Heart-V20 
0.15 
0.12 
0.8059355 
Heart-V5 
0.72 
0.62 
0.8108750 
Spinal cord-Dmax  
1131.90 
3490.7 
0.00000005 
 
4-field supine 
IMRT supine 
 
PTV-V50  
60.77 
94.59 
0.0000001 
Lung-V40 
12.29 
15.28 
0.2521097 
Lung-V20  
20.53 
27.22 
0.0027134 
Lung-V5  
29.78 
43.73 
0.0027134 
Heart-V20 
0.5 
0.12 
0.4401863 
Heart-V5 
1.84 
0.62 
0.4509997 
Spinal cord-Dmax  
836.2 
3490.7 
0.000000004 
Table 8 - Prone IMRT Compared to Prone 3F/4F 
  
Mean 
mean 
p-value 
 
3-field prone 
IMRT prone 
 
PTV-V50  
34.10 
95.48 
0.0000001 
Lung-V40 
3.81 
6.54 
0.0909352 
Lung-V20  
9.52 
12.48 
0.1876868 
Lung-V5  
13.57 
24.18 
0.0009626 
Hrt-V20 
0.04 
0.37 
0.1577367 
Hrt-V5 
0.38 
0.93 
0.2202274 
Cord-Dmax  
889.60 
2805.20 
0.0000091 
 
4-field prone 
IMRT prone 
 
PTV-V50  
38.93 
95.48 
0.0000001 
Lung-V40 
5.59 
6.54 
0.5635124 
Lung-V20  
10.93 
12.48 
0.5172072 
Lung-V5  
16.4 
24.18 
0.0200405 
Hrt-V20 
0.06 
0.37 
0.2744447 
Hrt-V5 
0.53 
0.93 
0.2089303 
Cord-Dmax  
739.1 
2805.20 
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telangiectasia was downgraded in 45% of patients. 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 tool in 
grading and recording late radiation toxicity as compared to the RTOG scale. Specifically, 
fibrosis scores correlated well with the LENT/SOMA scoring system (Spearman's rho 0.78, p = 
0.01). The LENT/SOMA scoring system will be used in the reporting of late radiation morbidity 
in this protocol. 
 
2.8.1 
Quantitative Measurement of Thyroid Function 
 
Patients undergoing radiotherapy for invasive breast cancer are at higher risk of 
hypothyroidism. One recent study documented hypothyroidism in 18% of patients with stage 
II/III invasive breast cancer who had undergone radiotherapy, compared to only 6% (p < 0.001) 
of an age-matched control group from the general population (Reinertsen, Cvancarova et al. 
2009). 
 
As such, patients will undergo thyroid function testing, including measurement of serum thyroid 
stimulating hormone (TSH) and free T4 levels, at baseline and at yearly intervals after 
completion of radiotherapy. 
 
2.8.2 
Quantitative Measurement of Lymphedema 
 
Patients will be assessed for lymphedema at baseline, end of treatment, and at yearly intervals 
after completion of radiotherapy. Arm circumference at sites 10 cm above and below the 
antecubital fossa will be obtained. Mild, moderate, and severe lymphedema is defined as a 
difference of 0.5 to 2 cm, 2.1 to 3 cm, and greater than 3 cm, respectively, of arm circumference 
at one or more measurement sites on the treated versus untreated side. Lymphedema 
progression is defined as transition from lower to higher grade at any time point. Similar 
lymphedema classification systems have been used in previously published studies 
(Keramopoulos, Tsionou et al. 1993; Bar Ad, Cheville et al. 2009). 
 
 
2.8.4  
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 identification of 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) 
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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 (Quarmby, Fakhoury et al. 2003). 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. 
 
2.8.5  
Blood Collection for Future Genomic Studies 
 
The purpose of this portion of the study will be to collect blood from each subject accrued to the 
study for 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 (Quarmby, Fakhoury et al. 2003). 
 
It is first important to note that Dr. Rosenstein’s (co-investigator) laboratory has extensive 
experience in the detection of genetic alterations using Denaturing High Performance Liquid 
Chromatography (DHPLC) (Atencio, Iannuzzi et al. 2001; Iannuzzi, Atencio et al. 2002; 
Bernstein, Teraoka et al. 2003). In addition, our group is part of the WECARE consortium of 
four laboratories that is in the process of using DHPLC to screen 2100 breast cancer patients for 
mutations and SNPs in a variety of genes associated with DNA repair and radiation responses. 
Hence, our laboratory has substantial expertise performing genetic analysis using DHPLC and 
will therefore be able to immediately implement this portion of the project. 
 
For the purpose of this trial blood will be collected to enable future genomic analysis for this 
polymorphism to explore association with the incidence of grade 3 and 4 late complications at 3 
years follow up and for other related research studies. Methods details of DHPLC are covered in 
Section 10.4.  
 
3 PATIENT SELECTION  
 
For Cohort A : Include patients who have undergone SLNB without completion 
ALND) 
 
3.1 
Inclusion Criteria 
3.1.1  
Pre- or post-menopausal women with stage II - III breast cancer (AJCC 
2002) 
3.1.2  
Biopsy-proven invasive breast cancer, excised with negative margins of at 

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least 1 mm 
3.1.3  
Status post segmental mastectomy or mastectomy and axillary node 
dissection with removal of at least 8 nodes  
3.1.4  
One to 5 involved lymph nodes identified at axillary staging 
3.1.5  
At least 2 weeks from last chemotherapy or before chemotherapy 
3.1.6  
No more than sixty days from final surgery to simulation if no systemic 
therapy (includes chemotherapy and Hormonal therapy) is given 
3.1.7  
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  
More than 5 involved nodes identified at axillary staging 
3.2.3  
Current treatment for active connective tissue disorders, such as lupus or 
scleroderma 
 
3.2.4 
Pregnant or lactating women 
3.2.5 
Less than 35 years old 
3.2.6 
Prior concurrent malignant other than basal or squamous cell carcinoma or 
carcinoma in situ of cervix unless disease free > 3years 
 
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 
entered into the left or right breast cancer strata. AJCC staging criteria will be used to identify 
clinical stage II - III 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 or their legal guardians 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 (IRB). 
All subjects/patients are informed in the consent that participation or refusal to participate in the 

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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. 
 
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 
or equivalent, to prevent skin dryness and reduce erythema. 
 
5.2 
Duration of Therapy 
 
The treatment will consist of 15 fractions, with one fraction daily for five days a week, for 3 
consecutive weeks. 
 
5.3 
Duration of Follow-up 
 
Patients will be seen for follow-up at 45 - 60 days from first radiotherapy treatment, and then 
yearly for up to 5 years. 
 
5.4 
Alternatives 
 
At the time of study accrual, all patients will be offered access to standard six weeks 
radiotherapy, including 5 weeks of treatment to the whole breast or chest wall and regional 
lymph nodes using a standard 4-field plan, followed by a boost to the tumor bed or scar if 
required. 
 
5.5 
Compensation 
 
No compensation is available for participating in the study. 
 
6 SURGERY 
 
Patients will have completed all breast cancer 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 entered onto the study. Patients must also undergo lymph node dissection of axillary levels 

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I/II with removal of at least 8 nodes. 
 
7 RADIOTHERAPY SPECIFICATIONS 
 
7.1 
Treatment Planning using Hybrid IMRT Technique 
 
In the context of a Phase I/II prospective study, this protocol will test whole breast and regional 
nodal radiotherapy using a hybrid approach. Patients will receive whole breast radiotherapy in a 
prone position with a concomitant daily boost to the tumor bed over three weeks, a technique 
which has previously been evaluated in over 500 patients (NYU 03-30 and NYU 05-181) and 
has shown excellent tolerance and results. In addition, an intensity modulated radiation therapy 
(IMRT) technique will be used to deliver concomitant radiotherapy to axillary level III and 
supraclavicular lymph nodes. In patient Cohort A, axilliary levels I and II will also be part of 
the radiation target. Patients status post mastectomy will receive whole reconstructed 
breast/chest wall radiotherapy and nodal irradiation. A concomitant boost to the scar region will 
be offered only to patients without reconstruction. 
 
7.2 
Dose Specification 
 
Patients will receive 15 daily radiation fractions of 2.7 Gy, Monday to Friday for three weeks, 
to the entire breast/chest wall and axillary level III and supraclavicular nodes with a daily 
concomitant boost of 0.5 Gy to the tumor bed, for a total daily dose of 3.2 Gy to the tumor bed 
(2.7 Gy + 0.5 Gy). The overall dose will be 40.5 Gy to the breast/chest wall, axillary level III 
and supraclavicular nodes, and 48.0 Gy to the tumor bed. 
 
7.3 
CT Simulation 
 
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 3.75 mm 
or less. Prior to the patient lying prone on the table for scanning, the borders of the breast/chest 
wall fields will be marked with radio-opaque CT fiducial markers. These markers will be used 
to outline the breast/chest wall 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. Patients status post mastectomy 
will also be simulated prone with similar field borders. In addition, the chest wall scar will 
carefully be marked with radio-opaque CT fiducial markers. 
 
Contouring of breast tumor bed, axillary level III nodes, supraclavicular nodes, indexed and 
contralateral breast tissue, ipsilateral brachial plexus, esophagus, heart, right and left lung, 
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performed in order to guide beam arrangement and optimal normal tissue avoidance. In patients 
who have undergone pre-operative breast MRI, the breast glandular tissue will be contoured 
with the help of a radiologist co-investigator (Drs. Moy and Newburg), to better inform the 
design of the treatment fields. 
 
The patient will be CT scanned and treated in the supine position if the patient cannot lie prone, 
or if the prone plan fails to satisfy the dose constraints specified in Section 7.5.6 
 
7.4 
Target Delineation 
 
7.4.1 
The physician designs tangent fields to encompass the whole breast. The 
PTVBreast is created from the 50% isodose line associated with the tangent 
fields. Technically 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 0.6 cm margin. The PTVBreast volume 
overlapping the heart and lung is excluded.  
7.4.2 
PTVTumor is the tumor bed, as identified on CT with an additional 1.0 cm 
3D margin. Post-mastectomy PTVTumor is the tumor bed and depending on 
clinical judgement may or may not include the scar. 
7.4.3 
PTVTumor Eval is the PTVTumor cropped 0.6 cm from the skin. 
7.4.3 
PTVNodes includes axillary level III and supraclavicular lymph nodal 
regions as identified on CT with an additional 0.5 cm 3D margin.For patients 
in Cohort A PTVNodes will include axillary levels I-III and supraclavicular 
nodal regions as identified on CT with an additional 0.5 cm 3D margin, 
However, the PTV will not be expanded medially to better spare the 
esophagus. 
7.4.4 
PTVNodesEval is the PTVNodes cropped 0.6 cm from the skin. 
 
7.5 
Technical Factors 
 
7.5.1 
Dose calculations will include heterogeneity corrections. 
7.5.2 
Whole Breast fields – 3D tangents plus IMRT tangents 
1. The prone position requires careful placement of the isocenter during 
planning to avoid collision between the gantry and the breast board, 
couch, or patient. 
2. 3D tangents deliver nominally 67% of the whole breast dose, using 6 MV 
photons and including 2-3 cm flash. The fields are wedged and weighted 
to obtain a uniform dose distribution, normalized to allow approximately 
105% maximum dose. 16 MV photons may be used for patients with 
large separations to reduce magnitude of dose maximum. 
3. IMRT tangents deliver nominally 33% of the whole breast dose, using 6 
MV photons and including 2-3 cm flash. The 3D tangents are used as a 
base for optimization. 
 

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7.5.3 
Axillary level I-III and supraclavicular nodes (PTVNodes) 
1. Three or more IMRT fields.  
 
7.5.4 
PTVTumor fields 
1. Non-coplanar beam arrangement is encouraged, but not required. 
2. Integrated boost within the IMRT tangents is allowed. 
3. Electron therapy may be utilized. 
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. 
6. If the PTVTumor, as visualized in the beams-eye-view (BEV), is within 1 
cm of the body surface, 1 cm of flash will be added to the field(s), 
painting fluence for IMRT fields. 
 
7.5.5 
IMRT Optimization 
 
IMRT optimization is performed either by using the 3D tangents plan as a base plan 
for all IMRT fields, or by using a plan with all tangent fields (IMRT and 3D) as a 
base for the IMRT nodal fields. Regardless, a single plan is created with 3D breast 
tangent fields, IMRT breast tangent fields, boost fields if used, and IMRT axillary 
level III and supraclavicular nodal fields. 
 
7.5.6 
Dose Constraints 
 
The dose constraints below represent acceptance criteria for the resulting dose 
distribution. 
 
1. Target volume dose constraints: 
• PTVTumor: V 48 Gy > 98% 
• PTVBreast: V 40.5 Gy ≥ 95% 
• PTVNodesEval: V 38.5 Gy > 95% 
2. Normal tissue dose constraints: 
a. Heart: V 5 Gy < 5% 
b. Ipsilateral lung: V 10 Gy < 20% 
c. Contralateral lung: V 5 Gy < 15% 
d. Spinal cord: 37.5 Gy maximum 
e. Spinal cord plus 0.5 cm margin: 40 Gy maximum 
f. Thyroid: contralateral lobe 15 Gy maximum 
g. Esophagus: V 30 Gy < 50%, 40.5 Gy maximum  
h. Ipsilateral brachial plexus: 42 Gy maximum 
i. Contralateral breast: Efforts should be made to keep the contralateral 
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7.6 
Portal Imaging 
 
Portal images of orthogonal setup fields will be acquired on days 1, 2, and 3 then weekly 
thereafter. In addition, portal images will be acquired of each treatment field (except where 
geometrically impractical) during the first three days of treatment.  
 
Cone beam CT (CBCT) of the nodal region will be acquired once on a day when orthogonal 
setup fields are imaged. No alignment adjustment will be made based on the CBCT. 
 
8 DOSE MODIFICATIONS AND STOPPING CRITERIA 
 
8.1 
Dose Modification 
 
In case of grade 3 acute skin toxicity occurring during the course of the 3-week treatment, the 
dose per fraction of the remaining treatment fractions will be reduced to 2 Gy/fraction until 
completion. 
 
8.2 
Stopping Criteria 
 
Regional nodal recurrences occur in 1 - 5% of patients with early stage breast cancer who have 
undergone mastectomy or breast conserving therapy (Fisher, Anderson et al. 2002; Moran and 
Haffty 2002; Harris, Hwang et al. 2003). While most nodal recurrences occur within the first 
five years after treatment, nodal recurrences have been documented for more than twenty years 
after completion of treatment (Lukens, Vapiwala et al. 2009). 
 
Based on this data, a stopping rule for regional node recurrences will be implemented with an 
evaluation after every 21 patients are observed for at least 1 year post treatment. The schema is 
described in Section 14. This rule allows early stopping based on an excess of incidence of 
regional node recurrences (greater than 5% of patients). 
 
9 ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
9.1 
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. Breast edema and tenderness are 
additional possible acute side effects. Acute (≤ 60 days after first day of treatment) and late 
toxicity (> 60 days after first day of treatment) will be reported as scheduled in the study 
calendar. This study will utilize the descriptions and grading scales as described in Common 
Terminology Criteria for Adverse Events v3.0 (CTCAE) for acute toxicity and in the 
LENT/SOMA classification for late toxicities (appendix 1). Toxicities will be tracked using the 
Toxicity Tracking Form (appendix 2). 
 
 

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9.2 
Expedited Adverse Event Reporting 
 
Expedited AE reporting will utilize the descriptions and grading scales as described in Common 
Terminology Criteria for Adverse Events v 3.0 (CTCAE). 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  and to the 
NYU Clinical Trials Office for reporting to the NYUCI Data Safety Monitoring Committee. 
 
9.3 
Routine Adverse Event Reporting Guidelines 
 
The IRB Reportable Events Forms (available electronically at 
http://irb.med.nyu.edu/sites/default/files/irb2/app.reportable.event_.2012.03.07.docx) will be 
used for all adverse events 
 
10 CORRELATIVE/SPECIAL STUDIES 
 
10.1 Blood Collection for TGF-beta 1 Polymorphism Determination 
 
Approximately 30 mL 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 specimen will be 
aliquoted and stored for future testing of other polymorphisms and other related research 
studies. 
 
10.2 Lymphocyte Isolation, DNA Extraction, PCR Amplification and DNA Sequencing 
 
The lymphocyte isolation and DNA extraction and DHPLC procedures will be performed as 
previously described (Iannuzzi, Atencio et al. 2002) using the WaveTM DNA Fragment Analysis 
System manufactured by Transgenomic. Any samples that appear, based upon the DHPLC 
screening, to be homozygous for either the –509C→T or +869T→C TGF-1 polymorphism, 
will be subjected to DNA sequencing using an automated DNA sequencer. 
 
10.3 Test Method 
 
The products of the PCRs will be subjected to DHPLC analysis with the 96 well plate placed in 
the DHPLC apparatus. The WaveTM DNA Fragment Analysis System (Transgenomic), which 
will be used for this project, represents a complete unit for the automated DHPLC analysis of 
PCR products using a DNASep cartridge specifically designed for separation of DNA 
fragments. DHPLC is a high throughput technique in which large numbers of DNA samples can 
be rapidly screened for base sequence alterations and relies upon the physical changes in DNA 
molecules induced by mismatched heteroduplex formation during reannealing of wild type and 
mutant DNA.  
 
In this method, a portion of a gene is amplified using standard PCR conditions and the products 
analyzed using DHPLC. Material from a homozygous sample will only form one species, the 
wild-type homoduplex. However, when the PCR products produced from a sample 

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heterozygous for a base sequence alteration are heated to 95C, and then slowly cooled, the 
DNA strands separate and randomly reanneal to form a mixture of four species; a mutant 
homoduplex, two heteroduplexes and a wild type homoduplex. When mutant and wild-type 
DNA strands reanneal to form a heteroduplex, the molecule is physically altered. At the region 
of base pair mismatches, a "bubble" forms yielding a short linear region of single-stranded 
DNA. This structural alteration provides the basis for separation of heteroduplex from 
homoduplex species and ultimately identifies samples with mutant alleles. The basis of this 
technique is that by heating the column during separation, it is possible to partially denature the 
sample and elute the homoduplexes and heteroduplexes separately. Heteroduplexes, having a 
greater percentage of single-stranded DNA than homoduplexes in the mismatch region at a 
given temperature, will elute first from the column. Therefore, if the DNA sample does not 
possess a base sequence alteration, only homoduplexes will form and there will be only one 
peak on the chromatogram representing the homogenous nature of the fragment. A sample that 
contains a heterozygous mutation will appear as 2, 3 or 4 peaks representing the two 
homoduplex and heteroduplex populations.  
 
It is also important to note that samples homozygous for a polymorphic allele can readily be 
detected using DHPLC by adding a roughly equal amount of DNA to the PCR from a sample 
known to be homozygous for the normal allele, thus essentially creating a potentially 
“heterozygous” sample. 
 
The first step in the process to detect the –509C→T and +869T→C TGF-1 gene 
polymorphisms will be to design primers for amplification of these regions following which the 
DHPLC buffer and temperature conditions will be optimized for detection of these 
polymorphisms. For each sample, the PCRs will be performed first without the addition of DNA 
from a sample that is known to be homozygous for the normal allele, and then, depending upon 
the DHPLC results, with the addition of known wild type DNA. 
 
For samples in which DNA homozygous for the normal allele was not added, one peak in the 
DHPLC will indicate it is homozygous for either the wild type or polymorphic allele, whereas 
multiple peaks will signify it is heterozygous. Next, the PCRs will be performed a second time 
for all of the putative homozygotes to determine for which allele they are homozygous. Thus, 
DNA homozygous for the normal allele will be added to the PCR. If there is still one peak in the 
DHPLC, this will indicate that it is homozygous for the normal allele, whereas if there are 
multiple peaks, this will signify that the subject is homozygous for the polymorphic allele. All 
samples which appear to be homozygous for the polymorphic allele will be subjected to DNA 
sequencing to confirm this assignment.  
 
An important step in this process will be a determination of the appropriate amount of 
homozygous normal allele DNA to be added to the PCR. Therefore, a titration will be 
performed with different concentrations of DNA to determine the amount for clearest detection 
of a sample homozygous for the polymorphic allele. 
 

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10.4 Denaturing High Performance Liquid Chromatography (DHPLC) 
 
The mutation screening technique to be used in this study will be denaturing high performance 
liquid chromatography or DHPLC (Huber, Oefner et al. 1993; Huber, Oefner et al. 1993; 
Kuklin, Munson et al. 1997; Oefner and Underhill 1998). DHPLC is a robust technique that can 
be used to screen any gene in a large population for single nucleotide substitutions, as well as 
small deletions and insertions. Subjects that are either homozygous or heterozygous for a 
particular allele can both be identified using DHPLC. The advantage of DHPLC is that it 
enables the rapid, sensitive, accurate and inexpensive identification of polymorphisms and 
mutations in an automated fashion. Of greatest importance for this project is the evidence that 
DHPLC possesses a sensitivity and specificity for mutation detection approaching 100% (Liu, 
Smith et al. 1998; O'Donovan, Oefner et al. 1998; Arnold, Gross et al. 1999; Choy, Dabora et al. 
1999; Gross, Arnold et al. 1999; Jones, Austin et al. 1999; Wagner, Stoppa-Lyonnet et al. 1999; 
Nickerson, Weirich et al. 2000; Taniguchi, Krishnadath et al. 2000) and that this approach 
possesses greater sensitivity than gel-based assays. 
 
The sensitivity and accuracy of DHPLC for detection of genetic alterations was probably best 
demonstrated by a quality control study (Bernstein, Teraoka et al. 2003) performed by the 
WECARE (Women’s Environment, Cancer and Radiation Epidemiology) Study Collaborative 
Group. There are four international laboratory centers (including the laboratory of Dr. 
Rosenstein, a co-investigator in this project) that are in the process of screening more than 2000 
breast cancer patients for mutations and polymorphisms in a variety of genes associated with 
DNA repair and radiation responses. The purpose of this quality control study was to investigate 
the sensitivity and specificity of DHPLC for the detection of ATM mutations and 
polymorphisms. A panel of 19 DNA samples consisting of 4 unaffected controls, 2 
heterozygous carriers, and 13 ataxia telangiectasia patients was supplied in a blinded fashion to 
each of the four laboratories and screened using DHPLC. Prior screening by Single-Strand 
Conformation Polymorphism (SSCP) and Protein Truncation Test (PTT) had detected 19 
mutations among these samples; 18 of these were detected by DHPLC, an efficiency of 95%. In 
addition to these 18 mutations, DHPLC screening identified 6 new mutations not detected in 
prior screening. No mutations were identified in control samples by DHPLC, nor were there 
excess mutations identified in any ataxia telangiectasia patient or carrier sample, suggesting a 
low rate of false positives. 
 
10.5 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. Any residual blood specimen 
after performing the listed laboratory studies will be destroyed. 
 
11 INVESTIGATOR RESOURCES 
 
11.1 Qualifications 
 

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Drs. Perez and  Huppert and will be responsible for the accrual and care of study patients. 
Victor Ty 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. Victor Ty will also provide the research nursing component of the study, including 
performing the QOL assessment of the patients. 
 
Drs. Rosenstein and DeWyngaert provide the necessary expertise in radiobiology and physics to 
conduct the proposed study. Dr. Goldberg will oversee the statistical analyses and collaborate in 
the interpretation and reporting of the study results. Benjamin Levinson will participate in the 
ongoing monitoring of this study and statistical analyses.  
 
11.2 Use of NYU Facilities 
 
Therapy will be administered in the Department of Radiation Oncology at the Clinical Cancer 
Center and at Tisch Hospital. 
 
11.3 Conflict of Interest 
 
There are no conflicts of interest to declare. 
 

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12 STUDY CALENDAR 
 
Study Procedure 
Pre 
Treatment 
Weekly 
Last week 
Post Treatment 
(day 45 - 60) 
Post Treatment 
(once/year) 
History & Physical 
X 
 
 
 
 
Mammogram and/or breast 
MRIa 
X 
 
 
 
Xb 
Lumpectomy 
pathology report 
X 
 
 
 
 
BREAST-focused exam, KPS 
X 
X 
 
X 
X 
Lymphedema assessment 
X 
 
X 
 
X 
Blood for TGF-BETA 
Polymorphisms and other 
related research studies 
X 
 
Xc 
 
Quality of Life Questionnairesd 
X 
 
X 
X 
X 
LENT/SOMA assessmente 
 
 
 
 
X 
Thyroid Testing (TSH, T4) 
X 
 
 
 
X 
a. Standard mammogram or MRI for both breasts. 
b. At each follow-up visit beginning 1 year after completion of radiation treatment a non invasive 
measurement of fibrosis in the treated breast will be performed using clinical breast exam. 
 c. Last day of treatment, after last dose of radiation  
d. QOL will be assessed using the RTOG validated self-assessment questionnaires QLB & QLF (see 
Appendix 3) at baseline, week 3, day 45 - 60 and 2-yr follow-ups. 
e. Patients will be seen after completion of treatment at day 45 - 60 and then yearly for 5 years total 
follow up to assess long term sequelae by LENT/SOMA scale. 
 
 
13 DATA REPORTING / REGULATORY CONSIDERATIONS 
 
13.1 Monitoring Plan 
 
An internal Data and Safety Monitoring Committee (DSMC) of the NYUCI 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 planned interim analyses described in Section 9 according to the 
NYUCI DSMC Charter.  
 

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13.2 Stopping Rules (for the individual patient and for the study as a whole) 
 
If safety concerns arise, the DSMC will identify these concerns and recommend modification or 
termination of the clinical trial. In case of grade 3 acute skin toxicity, the dose per fraction of 
the remaining treatment fractions will be reduced to 2 Gy/fraction until completion. The clinical 
trial will be stopped early if regional nodal recurrence is greater than expected (5% of patients) 
as described in Section 14.  
 
13.3 Data Management 
 
Data will be entered into the Oracle Clinical database and maintained at NYUSOM under the 
direction of staff in the BDM core. 
 
THE ORACLE SYSTEM PROVIDES AUDIT trails that track creation and modification of 
records that includes userID and time stamp. Once entered, the data are 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 are 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 are 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 userID 
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. 
 
13.4 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 

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secure links to the BDM core at NYU School of Medicine. Patient records will be made 
available for inspection to auditing agencies to satisfy regulatory requirements. 
 
14 STATISTICAL CONSIDERATIONS 
 
14.1 Endpoints/Objectives: 
 
The primary objectives of this study are to: 
1. 
To evaluate feasibility of prone IMRT to breast, level I- III (includes Cohort 
A) and supraclavicular nodes (physics and dosimetry parameters).  
2. 
To estimate acute toxicity of prone IMRT to breast, level I- III (includes 
Cohort A) and supraclavicular nodes 
 
Secondary objectives are to:  
1. 
estimate the incidence of re-simulation to improve dosimetry after initial 
prone set-up 
2. 
evaluate changes in QOL of patients assessed at baseline and after treatment 
3. 
estimate incidence of late radiation toxicity (e.g., lymphedema, fibrosis and 
telangiectasia) and to examine genetic determinants of breast fibrosis 
 
Exploratory objectives include: 
Estimation of local recurrence rates; estimation of median disease-free survival; 
estimation of median time to progression, and estimation of median overall survival 
time.  
 
 
 
14.2 Statistical Considerations, Sample Size and Interim Analysis Plans 
 
14.3 Statistical Analysis 
 
Descriptive statistics will be provided for all demographic and disease characteristics of patients 
at baseline using frequency distributions for qualitative variables and summary statistics (e.g., 
median, mean, etc.) and graphical displays (e.g., boxplots) for quantitative variables. 
 
14.3.1 Primary Endpoints 
 
The primary outcome of this study is the proportion of patients with acute toxicity greater than 
grade 2 (Skin toxicities grade 3 and above) occurring within 60 days after first day of treatment. 
This rate will be estimated with an exact 95% confidence interval. Treatment feasibility will be 
evaluated for each patient by the ability to meet all physics dose constraints as outlined in 
section 7.5.6.  The proportion of patients who meet the constraints will be estimated with an 
exact 95% confidence interval. 
 
14.3.2 Secondary Endpoints 

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The proportion of patients who undergo re-simulation to improve dosimetry after initial prone 
set-up will be estimated with an exact 95% confidence interval. Quality of life (QOL) defined 
by RTOG PRO will be assessed at baseline, week 3 and at the two follow up time points. 
Descriptive summary statistics, including median and interquartile range (IQR) will be 
calculated for each item, subscale, and total score, and will be presented at each time point. 
Methods for the analysis of longitudinal data will be used to provide an overall evaluation of 
changes in QOL over time. The proportion of patients with late toxicity (including fibrosis and 
telangiectasia) (greater than grades 2) occurring beyond 60 days post treatment will be 
estimated with an exact 95% confidence interval. The cumulative incidence of fibrosis will be 
estimated with 95% confidence interval. The genetic determinants of breast fibrosis will be 
evaluated by associating the –509C→T or +869T→C TGF-1 polymorphism results of the 
genetic screening with the cumulative incidence of fibrosis. 
 
14.3.3 Exploratory Endpoints 
 
Additional endpoints under study include: local recurrence-free survival, disease-free survival, 
time to progression, and overall survival. Kaplan Meier time to event curves will be calculated 
along with estimates of medians and 95% confidence intervals for all these endpoints. 
 
14.4 Accrual estimates 
 
Estimated number of eligible patients for this trial is 4 - 6 patients per month. Since the recent 
publication of Giuliano AE (JAMA, 2011 Feb 9; 305(6):606-70), fewer axillary node dissection 
are being performed nationwide. Consequently, it is expected that the accrual to study NYU 09-
0623 may slow down, because of fewer eligible patients. We expect to accrue 104 patients over 
5 years. 
 
14.5 Sample Size Considerations/Interim Analysis 
 
The primary endpoint for the estimation of sample size is the proportion of patients with acute 
skin toxicity of greater than grade 2 occurring within 60 days after first day of treatment. 
Overall, the regimen will be considered to be unacceptable if more than 5% of patients have 
acute skin toxicity of greater than grade 2. With 104 patients enrolled in this study, we will have 
80% power at a two-sided overall alpha level of 0.05 to test the null hypothesis that the 
proportion of patients with acute skin toxicity of greater than grade 2 is 0.05. With one interim 
analysis when 52 patients are evaluable for acute skin toxicity, Table 9 below provides the 
stopping boundaries for the alternative hypothesis that this proportion is greater than 0.10. 
 

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Table 9 - Stopping Boundaries for the Proportion of Patients with Acute Skin Toxicity > 
Grade 2 based on Pocock Boundaries, Overall 2-sided α = 0.05, Power =80%. H0=0.05; 
H1=0.10 [calculations from EAST 5.2, Cytel, 2008]. 
Analysis 
Number of 
Patients 
Reject H0=0.05 
 
Proportion 
observed 
Reject H0=0.05 
 
z-statistic  
Reject H0=0.05 
 
p-value 
Interim  
52 
≥ 0.1153 
≥ 2.57 
≤ 0.031 
Final  
104 
≥ 0.097 
≥ 2.201 
≤ 0.028 
 
Additional monitoring will be carried out to estimate the proportion of patients with > grade 2 
lymphedema. To test the null hypothesis that this proportion is 0.10 against the alternative that 
the proportion is 0.19, with 2-sided overall alpha level of 0.05 and power of 78%, at the time of 
the first interim analysis for skin toxicity, we can reject the null hypothesis if the observed 
proportion is ≥0.19; at the final analysis, we can reject the null hypothesis if the observed 
proportion is ≥0.165 based on Pocock boundaries.  There is no adjustment for these two parallel 
analyses. 
 
With 104 patients, we can estimate the exact 95% confidence interval for the proportion of 
patients for whom this procedure is feasible with a lower limit of 0.89 or greater if the observed 
proportion of patients is 0.95 or greater [calculations from PASS, NCSS, LLC (2008), J. Hintze, 
Kaysville, UT]. 
Safety Stopping Rule; In addition, regional nodal recurrence will be monitored as the study 
progresses.  If we enroll 104 patients over a three year period with follow-up of one year after 
the last patient is entered, the regimen will be considered ineffective if the null hypothesis that 
the proportion of regional nodal recurrences is 5% is rejected at an interim review. 
Regional nodal recurrence is defined as recurrence within the axilla, level III or supraclavicular 
nodes, documented by PET-CT imaging and/or biopsy. 
With 5 interim looks (every 21 patients who are followed for at least 1 year), with Pocock 
stopping boundaries, the trial would be stopped if the observed numbers of regional nodal 
recurrences are greater than or equal to 1 of the first 21 patients, and greater than 2, 4, 6, and 8 
respectively at the second – fifth looks with an overall 1-sided alpha level of 0.05 and power of 
0.62 [Calculations from EAST 5.2, Cytel, Inc., 2008]. 

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REFERENCES 
 
Archambeau, J. O., R. Pezner, et al. (1995). "Pathophysiology of irradiated skin and breast." Int 
J Radiat Oncol Biol Phys 31(5): 1171-85. 
Arnold, N., E. Gross, et al. (1999). "A highly sensitive, fast, and economical technique for 
mutation analysis in hereditary breast and ovarian cancers." Hum Mutat 14(4): 333-9. 
Atencio, D. P., C. M. Iannuzzi, et al. (2001). "Screening breast cancer patients for ATM 
mutations and polymorphisms by using denaturing high-performance liquid 
chromatography." Environ Mol Mutagen 38(2-3): 200-8. 
Baillet, F., M. Housset, et al. (1990). "The use of a specific hypofractionated radiation therapy 
regimen versus classical fractionation in the treatment of breast cancer: a randomized 
study of 230 patients." Int J Radiat Oncol Biol Phys 19(5): 1131-3. 
Bar Ad, V., A. Cheville, et al. (2009). "Time Course of Mild Arm Lymphedema After Breast 
Conservation Treatment for Early-Stage Breast Cancer." Int J Radiat Oncol Biol Phys. 
Barendsen, G. W. (1982). "Dose fractionation, dose rate and iso-effect relationships for normal 
tissue responses." Int J Radiat Oncol Biol Phys 8(11): 1981-97. 
Bartelink, H., J. C. Horiot, et al. (2001). "Recurrence rates after treatment of breast cancer with 
standard radiotherapy with or without additional radiation." N Engl J Med 345(19): 
1378-87. 
Bartelink, H., J. C. Horiot, et al. (2007). "Impact of a higher radiation dose on local control and 
survival in breast-conserving therapy of early breast cancer: 10-year results of the 
randomized boost versus no boost EORTC 22881-10882 trial." J Clin Oncol 25(22): 
3259-65. 
Bernstein, J. L., S. Teraoka, et al. (2003). "Designing and implementing quality control for 
multi-center screening of mutations in the ATM gene among women with breast 
cancer." Hum Mutat 21(5): 542-50. 
Chang, D. T., S. J. Feigenberg, et al. (2007). "Long-term outcomes in breast cancer patients 
with ten or more positive axillary nodes treated with combined-modality therapy: the 
importance of radiation field selection." Int J Radiat Oncol Biol Phys 67(4): 1043-51. 
Choy, Y. S., S. L. Dabora, et al. (1999). "Superiority of denaturing high performance liquid 
chromatography over single-stranded conformation and conformation-sensitive gel 
electrophoresis for mutation detection in TSC2." Ann Hum Genet 63 ( Pt 5): 383-91. 
Darby, S. C., P. McGale, et al. (2005). "Long-term mortality from heart disease and lung cancer 
after radiotherapy for early breast cancer: prospective cohort study of about 300,000 
women in US SEER cancer registries." Lancet Oncol 6(8): 557-65. 
Deutsch, M., S. Land, et al. (2008). "The incidence of arm edema in women with breast cancer 
randomized on the National Surgical Adjuvant Breast and Bowel Project study B-04 to 
radical mastectomy versus total mastectomy and radiotherapy versus total mastectomy 
alone." Int J Radiat Oncol Biol Phys 70(4): 1020-4. 
Donegan, W. L., S. B. Stine, et al. (1993). "Implications of extracapsular nodal metastases for 
treatment and prognosis of breast cancer." Cancer 72(3): 778-82. 
Douglas, B. G. and J. F. Fowler (1976). "The effect of multiple small doses of x rays on skin 
reactions in the mouse and a basic interpretation." Radiat Res 66(2): 401-26. 

NYU 09-0623 
Version 03/23/2017 
 
Protocol Type / Version # / Version Date Version 5.4 06/30/2017 
40 of 59 
 
Fisher, B., S. Anderson, et al. (2002). "Twenty-year follow-up of a randomized trial comparing 
total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of 
invasive breast cancer." N Engl J Med 347(16): 1233-41. 
Formenti, S. C. (2005). "External-beam partial-breast irradiation." Semin Radiat Oncol 15(2): 
92-9. 
Formenti, S. C., D. Gidea-Addeo, et al. (2007). "Phase I-II trial of prone accelerated intensity 
modulated radiation therapy to the breast to optimally spare normal tissue." J Clin Oncol 
25(16): 2236-42. 
Fowler, J. (1989). "The linear-quadratic formula and progress in fractionated radiotherapy." Br J 
Radiol 62: 679-694. 
Garg, A. K., E. A. Strom, et al. (2004). "T3 disease at presentation or pathologic involvement of 
four or more lymph nodes predict for locoregional recurrence in stage II breast cancer 
treated with neoadjuvant chemotherapy and mastectomy without radiotherapy." Int J 
Radiat Oncol Biol Phys 59(1): 138-45. 
Gross, E., N. Arnold, et al. (1999). "A comparison of BRCA1 mutation analysis by direct 
sequencing, SSCP and DHPLC." Hum Genet 105(1-2): 72-8. 
Harris, E. E., W. T. Hwang, et al. (2003). "Prognosis after regional lymph node recurrence in 
patients with stage I-II breast carcinoma treated with breast conservation therapy." 
Cancer 98(10): 2144-51. 
Haustermans, K., J. Fowler, et al. (1998). "Relationship between potential doubling time (Tpot), 
labeling index and duration of DNA synthesis in 60 esophageal and 35 breast tumors: Is 
it worthwhile to measure Tpot?" Radiother Oncol 46(2): 157-67. 
Hayes, S. B., G. M. Freedman, et al. (2008). "Does axillary boost increase lymphedema 
compared with supraclavicular radiation alone after breast conservation?" Int J Radiat 
Oncol Biol Phys 72(5): 1449-55. 
Hoeller, U., S. Tribius, et al. (2003). "Increasing the rate of late toxicity by changing the score? 
A comparison of RTOG/EORTC and LENT/SOMA scores." Int J Radiat Oncol Biol 
Phys 55(4): 1013-8. 
Huang, E. H., S. L. Tucker, et al. (2005). "Predictors of locoregional recurrence in patients with 
locally advanced breast cancer treated with neoadjuvant chemotherapy, mastectomy, and 
radiotherapy." Int J Radiat Oncol Biol Phys 62(2): 351-7. 
Huber, C. G., P. J. Oefner, et al. (1993). "High-resolution liquid chromatography of 
oligonucleotides on nonporous alkylated styrene-divinylbenzene copolymers." Anal 
Biochem 212(2): 351-8. 
Huber, C. G., P. J. Oefner, et al. (1993). "High-resolution liquid chromatography of DNA 
fragments on non-porous poly(styrene-divinylbenzene) particles." Nucleic Acids Res 
21(5): 1061-6. 
Iannuzzi, C. M., D. P. Atencio, et al. (2002). "ATM mutations in female breast cancer patients 
predict for an increase in radiation-induced late effects." Int J Radiat Oncol Biol Phys 
52(3): 606-13. 
James Melissa, L., M. Lehman, et al. (2008) "Fraction size in radiation treatment for breast 
conservation in early breast cancer." Cochrane Database of Systematic Reviews DOI: 
10.1002/14651858.CD003860.pub2. 
Jones, A. C., J. Austin, et al. (1999). "Optimal temperature selection for mutation detection by 

NYU 09-0623 
Version 03/23/2017 
 
Protocol Type / Version # / Version Date Version 5.4 06/30/2017 
41 of 59 
 
denaturing HPLC and comparison to single-stranded conformation polymorphism and 
heteroduplex analysis." Clin Chem 45(8 Pt 1): 1133-40. 
Keramopoulos, A., C. Tsionou, et al. (1993). "Arm morbidity following treatment of breast 
cancer with total axillary dissection: a multivariated approach." Oncology 50(6): 445-9. 
Kuklin, A., K. Munson, et al. (1997). "Detection of single-nucleotide polymorphisms with the 
WAVE DNA fragment analysis system." Genet Test 1(3): 201-6. 
Kurtz, J. M. (2005). "The clinical radiobiology of breast cancer radiotherapy." Radiother Oncol 
75(1): 6-8. 
Lea, D. (1942). "The mechanism of the induction by radiation of chromosome aberrations." J 
Genet 44(13): 216-245. 
Liengsawangwong, R., T. K. Yu, et al. (2007). "Treatment optimization using computed 
tomography-delineated targets should be used for supraclavicular irradiation for breast 
cancer." Int J Radiat Oncol Biol Phys 69(3): 711-5. 
Liu, W., D. I. Smith, et al. (1998). "Denaturing high performance liquid chromatography 
(DHPLC) used in the detection of germline and somatic mutations." Nucleic Acids Res 
26(6): 1396-400. 
Lukens, J. N., N. Vapiwala, et al. (2009). "Regional nodal recurrence after breast conservation 
treatment with radiotherapy for women with early-stage breast carcinoma." Int J Radiat 
Oncol Biol Phys 73(5): 1475-81. 
Matthews, J., B. Meeker, et al. (1989). "Response of human tumor cell lines in vitro to 
fractionated irradiation." Int J Radiat Oncol Biol Phys 16: 133-138. 
Moran, M. S. and B. G. Haffty (2002). "Local-regional breast cancer recurrence: prognostic 
groups based on patterns of failure." Breast J 8(2): 81-7. 
Nickerson, M. L., G. Weirich, et al. (2000). "Signature-based analysis of MET proto-oncogene 
mutations using DHPLC." Hum Mutat 16(1): 68-76. 
O'Donovan, M. C., P. J. Oefner, et al. (1998). "Blind analysis of denaturing high-performance 
liquid chromatography as a tool for mutation detection." Genomics 52(1): 44-9. 
Oefner, P. J. and P. A. Underhill (1998). DNA mutation detection using denaturing high 
performance liquid chromatography (DHPLC). Current protocols in Human Genetics. 
7.10.1-7.10.12. 
Powell, S., J. Cooke, et al. (1990). "Radiation-induced brachial plexus injury: follow-up of two 
different fractionation schedules." Radiother Oncol 18(3): 213-20. 
Quarmby, S., H. Fakhoury, et al. (2003). "Association of transforming growth factor beta-1 
single nucleotide polymorphisms with radiation-induced damage to normal tissues in 
breast cancer patients." Int J Radiat Biol 79(2): 137-43. 
Reinertsen, K. V., M. Cvancarova, et al. (2009). "Thyroid Function in Women after Multimodal 
Treatment for Breast Cancer Stage II/III: Comparison with Controls from a Population 
Sample." Int J Radiat Oncol Biol Phys. 
Shelbourne, C. D. (1992). Measuring functioning and well-being: the medical outcomes study 
approach. Durham, Duke University Press. 
Stanton, A. L., L. Krishnan, et al. (2001). "Form or function? Part 1. Subjective cosmetic and 
functional correlates of quality of life in women treated with breast-conserving surgical 
procedures and radiotherapy." Cancer 91(12): 2273-81. 
Stanton, P. D., T. G. Cooke, et al. (1996). "Cell kinetics in vivo of human breast cancer." Br J 

NYU 09-0623 
Version 03/23/2017 
 
Protocol Type / Version # / Version Date Version 5.4 06/30/2017 
42 of 59 
 
Surg 83(1): 98-102. 
Steel, G., J. Deacon, et al. (1987). "The dose-rate effect in human tumour cells." Radiother 
Oncol 9: 299-310. 
Taghian, A., J. H. Jeong, et al. (2004). "Patterns of locoregional failure in patients with operable 
breast cancer treated by mastectomy and adjuvant chemotherapy with or without 
tamoxifen and without radiotherapy: results from five National Surgical Adjuvant Breast 
and Bowel Project randomized clinical trials." J Clin Oncol 22(21): 4247-54. 
Taniguchi, K., K. Krishnadath, et al. (2000). High sensitivity of denaturing high performance 
liquid chromatography (DHPLC) in detection of p53 mutations in adenocarcinoma of 
the esophagus. Proceedings of the 91st Annual Meeting of the American Association for 
Cancer Research. 
Thames, H., S. Bentzen, et al. (1990). "Time-dose factors in radiotherapy: A review of the 
human data." Radiother Oncol 19(219-235). 
Thames, H. and J. Hendry (1987). Fractionation in Radiotherapy. London 
New York, Taylor and Francis. 
Tian, L., Z. Jun, et al. (2008). Measurements of Radiation-Induced Skin Changes in Breast-
Cancer Radiation Therapy Using Ultrasonic Imaging. BioMedical Engineering and 
Informatics, 2008. BMEI 2008. International Conference on. 
Travis, E. and S. Tucker (1987). "Isoeffect models and fractionated radiation therapy." Int J 
Radiat Oncol Biol Phys 13: 283-287. 
Turesson, I. and H. Thames (1989). "Repair capacity and kinetics of human skin during 
fractionated radiotherapy: Erythema. Desquamation, and telangiectasia after 3 and 5 
years follow-up." Int J Radiat Oncol Biol Phys 15: 169-188. 
Wagner, T., D. Stoppa-Lyonnet, et al. (1999). "Denaturing high-performance liquid 
chromatography detects reliably BRCA1 and BRCA2 mutations." Genomics 62(3): 369-
76. 
Ware, J. E., Jr. and C. D. Sherbourne (1992). "The MOS 36-item short-form health survey (SF-
36). I. Conceptual framework and item selection." Med Care 30(6): 473-83. 
Whelan, T., R. MacKenzie, et al. (2002). "Randomized trial of breast irradiation schedules after 
lumpectomy for women with lymph node-negative breast cancer." J Natl Cancer Inst 
94(15): 1143-50. 
Williams, M., J. Denekamp, et al. (1985). "A review of  / ratios for experimental tumors: 
Implications for clinical studies of altered fractionation." Int J Radiat Oncol Biol Phys 
11: 87-96. 
Yamada, Y., I. Ackerman, et al. (1999). "Does the dose fractionation schedule influence local 
control of adjuvant radiotherapy for early stage breast cancer?" Int J Radiat Oncol Biol 
Phys 44: 99-104. 
 
 

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APPENDICIES 
 
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 – TOXICITY TRACKING FORM 
 

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APPENDIX 3 – QUALITY OF LIFE QUESTIONNAIRES 

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